Metformin reduces proteinuria in spontaneously hypertensive rats by activating the HIF-2α-VEGF-A pathway.
Metformin has protective effects on diabetic nephropathy. However, the mechanism underlying the renoprotective action of metformin in spontaneously hypertensive rats (SHR) is not completely understood. We determined the role of metformin in proteinuria and investigated the mechanism. We measured the urinary protein concentration (mg/day) in 48-week-old SHR. Matched control animals were of the same genetic strain, Wistar-Kyoto (WKY). The rats received metformin (100 mg/kg/day) or vehicle for 10 months. Metformin improved renal function and reduced the proteinuria (urine protein: 48.4 ± 3.7 vs. 25.4 ± 1.8 mg, P < 0.01) induced by long-term high blood pressure. Metformin increased the production of vascular endothelial growth factor (VEGF)-A in rat kidneys and cultured rat podocytes. Metformin activated hypoxia-inducible factor-2α (Hif-2α) in response to VEGF but did not affect Hif-1α in rat kidneys and cultured rat podocytes. Metformin reduced the proteinuria induced by long-term high blood pressure in vivo and increased the VEGF-A production in rat kidneys and cultured rat podocytes, probably by activating the Hif-2α-VEGF signaling pathway. These findings provide a new mechanism for the renoprotective effects of metformin.


Opioid receptors signaling network.
Opioid receptors belong to the class A G-protein-coupled receptors and are activated by alkaloid opiates such as morphine, and endogenous ligands such as endorphins and enkephalins. Opioid receptors are widely distributed in the human body and are involved in numerous physiological processes through three major classical opioid receptor subtypes; the mu, delta and kappa along with a lesser characterized subtype, opioid receptor-like (ORL1). Opioids are the most potent analgesics and have been extensively used as a therapeutic drug for the treatment of pain and related disorders. Chronic administration of clinically used opioids is associated with adverse effects such as drug tolerance, addiction and constipation. Several investigations attempted to identify the molecular signaling networks associated with endogenous as well as synthetic opiates, however, there is a paucity of a cumulative depiction of these signaling events. Here, we report a systemic collection of downstream molecules pertaining to four subtypes of opioid receptors (MOR, KOR, DOR and ORL1) in the form of a signaling pathway map. We manually curated reactions induced by the activation of opioid receptors from the literature into five categories- molecular association, activation/inhibition, catalysis, transport, and gene regulation. This led to a dataset of 180 molecules, which is collectively represented in the opioid receptor signaling network following NetPath criteria. We believe that the public availability of an opioid receptor signaling pathway map can accelerate biomedical research in this area because of its high therapeutic significance. The opioid receptors signaling pathway map is uploaded to a freely available web resource, WikiPathways enabling ease of access ( https://www.wikipathways.org/index.php/Pathway:WP5093 ).


[Products for hand hygiene and antisepsis: use by health professionals and relationship with hand eczema].
Hand hygiene is the most important measure for the prevention of nosocomial infection. We describe the different products available for hygiene and antisepsis of the hands and the use of these products in daily practice. Hand hygiene products such as soaps and detergents are a cause of irritant dermatitis in health professionals. This irritation is one of the principal factors affecting their use in clinical practice. Alcohol-based products are better tolerated and less irritant than soap and water; irritation should not therefore be a limiting factor in the use of these products and they are to be recommended in place of soap and water. Informative and continued education programs could increase their use.


Gallbladder contraction and its relationship to interdigestive duodenal motor activity in normal human subjects.
Gallbladder volume and interdigestive gastric and duodenal motor activity were evaluated simultaneously in 12 normal subjects. After overnight fasting, gallbladder volume was monitored every 4 min in each subject by means of real-time ultrasonography, and gastroduodenal motor activity was measured by means of a probe consisting of three polyvinyl catheters with one side opening for each catheter, placed 15 cm apart and constantly perfused with deionized water. Real-time ultrasonography and intestinal manometry were performed by different investigators and continued until at least two consecutive spontaneous phase III activities of migrating motor complexes were observed. The results show a cyclic variation of gallbladder volume, which reached its minimum value before the end of phase II in the proximal duodenum and its maximum in early phase II, 25 min after the beginning of phase III. These results suggest that there is a relationship between the cyclic gallbladder volume changes, which occur during fasting in humans, and with the various phases of duodenal migrating motor complex.


Nontransmission of porcine circovirus 2 (PCV2) by embryo transfer.
Two experiments were conducted to determine the association of porcine circovirus type 2 (PCV2) with embryos and the risk of viral transmission by embryo transfer. In the first experiment, 240 embryos from uninfected donors were exposed to PCV2a 10(4)TCID50/mL in vitro before transfer to seronegative recipients; in the second experiment, 384 embryos recovered from infected donors, 10 days after donor inoculation with PCV2, were transferred to seronegative recipients. In total, 1120 embryos and/or ova were collected from 37 viral-free donors (experiment 1) and 1019 from 59 PCV2-infected donors (experiment 2) (P < 0.01). The washing and/or disinfection procedure recommended by the International Embryo Transfer Society was applied to embryos in both experiments. Transfer of embryos experimentally exposed in vitro to high titers of virus caused seroconversion of recipients (58%; N = 7/12) and their piglets (81%; N = 13/16). Postmortem, PCV2 DNA was detected in various organs of embryo transfer recipients and their embryo transfer-derived piglets. In contrast, the transfer of embryos recovered from infectious PCV2 donors did not result in the seroconversion of embryo recipients (N = 24) or their embryo transfer-derived piglets (N = 76). Neither PCV2 DNA nor infectious virus was detected in the tissues of either recipients or embryo transfer-derived piglets collected postmortem in the second experiment. The results obtained in this study indicate that the transmission of PCV2 from infected donors by embryo transfer is unlikely if the sanitary recommendations of the International Embryo Transfer Society are followed. In practical terms, this means that embryo transfer can be successfully used for the intentional elimination of PCV2 and to create virus-free offspring for the safe exchange of swine genetic materials.


The locus and nature of semantic congruity in symbolic comparison: evidence from the Stroop effect.
Pictures of animals with names of animals printed within the pictures were presented for comparative judgments of size based on either the pictures or the names. The picture-word compounds were compared faster with picture than with word as the relevant dimension. The comparisons of pictures were free of interference from the irrelevant names, but the comparisons of names suffered considerable Stroop interference from the irrelevant pictures. Large effects of semantic congruity characterized the comparisons of both pictures and words. Stroop congruity and semantic congruity did not interact even for comparison of words in which both were present, leading instead to additive effects. The results support theories that (1) place semantic congruity in the decision stage and (2) minimize the role of semantic processing as the basis of the semantic congruity effect.


Carotid endothelial shear stress reduction with aging is associated with plaque development in twelve years.
Atherosclerosis is associated with clinical, biochemical and haemodynamic risk factors. In a group of subjects studied twelve years apart, we evaluated carotid plaque development in relation to baseline and to changes at follow-up in common carotid haemodynamic profile. Forty-eight participants were recruited to a cardiovascular disease prevention programme. Atherosclerotic plaques were evaluated and scored by echography. Endothelial shear stress, circumferential wall tension, and Peterson's elastic modulus as an index of arterial stiffness, were computed by echo-Doppler, along with blood viscosity data. Binary logistic regression analyses were used to test the association among the development of atherosclerosis, cardiovascular risk factors and haemodynamic variations. Analyses were also performed on participants who presented at the follow-up with carotid haemodynamic variations in the left or right common carotid only. Participants (69% male) were aged 64.5 ± 9.7 years at follow-up. Peak and mean endothelial shear stress was significantly lower at follow-up as previously reported; circumferential wall tension and arterial stiffness were significantly higher. Carotid plaque scores increased after 12 years (0.39 ± 0.72 vs. 0.67 ± 0.86, p < 0.01). Of the 96 common carotids analysed, shear stress reduction with aging was an independent predictor of carotid atherosclerosis (B = -0.063; odds ratio = 0.94; p = 0.01). Out of 48 participants, 21 (44%) showed shear stress reduction with aging in only one side of the body and, on this side, the plaque score increased (0.52 ± 0.98 vs. 0.90 ± 0.94, p < 0.05), remaining unchanged in the contralateral carotid tree. Aging-related shear stress reduction is an independent predictor of atherosclerosis development.


The use of EPR spectroscopy to study transcription mechanisms.
Electron paramagnetic resonance (EPR) spectroscopy has become a promising structural biology tool to resolve complex and dynamic biological mechanisms in-vitro and in-cell. Here, we focus on the advantages of continuous wave (CW) and pulsed EPR distance measurements to resolve transcription processes and protein-DNA interaction. The wide range of spin-labeling approaches that can be used to follow structural changes in both protein and DNA render EPR a powerful method to study protein-DNA interactions and structure-function relationships in other macromolecular complexes. EPR-derived data goes well beyond static structural information and thus serves as the method of choice if dynamic insight is needed. Herein, we describe the conceptual details of the theory and the methodology and illustrate the use of EPR to study the protein-DNA interaction of the copper-sensitive transcription factor, CueR.


Prognostic models for estimating severity of disease and predicting 30-day mortality of Hypervirulent Klebsiella pneumoniae infections: a bicentric retrospective study.
Hypervirulent Klebsiella pneumoniae (hvKP) is emerging globally and can cause various, severe infections in healthy individuals. However, the clinical manifestations of hvKP infections are nonspecific, and there is no gold standard for differentiating hvKP strains. Our objective was to develop prognostic models for estimating severity of disease and predicting 30-day all-cause mortality in patients with hvKP infections. We enrolled 116 patients diagnosed with hvKP infections and obtained their demographic and clinical data. Taking septic shock and acute respiratory distress syndrome (ARDS) as the primary outcomes for disease severity and 30-day all-cause mortality as the primary outcome for clinical prognosis, we explored the influencing factors and constructed prognostic models. The results showed that increased Acute Physiologic and Chronic Health Evaluation (APACHE) II score [odds ratio (OR) = 1.146; 95% confidence interval (CI), 1.059-1.240], decreased albumin (ALB) level (OR = 0.867; 95% CI, 0.758-0.990), diabetes (OR = 9.591; 95% CI, 1.766-52.075) and high procalcitonin (PCT) level (OR = 1.051; 95%CI, 1.005-1.099) were independent risk factors for septic shock. And increased APACHE II score (OR = 1.254; 95% CI, 1.110-1.147), community-acquired pneumonia (CAP) (OR = 11.880; 95% CI, 2.524-55.923), and extrahepatic lesion involved (OR = 14.718; 95% CI, 1.005-215.502) were independent risk factors for ARDS. Prognostic models were constructed for disease severity with these independent risk factors, and the models were significantly correlated with continuous renal replacement therapy (CRRT) duration, vasopressor duration, mechanical ventilator duration and length of ICU stay. The 30-day all-cause mortality rate in our study was 28.4%. Younger age [hazard ratio (HR) = 0.947; 95% CI, 0.923-0.973)], increased APACHE II score (HR = 1.157; 95% CI, 1.110-1.207), and decreased ALB level (HR = 0.924; 95% CI, 0.869-0.983) were the independent risk factors for 30-day all-cause mortality. A prediction model for 30-day mortality was constructed, which had a good validation effect. We developed validated models containing routine clinical parameters for estimating disease severity and predicting 30-day mortality in patients with hvKP infections and confirmed their calibration. The models may assist clinicians in assessing disease severity and estimating the 30-day mortality early.


Primary human hepatocytes are protected against prolonged and repeated exposure to ethanol by silibinin-dihemisuccinate.
We investigated the effect of silibinin-C-2',3'-dihydrogensuccinate (SDH) on primary human hepatocytes when exposed to ethanol for 14 days. At regular intervals, the medium was refreshed and liver enzymes and secreted protein in the medium were determined. The ethanol-induced release of lactate dehydrogenase (at 34 mM ethanol) was completely blocked by 20 microM SDH. SDH itself stimulated fibrinogen release and had no toxic effect. We can conclude that SDH has a beneficial effect on human hepatocytes when exposed to ethanol in vitro.


Atrial function analysis after percutaneous umbrella device and suture-mediated patent fossa ovalis closure.
Atrial fibrillation is an undesirable event following percutaneous patent fossa ovalis (PFO) closure with metallic occluders, suggesting that implanting a rigid closure device could alter atrial function. Suture-mediated PFO closure is a new technique, achieving closure of the PFO by means of a simple suture. Aim of this study was to evaluate left atrial function after closure of PFO by direct suture and traditional occluders. We studied 40 age and sex homogeneous patients, 20 undergoing PFO closure by device (OCL) and 20 by suturing (NS). Twenty healthy sex-age matched subjects made up the control group (CT). Left atrial function was evaluated by using volumetric and speckle-tracking analysis assessing the following parameters: total emptying fraction (EF), Expansion Index (EI), active emptying fraction (AEF), strain values of the reservoir (r-ED), conduit (cd-ED) and contraction phase (ct-ED). Compared to CT and NS, OCL patients had significantly worst indices of left atrial reservoir function (EF P=0.001, EI P=0.003, r-ED P<0.001), conduit function (cd-ED P=0.018) and contraction function (AEF P=0.010; ct-ED P<0.001). No significant differences were observed in left atrial function indices between CT and NS patients. Suture-mediated PFO closure does not alter left atrial function. Conversely, metallic occluder is associated with worse left atrium function. This detrimental effect on atrial function could favor the development of atrial arrhythmias.


Application of Kendall's partial tau to a problem in accident analysis.
Kendall's partial rank correlation coefficient is suggested as a method of nonparametric analysis of covariance when the independent variable of interest is dichotomous.


The clinical value of lymphangiography: are the nodes surrounding the obturator nerve visualized?
Twenty-five patients subjected to pelvic node dissection for urologic malignancies underwent bilateral pedal lymphangiography preoperatively. Postoperatively, 50 samples of the nodes selectively removed from the regions surrounding the obturator nerve were radiographed. All 50 samples revealed the presence of radiopaque dye. The lymph nodes surrounding the obturator nerve represent the first point of lymphatic metastases in carcinoma of the prostate and the bladder. Their visualization by lymphangiography emphasizes the importance of such a diagnostic study for the correct clinical staging of these diseases. The lymphatic anatomy of the pelvis is reviewed and compared to the radiological findings in lymphangiography.


Neuronal spatiotemporal pattern discrimination: the dynamical evolution of seizures.
We developed a modern numerical approach to the multivariate linear discrimination of Fisher from 1936 based upon singular value decomposition that is sufficiently stable to permit widespread application to spatiotemporal neuronal patterns. We demonstrate this approach on an old problem in neuroscience--whether seizures have distinct dynamical states as they evolve with time. A practical result was the first demonstration that human seizures have distinct initiation and termination dynamics, an important characterization as we seek to better understand how seizures start and stop. Our approach is broadly applicable to a wide variety of neuronal data, from multichannel EEG or MEG, to sequentially acquired optical imaging data or fMRI.


Effectiveness of image-guided radiotherapy for locally advanced esophageal squamous cell carcinoma patients treated with definitive concurrent chemoradiotherapy.
Image-guided radiotherapy (IGRT) is an advanced radiotherapy technique to improve the accuracy of treatment delivery. However, a recent randomized controlled trial (RCT) for prostate cancer patients treated with radiotherapy either via IGRT or routine care (no daily IGRT) reported a statistically significant worse overall survival for those treated with IGRT. This raised the concern regarding the effectiveness of IGRT for definitive concurrent chemoradiotherapy (dCCRT) for locally advanced esophageal squamous cell carcinoma (LA-ESqCC). Eligible LA-ESqCC patients diagnosed between 2011 and 2015 were identified via the Taiwan Cancer Registry. We estimated propensity scores to construct a 1:1 propensity-score-matched groups and balance observable potential confounders. The hazard ratio (HR) of death as well as other outcomes was compared between IGRT and non-IGRT matched groups during the entire follow-up period. The impact of additional covariables was considered in the sensitivity analysis. Our study population included 590 patients in the primary analysis. The HR for death when IGRT was compared with non-IGRT was 0.92 (95% confidence interval 0.77-1.10, P = 0.35). There were also no significant differences for other outcomes or sensitivity analyses. In this updated nonrandomized study using real world data, we found that the overall survival of LA-ESqCC patients treated with dCCRT was not statistically different between those treated with IGRT versus those without IGRT, although the hazard ratio was less than unity, ie, in favor of IGRT. The results should be interpreted with caution given the nonrandomized design and RCTs are needed to clarify our findings. Significant findings of the study: The OS of LA-ESqCC patients treated with dCCRT was not statistically different between those treated with IGRT versus those without IGRT, although the hazard ratio was less than unity, ie, in favor of IGRT. In this updated nonrandomized study using real world data with additional potential confounders, our study provided a reasonable tentative evidence of lack of RCT as suggested in the literature.


When do we know which way is up? The time course of orientation perception.
There is evidence that global visual context affects orientation perception in later stages of processing than local context. We measured the relative time courses of two orientation illusions: The Tilt Illusion (TI) involves dense gratings in close proximity; the Rod and Frame Illusion (RFI) involves a solitary bar surrounded by a distant frame. We also varied whether the context was flashed briefly (Experiment 1) or remained visible (Experiment 2). Results showed that the TI (but not the RFI) occurs when the context is briefly flashed in advance of the test, that both illusions are strongest when the context and inducer appear simultaneously, and that the RFI frame must be visible for at least 800 ms to induce an illusion with asynchronous displays. Experiment 3 confirmed these patterns held for measures of illusion magnitude and discriminability. Results are consistent with an earlier effect of local spatial context and a later effect of global spatial context on orientation perception.


The yin and yang of leukotriene B4 mediated inflammation in cancer.
The high affinity leukotriene B4 receptor, BLT1 mediates chemotaxis of diverse leukocyte subsets to the sites of infection or inflammation. Whereas the pathological functions of LTB4/BLT1 axis in allergy, autoimmunity and cardiovascular disorders are well established; its role in cancer is only beginning to emerge. In this review, we summarize recent findings on LTB4/BLT1 axis enabling distinct outcomes toward tumor progression. In a mouse lung tumor model promoted by silicosis-induced inflammation, genetic deletion of BLT1 attenuated neutrophilic inflammation and tumor promotion. In contrast, in a spontaneous model of intestinal tumorigenesis, absence of BLT1 led to defective mucosal host response, altered microbiota and bacteria dependent colon tumor progression. Furthermore, BLT1 mediated CD8+ T cell recruitment was shown to be essential for initiating anti-tumor immunity in number of xenograft models and is critical for effective PD1 based immunotherapy. BLT2 mediated chemotherapy resistance, tumor promotion and metastasis are also discussed. This new information points to a paradigm shift in our understanding of the LTB4 pathways in cancer.


Anti-mitochondrial antibodies in Indian patients with idiopathic inflammatory myopathies.
Anti-mitochondrial antibodies (AMAs) are associated with distinct clinical phenotypes including cardiac and hepatic manifestations in idiopathic inflammatory myopathies (IIMs). This article studies the prevalence, clinical characteristics and outcomes of AMA in Indian patients with IIM. Patients (97: 81 adult, 16 juvenile) clinically diagnosed with polymyositis or antibody-negative IIM were retrieved from the MyoCite bio-archive. They were tested for myositis-specific autoantibodies / myositis autoantibodies (MSAs/MAAs) using line immunoassay and antinuclear antibodies and AMAs using immunofluorescence assay (IFA). Patients were also screened for cardiac biomarkers (cardiac troponin I [c-TnI] and N terminal-pro brain natriuretic peptide [NT-pro-BNP] using immunometric immunoassay technique and enhanced chemiluminescence assay testing respectively) and hepatic manifestations using AMA testing. Results were formulated after carrying out analytical tests. Of the cohort, 5 adults (6.2%) (M:F 0:1) with a median age and disease duration of 37 years and 2 months respectively, tested AMA+ while the children tested negative. Dermatomyositis was the commonest phenotype, with amyopathic forms being common, often with MSA positivity. Cancer-associated myositis and polymyositis were also seen. AMA positivity is associated with Gottron's sign and calcinosis. Comparable levels of C-TnI and NT-pro-BNP and AMA testing in patients help to rule out subclinical cardiac and hepatic involvement respectively. Anti-mitochondrial antibodies are rare (6.2%) in different subtypes of IIM in the Indian population, and often coexist with MSAs. Their negative association with cardiac and hepatic involvement and probable association with Gottron's sign and calcinosis merit further investigation and long-term follow-up to understand the entire spectrum of the disease.


Modelling the cell-mediated immunity in homograft refection.
Lymphocytes which become sensitised at the periphery travel to the regional lymph nodes where they initiate an immunological response by increasing the production of immuno-competent lymphocytes. These lymphocytes migrate into the tissues via the blood stream and bring about the destruction of target cells. These notions, in the present analysis, are translated into a simple mathematical model. The model specifically considers the lymphocyte memory and increased secondary response.


Nondilated obstructive uropathy.
Four patients presented with severe renal failure secondary to urinary tract obstruction, yet ultrasonography and/or computed tomography revealed only minimal dilatation in 1 patient and no dilatation in the other three. Two patients had prostate cancer, one had bladder cancer, and one had retroperitoneal fibrosis. In all cases, relief of obstruction led to a dramatic improvement in renal function. These cases, and others in the literature, illustrate that in certain settings severe urinary tract obstruction may be present in the absence of dilatation and hence may be missed by noninvasive imaging techniques. Nondilated obstructive uropathy should be suspected in any elderly patient who presents with the acute onset of oliguria in the absence of an identifiable cause, especially if there is a previous history of malignancy in the pelvis. Left undiagnosed, this potentially reversible cause of renal failure can lead to end-stage renal disease.


REIN: a tool to evaluate pratices
On the occasion of the 20th anniversary of the REIN (French Renal Epidemiology and Information Network), a summary work on the contributions of the national French ESKD register was carried out. On the issue of its role in practices evaluation, the following key messages were retained. The evaluation of our practices allows improving them as proposed by the concept of the Edward Deming wheel (Plan, Do, Check, Act). Measurement also allows setting goals and targets. Where there are recommendations available, the REIN indicators allow comparison with the identified targets. The REIN registry is an interesting tool to observe the deployment and impact of the recommendations in dialysis units and to evaluate the professional practices taking into account the patients' characteristics and the changes in the recommendations. Finally, the treatment indicators analysed using REIN data show the great diversity of practices from one region to another, the result of habits, training of nephrologists, the history of the care offered and sometimes the geography of the region and its population.


Discovery of HyT-Based Degraders of CDK9-Cyclin T1 Complex.
Direct modulation of the non-kinase functions of cyclin and CDK-cyclin complexes poses challenges. We utilize hydrophobic tag (HyT) based small-molecule degraders induced degradation of cyclin T1 and its corresponding kinase partner CDK9. LL-CDK9-12 demonstrated the most potent and selective degradation ability, with DC50 values of 0.362 μM against CDK9 and 0.680 μM against cyclin T1. In prostate cancer cells, LL-CDK9-12 showed enhanced anti-proliferative activity than its parental molecule SNS032 and LL-K9-3, the previous reported CDK9-cyclin T1 degrader. Moreover, LL-CDK9-12 suppressed the downstream signaling of CDK9 and AR efficiently. Altogether, LL-CDK9-12 was an effective dual degrader of CDK9-cyclin T1 and helped study the unknown function of CDK9-cyclin T1. These results suggest that HyT-based degraders could be used as a strategy to induce the degradation of protein complexes, providing insights for the design of protein complexes' degraders.


DNA Repair Protein Rad51 Induces Tumor Growth and Metastasis in Esophageal Squamous Cell Carcinoma via a p38/Akt-Dependent Pathway.
Rad51 is a protein which plays a vital role in DNA double-strand break repair and maintenance of telomeres. However, the underlying mechanism for its action in esophageal squamous cell carcinoma (ESCC) remains unclear. Eighty-seven patients with ESCC were enrolled in this study. Expression of Rad51 in ESCC was determined by immunohistochemistry and correlated with clinicopathological variables by Chi square test. The role of Rad51 in patient survival was determined by Kaplan-Meier estimates. The effects of Rad51 knockdown and overexpression on esophageal cancer growth, migration, and invasion were examined using TE8, CE81T, and KYSE70 cells. The mechanisms involved were also analyzed. Nude mice models were used for assessment of tumor growth. Rad51 staining was predominantly observed in ESCC patients. ESCC patients with high Rad51 expression had significantly decreased survival (P < 0.001) combined with increased tumor size (P = 0.034) and lymph node metastasis (P = 0.039). Rad51 overexpression promoted, while its knockdown attenuated, esophageal cancer cell viability through cell cycle entry and migration/invasion via epithelial-mesenchymal transition. Moreover, Rad51 overexpression increased colony formation in vitro and tumor growth in vivo. In addition, high Rad51 expression increased cancer progression through the p38/Akt/Snail signaling pathway. This study indicates a new biological role for Rad51 in ESCC progression. Rad51 may serve as a potential prognostic biomarker and therapeutic target for ESCC patients.


Stem cell-based therapy for ameliorating intrauterine adhesion and endometrium injury.
Intrauterine adhesion refers to endometrial repair disorders which are usually caused by uterine injury and may lead to a series of complications such as abnormal menstrual bleeding, recurrent abortion and secondary infertility. At present, therapeutic approaches to intrauterine adhesion are limited due to the lack of effective methods to promote regeneration following severe endometrial injury. Therefore, to develop new methods to prevent endometrial injury and intrauterine adhesion has become an urgent need. For severely damaged endometrium, the loss of stem cells in the endometrium may affect its regeneration. This article aimed to discuss the characteristics of various stem cells and their applications for uterine tissue regeneration.


[Endometriosis localized in the sigmoid. Apropos of a case].
Colic endometriosis is a classical but rare localization. The authors present one case treated by partial colectomy associated with a total hysterectomy and preservation of ovarian parenchyma. The hysterectomy was necessary because of adenomyosis and inflammatory adhesions undissociable from the sigmoid.


Examining aspects of the built environment: an evaluation of a community walking map project.
Interventions that address the built environment present an opportunity to affect behaviours such as physical activity. The purpose of this study was to evaluate a community walking map developed for eight neighbourhoods in the City of Edmonton (COE). A walking map developed in partnership with the COE's Walkable Initiative was distributed to 11,994 households across eight neighbourhoods in July 2010. In total, 149 respondents completed an online follow-up survey that assessed the effectiveness of the walking maps in influencing physical activity. Of the 149 respondents, 89 (59.7%) reported that they had received a copy of the map, and 60 (40.2%) reported that they had not. Of those who had a copy, 76.4% (n=68) indicated that the routes and destinations on the map encouraged them to walk more in the community, 64.0% (n=57) stated they would walk more often to get to destinations, and 55.1% (n=49) indicated they would walk more often for physical activity or exercise as a result of having a copy of the map. Finally, 91.0% (n=81) stated that they found the map to be useful, as it provided walking routes (60/81, 74.1%,) and places to go in the community (57/81, 70.4%). Of those who did not receive a copy, 95.0% (n=57) indicated that they would use a community walking map. This evaluation demonstrated that a community walking map was a valuable tool for not only encouraging walking for physical activity but also motivating individuals to explore their communities and visit local community destinations.


Effects of excitotoxic lesions of the rat ventral striatum on the perception of reward cost.
This study examined the possibility that lesions of the nucleus accumbens in rats impair the perception of the "cost of reward", as defined by the number of operant responses needed to obtain a food pellet. In a first experiment, visual cues indicated the cost of reward under a multiple-ratio schedule of reinforcement. In a second experiment, the number of lever presses required for each reward incremented with each trial in a progressive-ratio schedule of reinforcement. Lesions of the nucleus accumbens altered the behavioral response to the increasing cost of reward when there was an absence of external cues. There was no change in the ability of the lesioned rats to respond to visual cues that indicated reward availability. The results are considered in terms of the traditional idea of the nucleus accumbens as a limbic-motor interface: it is suggested that, if the nucleus accumbens serves such a function, it is limited to only some contexts.


Effects of Exergames on Quality of Life, Pain, and Disease Effect in Women With Fibromyalgia: A Randomized Controlled Trial.
To evaluate the effects of an exergame-based intervention on a population sample of women with fibromyalgia. Single-blinded, randomized controlled trial with 8-week intervention. Fibromyalgia center. Participants (all women) (N=83) were divided into 2 groups: an exercise group (n=42; mean age ± SD, 52.52±9.73y) and a nonexercise group (n=41; mean age ± SD, 52.47±8.75y). Women in the exercise group completed an 8-week exergame-based training program, which was focused on postural control and coordination of the upper and lower limbs, aerobic conditioning, strength, and mobility. Women (groups of 3) were encouraged to exercise for 120 minutes (over 2 sessions) per week. Main outcome measures included pain and disease effect, which were assessed with the Fibromyalgia Impact Questionnaire (FIQ), a specific measure for fibromyalgia. Secondary outcome measure included quality of life, which was assessed with the EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) generic instrument. The results showed that 97.62% of participants in the exercise group completed the 8-week intervention. The exercise group showed a significant improvement (P<.05) in the EQ-5D-5L utility index, and in 3 of 5 dimensions. For the FIQ, significant improvements were observed in the dimensions of pain, stiffness, anxiety, and feel good. The FIQ score was also reduced. The mean between-group improvement was 8.25 (95% confidence interval, 2.85-13.65). The results and levels of compliance/adherence suggest this exergame-based training program is an effective intervention for reducing pain and increasing health-related quality of life in women with fibromyalgia.


Wilson Disease Presenting With Acute on Chronic Liver Failure: A Single-Center Experience of Outcome and Predictors of Mortality in 68 Patients.
Acute on chronic liver failure (ACLF) is an emerging entity whose unique pathogenesis, presentation, and outcome are different from those with decompensated cirrhosis. Patients with Wilson disease (WD) often present with ACLF. The outcome in this setting and predictors of mortality have not been well delineated. We describe the clinical features, laboratory characteristics, and prognostic factors in patients with WD with ACLF. We compared the outcome in those without criteria for ACLF. We analyzed the admission characteristics of 68 patients with WD presenting with features of ACLF among a cohort of WD patients from 1997 to 2017. WD was diagnosed as per European association for the study of the liver (EASL)/Leipzig criteria and ACLF by the Asia-Pacific Association of Study of Liver and World Gastroenterology Organization consensus criteria. Factors associated with mortality were analyzed by univariate followed by multivariate analysis and receiver operating characteristic curve. Of the 272 patients with WD, 68 fulfilled criteria for ACLF. The mean age was 14.4 years (Range 5-42 years). Males constituted 38/68 (56%). Acute viral or drug induced hepatitis as precipitating factors was seen in 11.7%. Forty-nine patients (49/67; 73%) died including 30/32 (93.8%) with encephalopathy and 45/62 (72.6%) with ascites. Prognostic factors on univariate analysis significant for mortality included encephalopathy, international normalized ratio, white blood cell count and model for end-stage liver disease (MELD) score. On multivariate analysis, only encephalopathy was significant with 82% accuracy in differentiating survivors versus non-survivors. Post mortem liver biopsy in 21 patients and explant biopsy in 2 patients showed features of cirrhosis in all. WD with ACLF is associated with a high mortality Precipitating factors such as viral and drug-induced hepatitis was seen in 11.7% patients. Liver histology in patients subjected to biopsy showed cirrhosis in all. Only encephalopathy is a prognostic marker of non-survival with an accuracy of 82%.


Comparison of two techniques for the quantitative measurement of acid phosphatase in normal and regenerating epithelium of the female hairless hamster.
Two methods have been employed for measuring acid phosphatase activity in normal and regenerating epithelium of the female hairless hamster. The first method entails histochemical preparation followed by television scanning microdensitometric measurements using a Quantimet 72OD. The second method involves incubation of freeze-dried epidermis in a suitable substrate medium followed by measurement of the fluorescence of the released product by a spectrophotofluorometer. The results were compared against each other by performing best-fit polynomial regression line analysis to the data produced by both methods. A correlation coefficient of 0.99 was obtained when interpolated data from the two 'best-fit' curves were compared with each other. This indicates that the histochemical technique and the subsequent measurement using television scanning microdensitometry is 'quantitative' and can, therefore, be employed in quantitative histochemistry.


Homologous activators of ras in fission and budding yeast.
The ras proto-oncogene products are plasma membrane-bound, guanine nucleotide-binding proteins implicated in signal transduction across the plasma membrane. But the signal(s) that activates the ras pathway(s) is not known. In the budding yeast Saccharomyces cerevisiae, the CDC25 gene product acts upstream of Ras proteins, but it has not been clear whether CDC25 function is unique to the S. cerevisiae ras pathway. Here we report that the ste6 gene of fission yeast Schizosaccharomyces pombe is a homologue of CDC25: the ste6 gene product and the CDC25 gene product have significant amino-acid similarity in their C-terminal regions. Like the S. pombe ras1 gene, ste6 is essential for mating. Epistatic interactions indicate that the ste6 gene functions upstream of ras1. We propose that ste6 and CDC25 activate Ras protein through a common mechanism, perhaps by promoting GDP-GTP exchange, even though it seems that the function of Ras protein in budding yeast differs from that in fission yeast. Homologues of ste6 and CDC25 could regulate ras activity in other eukaryotic cells.


Fluorescence Lifetime Imaging of Cancer In Vivo.
Optical imaging of fluorescent reporters in animal models of cancer has become a common tool in oncologic research. Fluorescent reporters including fluorescent proteins, organic dyes, and inorganic photonic materials are used in fluorescence spectroscopy, microscopy, and whole body preclinical imaging. Fluorescence lifetime imaging provides additional, quantitative information beyond that of conventional fluorescence intensity signals, enabling signal multiplexing, background separation, and biological sensing unique to fluorescent materials.


[Effect of ethanol and the catalase inhibitor aminotriazole on lipid peroxidation in the rat myocardium].
The influence of chronic alcohol consumption and catalase inhibitor aminotriazole administration on the level of nonenzymatic lipid peroxidation has been studied in the rat myocardium. It was demonstrated that combined as well as separate treatment with ethanol or aminotriazole elevated the levels of chemiluminescence and enhanced the rate of accumulation of thiobarbituric acid-reactive products in the nuclei-free and total particulate fraction of the rat heart homogenate. The most pronounced effect was noted during combined application of ethanol and aminotriazole. The induction of chemiluminescence by ethanol was prevented by addition of natural (vitamin E, reduced glutathione) or artificial (dibunol) antioxidants into the incubation media. A putative role of the myocardial catalase-containing micro-peroxisomes in stimulation of the intracellular lipid peroxidation is discussed.


Changes of glucose metabolism and skin-collagen neogenesis in vitamin B6 deficiency.
The mechanism of pellagrous changes in skin caused by a deficiency of vitamin B6 was studied in respect to neogenesis of proline in skin collagen and glucose metabolism. In vitamin B6 deficiency the insulin/glucagon coefficient in serum decreased significantly from 3.02 to 2.32, indicating a metabolic change towards gluconeogenesis. A deficiency of vitamin B6 caused a decrease in the levels of vitamin B6-dependent enzymes, such as ornithine aminotransferase, alanine aminotransferase, and aspartate aminotransferase, which also contribute to gluconeogenesis. Because the conversion of ornithine to proline via pyrroline-5-carboxylate was suppressed due to the decrease in ornithine aminotransferase activity, the amount of proline in the skin collagen fraction also decreased significantly in vitamin B6-deficient rats compared with the pair-fed control. These results suggest that the pellagrous lesions in vitamin B6-deficiency are caused by an impaired synthesis of proline from ornithine, which results in the suppression of collagen neogenesis in the skin.


Rise and fall of Caribbean mangroves.
Mangrove forests, which are essential for the maintenance of terrestrial and marine biodiversity on tropical coasts and constitute the main blue‑carbon ecosystems for the mitigation of global warming, are among the world's most threatened ecosystems. Mangrove conservation can greatly benefit from paleoecological and evolutionary studies, as past analogs documenting the responses of these ecosystems to environmental drivers such as climate change, sea level shifts and anthropogenic pressure. A database (CARMA) encompassing nearly all studies on mangroves from the Caribbean region, one of the main mangrove biodiversity hotspots, and their response to past environmental shifts has recently been assembled and analyzed. The dataset contains over 140 sites and ranges from the Late Cretaceous to the present. The Caribbean was the cradle of Neotropical mangroves, where they emerged in the Middle Eocene (∼50 million years ago; Ma). A major evolutionary turnover occurred in the Eocene/Oligocene transition (34 Ma) that set the bases for the shaping of modern-like mangroves. However, the diversification of these communities leading to their extant composition did not occur until the Pliocene (∼5 Ma). The Pleistocene (the last 2.6 Ma) glacial-interglacial cycles caused spatial and compositional reorganization with no further evolution. Human pressure on Caribbean mangroves increased in the Middle Holocene (∼6000 years ago), when pre-Columbian societies began to clear these forests for cultivation. In recent decades, deforestation has significantly reduced Caribbean mangrove cover and it has been estimated that, if urgent and effective conservation actions are not undertaken, these 50 million-year-old ecosystems might disappear in a few centuries. A number of specific conservation and restoration applications based on the results of paleoecological and evolutionary studies are suggested.


Large and giant ventral paraclinoid carotid aneurysms: surgical techniques, complications and outcomes.
Surgical treatment of large and giant ventral paraclinoid carotid aneurysms (vPCAs) continues to be challenging and technically demanding for vascular neurosurgeons. Due to both physiological barriers and limitations of current surgical technology in the treatment of vPCAs, higher rates of morbidity and mortality are a given. To improve the current available data and assess the most effective microsurgical management techniques with the goal of decreased morbidity and mortality, we present this retrospective study of a series of 15 consecutive patients with large and giant vPCAs. Between January 2005 and December 2010, fifteen patients presented with large or giant vPCAs were surgically treated at West China Hospital and were included in this study. The data was retrospectively analyzed. Five men and ten women with an averaging 50 years of age (ranged 32-70 years) were included in this study. The average aneurysm size was 21 mm (ranged 13-36 mm). All patients were treated microsurgically. Twelve patients (80%) had desirable surgical outcomes (Glasgow Outcome Score 4-5) at follow-up for a mean of 32 months (range 3-72 months). One patient (7%) died of severe vasospasm after surgery. The surgical mortality was 7%; overall morbidity was 27%, including the hemiplegia, oculomotor paresis and visual deficit. None of the 14 following patients had rebleeding or regrowth of residual aneurysm during this follow-up period. Age and Hunt-Hess grade were significantly correlated with clinical outcome. Despite the difficulties presented by large and giant vPCAs, our increased knowledge of anatomy and refinements in operative techniques and intraoperative monitoring have greatly improved the clinical outcome with a more acceptable mortality and morbidity.


New proximal L-shaped clamp for use in low anterior resection of the rectum.
The authors have designed a new proximal clamp for use in low anterior resection of the rectum. The new clamp enables the surgeon to section the rectum sharply at a right angle without fear of injuring the surrounding tissue.


A review of topical high-concentration L-menthol as a translational model of cold allodynia and hyperalgesia.
Cold allodynia and cold hyperalgesia are both elusive features of neuropathic pain, particularly in patients with various polyneuropathies. Numerous studies have suggested that topical application of L-menthol causes temporary cold hypersensitivity and thus acts as a proxy for associated symptoms. This review summarizes studies on L-menthol-induced nociception, cold allodynia and cold hyperalgesia in vitro, in animals and in humans. A comprehensive literature search was performed using the PubMed and Google Scholar databases until February 2013. Obtained manuscripts were reviewed for relevancy and reference lists of the retrieved articles were cross-checked for additional important studies. Solely the literature regarding topical application of L-menthol in humans was attained systematically. Of the total identified studies (96), 10 met the inclusion criteria being controlled studies applying L-menthol at a concentration of ≥ 30%. The extracted data are meticulously compared and presented with emphasis on clarity and transparency. In seven animal studies, cold allodynia or hyperalgesia was successfully established utilizing various methods. Eight studies in healthy volunteers unanimously reported a significant increase in cold pain threshold, representing cold allodynia and increased supra-threshold cold pain sensitivity, thus demonstrating cold hyperalgesia. Topical high-concentration L-menthol consistently induces cold hypersensitivity in animals and humans, thus constituting a predictable surrogate model of cold allodynia and hyperalgesia. Understanding translational features of this model and its underlying mechanisms could be valuable in preclinical and human phases of drug development and in improving current treatment of patients with polyneuropathy.


Postharvest fruit quality of tomatoes influenced by an ethylene signaling component during long-term cold storage.
Ethylene production is essential for improving cold resistance of postharvest tomatoes. However, the role of ethylene signaling pathway in maintaining fruit quality during long-term cold storage remains poorly understood. Here, we demonstrated that a partial loss of function in ethylene signaling by mutation of Ethylene Response Factor 2 (SlERF2), worsened fruit quality during cold storage, as determined by visual characterization, and physiological analyses of membrane damage and reactive oxygen species metabolism. In addition, the transcriptions of genes related to abscisic acid (ABA) biosynthesis and signaling were also altered by SlERF2 gene in response to cold storage. Furthermore, mutation of SlERF2 gene compromised cold-induced expression of genes in the C-repeat/dehydration-responsive binding factor (CBF) signaling pathway. Therefore, it's concluded that an ethylene signaling component, SlERF2 contributed to the regulations of ABA biosynthesis and signaling, as well as CBF cold signaling pathway, ultimately affecting the fruit quality during long-term cold storage of tomatoes.


Adrenal medullary secretion of dopamine in response to hemorrhagic and endotoxin-induced shock in dogs.
Adrenal medullary secretion of dopamine (DA) was investigated during acute hemorrhagic and endotoxin-induced shock in mongrel dogs. Blood samples were collected directly from the adrenal vein and DA content was measured using gas-liquid chromatography equipped with an electron-capture detector (GLC-ECD). The adrenal medullary secretion of DA increased markedly during hemorrhagic and endotoxin-induced shock. In the former, the rate of secretion of DA increased from 0.22 ng/kg/min to 10.7 ng/kg/min in 90 min. After blood transfusion, the rate of secretion of DA decreased rapidly. In the case of endotoxin-induced shock, the rate of secretion of DA increased from 0.20 ng/kg/min to 9.6 ng/kg/min in 120 min. In the cervical spinal transected dogs, the rate of secretion of DA did not increase during hemorrhagic shock. Thus, secretion of DA from the adrenal medulla seems to be primarily controlled by the central nervous system, through the baroreceptor reflex.


Pesticide contamination profiles of water, sediment and aquatic organisms in the effluent of Gaobeidian wastewater treatment plant.
Organochlorine pesticides (OCPs, including DDT, HCH and HCB) and six indicator polychlorinated biphenyls (PCB 28, 52, 101, 138, 153, and 180) were measured in water, sediment, zooplankton, fish and Chinese softshell turtle (Pelodiscus sinensis) from Gaobeidian Lake, which is located in the effluent of Gaobeidian wastewater treatment plant (WWTP) in Beijing, China. DDTs were dominant except for in water. In water, the concentrations of DDTs (6.22 ng l(-1)) and HCHs (18.0 ng l(-1)) were less than the limits (l000 ng l(-1) for DDTs and 5000 ng l(-1) for HCHs). However, PCBs concentration (20.8 ng l(-1)) exceeded the limit (14 ng l(-1)) suggested by the United States Environmental Protection Agency (USEPA). The high ratio of p,p'-DDT/DDTs (0.80) in water suggested that DDTs had recently been discharged into the ambient environment despite a longtime ban in China. For fish and Pelodiscus sinensis, the accumulation patterns of OCPs and PCBs were different in muscle and liver. And HCB and PCB 153 were significant different in different species (p<0.05). PCBs were dominated by PCB 52 in zooplankton, but by PCB 138 and 153 in Pelodiscus sinensis. The highest food web magnification factor (FWMF) was 4.83 for p,p'-DDT and the second highest was 4.36 for PCB 101 in Gaobeidian Lake. As compared with the other studies, biomagnification in the present study was not obvious. Trophic levels and age were two important factors that might contribute to the bioaccumulation in the present study.


Catalase and dehydroascorbate reductase in human polymorphonuclear leukocytes (PMN): possible functional relationship.
In leukocytes (PMN) of individuals with Swiss type acatalasemia, the rate of dehydroascorbate reduction is 4 times normal. This observation suggests that the protective function served by catalase in human PMN is supported by dehydroascorbate reductase.


Root strains associated with different obturation techniques.
The influence of different obturation techniques (lateral condensation, Obtura, and Thermafil) on root strains was assessed in 27 upper central incisors using strain gauges mounted on the coronal and apical one-thirds of the root surface. The vertical load applied with each obturation technique was also measured. Comparison of the strains was conducted with two-way analysis of covariance (with condensation load as covariate). The technique of obturation significantly influenced the root strains, with the Obtura generating the highest strains. The Thermafil group showed significantly less strain than the Obtura or lateral condensation groups. Thermal expansion of dentin was an unexpected finding. A large proportion of strain in the Obtura and Thermafil groups was found to be thermal strain. The mean load required to cause vertical root fracture was five to six times higher than the load used in obturation.


Identifying the factors influencing practice variation in thrombosis medicine: A qualitative content analysis of published practice-pattern surveys.
Practice variation, the differences in clinical management between physicians, is one reason why patient outcomes may differ. Identifying factors that contribute to practice variation in areas of clinical uncertainty or equipoise may have implications for understanding and improving patient care. To discern what factors may influence practice variation, we completed a qualitative content analysis of all practice-pattern surveys in thrombosis medicine in the last 10years. Out of 2117 articles screened using a systematic search strategy, 33 practice-pattern surveys met eligibility criteria. Themes were identified using constant comparative analysis of qualitative data. Practice variation was noted in all 33 practice-pattern surveys. Contributing factors to variation included lack of available evidence, lack of clear and specific guideline recommendations, past experience, patient context, institutional culture and the perceived risk and benefit of a particular treatment. Additional themes highlight the value placed on expertise in challenging clinical scenarios, the complexity of practice variation and the value placed on minimizing practice variation.


Molecular mechanisms of probiotic action: a proteomic perspective.
Probiotics are living microorganisms that confer beneficial effects to human health when supplied in adequate amounts, by promoting digestion and uptake of dietary nutrients, strengthening intestinal barrier function, modulating immune response and enhancing antagonism towards pathogens. The purpose of the present article is to focus on microbial proteomics, pointing out its usefulness in the investigation of molecular mechanisms underlying probiotic effects. It deals, in particular, with molecular strategies responsible for adaptation to the harsh physical-chemical environment of the gastro-intestinal tract, bacterial adhesion to host epithelial cells and intestinal mucosa and probiotic immunomodulatory properties, as analyzed by proteomics in the past few years.


Cerebral microembolism during cardiopulmonary bypass. Retinal microvascular studies in vivo with fluorescein angiography.
To observe microembolic events in the central nervous system during cardiopulmonary bypass, we subjected 21 patients undergoing elective coronary operations to retinal fluorescein angiograms 5 minutes before cardiopulmonary bypass was discontinued. Patients with diabetes or clinically evident cerebrovascular disease were excluded. Bubble oxygenation and nonpulsatile perfusion were used for bypass. After 31 to 167 minutes of cardiopulmonary bypass, all 21 (100%) patients had retinal microvascular occlusions indicative of microembolism. Control fluorescein angiograms obtained preoperatively and in five patients immediately before bypass but after aortic cannulation showed retinal perfusion. During bypass there was a mean of 3.5 (range 1 to 7) blocked arterioles of less than 50 micron caliber and a mean of 6.3 (range 1 to 10) focal areas of capillary nonperfusion per 30-degree field of retina centered on the macula per patient. Repeat studies 30 minutes after discontinuation of bypass showed partial reperfusion with occlusions in four of the five (80%) patients and a decrease in the mean total microembolic count from 12.6 to 4.8 (38%). In later studies at a median of 8 days postoperatively, only two of 16 (12.5%) patients had persistently occluded retinal vessels. The total microembolic count did not correlate with bypass time (r = 0.14) and was not reduced by arterial line filtration with a Pall 40 micron filter (Ultipore) in a subgroup of 11 patients. Twenty patients completed four standardized psychometric tests. Retinal microvascular occlusions were more numerous in those patients with a psychometric deficit (n = 7) than in those with no deficit (n = 13; p = 0.075). In a dog model of cardiopulmonary bypass, eight of nine (88.9%) had retinal microvascular occlusions after 10 to 90 minutes of bypass. Retinal histologic studies revealed intravascular platelet-fibrin microaggregates 20 to 70 micron in diameter and focal ischemic changes in seven of the nine (77.8%) dogs. Six dogs undergoing sham bypass had normal retinal perfusion and histologic findings. This study demonstrates a very high incidence of microvascular occlusions in the territory of the internal carotid artery during bypass consistent with a microembolic origin. The clinical significance of these findings is uncertain.


Sentinel lymph node biopsy in melanoma patients: the medical oncologist's perspective.
With the advent of sentinel node (sN) biopsy in melanoma patients, elective lymph node dissection (ELND) can be considered an exceeded procedure. Regardless of the possible therapeutic benefits, sN biopsy efficiently predicts prognosis avoiding the morbidity rate of ELND. The importance of the sN is underlined by multivariate analyses, which show that the sN status represents the most important prognostic factor influencing disease-free and distant disease-free survival in patients with stage I and II melanoma. Moreover, sN biopsy provides a minimally invasive method for identifying those patients with subclinical nodal metastasis who actually have stage III disease, with a very high risk of occult distant metastases and who may benefit by adjuvant therapy.


Stabilization of ERK-Phosphorylated METTL3 by USP5 Increases m6A Methylation.
N6-methyladenosine (m6A) is the most abundant mRNA modification and is installed by the METTL3-METTL14-WTAP methyltransferase complex. Although the importance of m6A methylation in mRNA metabolism has been well documented recently, regulation of the m6A machinery remains obscure. Through a genome-wide CRISPR screen, we identify the ERK pathway and USP5 as positive regulators of the m6A deposition. We find that ERK phosphorylates METTL3 at S43/S50/S525 and WTAP at S306/S341, followed by deubiquitination by USP5, resulting in stabilization of the m6A methyltransferase complex. Lack of METTL3/WTAP phosphorylation reduces decay of m6A-labeled pluripotent factor transcripts and traps mouse embryonic stem cells in the pluripotent state. The same phosphorylation can also be found in ERK-activated human cancer cells and contribute to tumorigenesis. Our study reveals an unrecognized function of ERK in regulating m6A methylation.


Medication-Enhanced Psychotherapy for Posttraumatic Stress Disorder: Recent Findings on Oxytocin's Involvement in the Neurobiology and Treatment of Posttraumatic Stress Disorder.
Traumatic experiences may result in Posttraumatic Stress Disorder (PTSD), which is characterized as an exaggerated fear response that cannot be extinguished over time or in safe environments. What are beneficial psychotherapeutic treatment options for PTSD patients? Can oxytocin (OXT), which is involved in the stress response, and safety learning, ameliorate PTSD symptomatology and enhance psychotherapeutic effects? Here, we will review recent studies regarding OXT's potential to enhance psychotherapeutic therapies for PTSD treatment. We conducted a literature review on the neurobiological underpinnings of PTSD especially focusing on OXT's involvement in the biology and memory formation of PTSD. Furthermore, we researched successful psychotherapeutic treatments for PTSD patients and discuss how OXT may facilitate observed psychotherapeutic effects. For a relevant proportion of PTSD patients, existing psychotherapies are not beneficial. OXT may be a promising candidate to enhance psychotherapeutic effects, because it dampens responses to stressful events and allows for a faster recovery after stress. On a neural basis, OXT modulates processes that are involved in stress, arousal and memory. OXT effectively counteracts memory impairments caused by stress and facilitates social support seeking which is a key resilience factor for PTSD and which is beneficial in psychotherapeutic settings. OXT has many characteristics that are promising to positively influence psychotherapy for PTSD patients. It potentially reduces intrusions, but preserves memory of the event itself. Introducing OXT into psychotherapeutic settings may result in better treatment outcomes for PTSD patients. Future research should directly investigate OXT's effects on PTSD, especially in psychotherapeutic settings.


The affective and cognitive processing of touch, oral texture, and temperature in the brain.
Some of the principles of the representation of affective touch in the brain are described. Positively affective touch and temperature are represented in parts of the orbitofrontal and pregenual cingulate cortex. The orbitofrontal cortex is implicated in some of the affective aspects of touch that may be mediated through C fibre touch afferents, in that it is activated more by light touch to the forearm (a source of C-tactile (CT) afferents) than by light touch to the glabrous skin of the hand. Oral somatosensory afferents implicated in sensing the texture of food including fat in the mouth also activate the orbitofrontal and pregenual cingulate cortex, as well as the insular taste cortex. Top-down cognitive modulation of the representation of affective touch produced by word labels is found in parietal cortex area 7, the insula and ventral striatum. The cognitive labels also influence activations to the sight of touch and also the correlations with pleasantness in the pregenual cingulate/orbitofrontal cortex and ventral striatum.


Liver fibrotic development is reduced through inflammation prevention by an adenosine derivative compound.
Liver fibrosis is a global health problem, and studying its development provides important information to address its treatment. Here, we characterized the effects of an adenosine compound (IFC-305) on preventing fibrosis and liver inflammation. We studied the impact of IFC-305 on a carbon tetrachloride-induced liver fibrosis model in Wistar male rats at 4, 6, and 8 weeks. The effects were characterized by liver tissue histology, macrophages identification by flow cytometry with CD163+/CD11b/c+ antibodies, hepatic and plasmatic cytokine levels employing MILLIPLEX MAP and ELISA, Col1a1 and Il6 gene expression by RTqPCR, lipoperoxidation by TBARS reaction, and reactive oxygen species using 2'-7'dichlorofluorescin diacetate. CCl4-induced liver fibrosis and inflammation were significantly reduced in rats treated with IFC-305 at 6 and 8 weeks. In addition, we observed diminished expression of Col1a1; a decrease in the inflammatory cytokines IL-1β, IL-6, MCP-1, TNF-α, and IL-4 a; reduction in inflammatory macrophages; inhibition of lipoperoxidation; and ROS production in Kupffer cells. This study showed that IFC-305 can inhibit liver fibrosis establishment by regulating the immune response during CCl4-induced damage. The immunomodulatory action of IFC-305 supports its use as a potential therapeutic strategy for preventing liver fibrosis.


Cardiac involvement in antiphospholipid syndrome: The diagnostic role of noninvasive cardiac imaging.
The antiphospholipid syndrome (APS) is an autoimmune disorder of acquired hypercoagulability characterized by vascular thrombosis, increased pregnancy morbidity, and elevated levels of antiphospholipid antibodies. Cardiac involvement in APS may be presented as heart valve disease affecting approximately a third of patients or less frequently as intracardial thombosis, pulmonary hypertension, right or left ventricular dysfunction, micro-vascular thrombosis, coronary artery, or micro-vascular disease with overt or silent clinical presentation. Noninvasive cardiovascular imaging plays a crucial role in the evaluation of heart involvement in APS. Transthoracic or transoesophageal echocardiography enable early, accurate diagnosis and severity assessment of HVD as well as of ventricular dysfunction and pulmonary hypertension. Studies by echocardiography and nuclear imaging have detected abnormalities in myocardial perfusion in approximately 30% of primary APS. CT scan is the technique of choice for the assessment of pulmonary embolism and can effectively detect intracardiac thrombi. Myocardial perfusion defects have been detected by 13N-ammonia PET in 40% of APS. Cardiovascular magnetic resonance (CMR) has identified an unexpectedly high prevalence of occult myocardial scarring and endomyocardial fibrosis in APS, and is the technique of choice, if quantification of heart valve disease and stress myocardial perfusion-fibrosis is needed. Noninvasive, nonradiating imaging techniques, such as echocardiography and CMR are superior to CT or nuclear techniques and are of great value for the diagnosis and follow-up of both clinically overt and silent cardiac disease in APS. The high incidence of cardiac involvement in APS demands early diagnosis/treatment and multimodality cardiovascular imaging is of great importance.


Tumor-specific DNA sequences in human gliomas.
Utilizing the technique of hydroxyapatite chromatography, normal cellular DNAs were used to recycle off the repeat or normal sequences found in [3H]DNA copied off 70S RNA from malignant astrocytomas. The recycled [3H]DNA were then used to hybridize against DNAs from normal human brain tissues and DNAs from malignant astrocytomas or Grade IV astrocytomas. The results indicated the presence of tumor-specific DNA sequences in malignant astrocytomas, absent in normal brain tissues. The percentages were 88% and 7%, respectively. When recycled medulloblastoma 70S[3H]DNA probes were utilized against DNA'S FROM Grade IV astrocytomas and from normal brain, similar results were obtained. The respective percentages of hybridization were 67% and 7%. Thus it would appear that malignant gliomas contain tumor-specific DNA sequences which are not found in normal brain tissues.


Analyzing the role of AP-1B in polarized sorting from recycling endosomes in epithelial cells.
Epithelial cells polarize their plasma membrane into apical and basolateral domains where the apical membrane faces the luminal side of an organ and the basolateral membrane is in contact with neighboring cells and the basement membrane. To maintain this polarity, newly synthesized and internalized cargos must be sorted to their correct target domain. Over the last ten years, recycling endosomes have emerged as an important sorting station at which proteins destined for the apical membrane are segregated from those destined for the basolateral membrane. Essential for basolateral sorting from recycling endosomes is the tissue-specific adaptor complex AP-1B. This chapter describes experimental protocols to analyze the AP-1B function in epithelial cells including the analysis of protein sorting in LLC-PK1 cells lines, immunoprecipitation of cargo proteins after chemical crosslinking to AP-1B, and radioactive pulse-chase experiments in MDCK cells depleted of the AP-1B subunit μ1B.


Cerebral blood volume imaging by flat detector computed tomography in comparison to conventional multislice perfusion CT.
We tested the hypothesis that Flat Detector computed tomography (FD-CT) with intravenous contrast medium would allow the calculation of whole brain cerebral blood volume (CBV) mapping (FD-CBV) and would correlate with multislice Perfusion CT (PCT). Twenty five patients were investigated with FD-CBV and PCT. Correlation of the CBV maps of both techniques was carried out with measurements from six anatomical regions from both sides of the brain. Mean values of each region and the correlation coefficient were calculated. Bland-Altman analysis was performed to compare the two different imaging techniques. The image and data quality of both PCT and FD-CBV were suitable for evaluation in all patients. The mean CBV values of FD-CBV and PCT showed only minimal differences with overlapping standard deviation. The correlation coefficient was 0.79 (p < 0.01). Bland-Altman analysis showed a mean difference of -0.077 ± 0.48 ml/100 g between FD-CBV and PCT CBV measurements, indicating that FD-CBV values were only slightly lower than those of PCT. CBV mapping with intravenous contrast medium using Flat Detector CT compared favourably with multislice PCT. The ability to assess cerebral perfusion within the angiographic suite may improve the management of ischaemic stroke and evaluation of the efficacy of dedicated therapies.


Synthesis, optimization and characterization of silver nanoparticles using the catkin extract of Piper longum for bactericidal effect against food-borne pathogens via conventional and mathematical approaches.
Inspired with an increasing environmental awareness, we performed an eco-friendly amenable process for the synthesis of silver nanoparticles (AgNPs) using the catkins of Piper longum as an alternative approach with the existing methods of using plant extracts. The fabrication of nanoparticles occurred within 10 min. This was initially observed by colour change of the solution. UV-visible spectroscopic studies (UV-Vis) were performed for further confirmation. The analysis elucidated that the surface plasmon resonance (SPR) was specifically corresponding to AgNPs. Fourier transform infrared spectrophotometry (FTIR) studies indicated that polyphenols could possibly be the encapsulating agents. The size and shape of the nanoparticles was analysed using Transmission electron microscopy (TEM). The nanoparticles were predominant spheres ranging between 10 and 42 nm at two different scales. The formation of elemental silver was confirmed further by X-ray photoelectron spectroscopy (XPS) and X-ray powder diffraction (XRD). GC-MS analysis was used to identify the possible encapsulates on the nanoparticles. The antibacterial effect of the biosynthesized AgNPs was tested against two gram-positive (Bacillus cereus and Staphylococcus aureus), and five gram-negative (Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Pseudomonas aeruginosa and Salmonella typhi) bacteria. Outcomes of the study suggest that these pathogens were susceptible to the AgNPs. This is the first ever international report on correlating the antibacterial effect of silver nanoparticles using mathematical modelling with a conventional antimicrobial assay. The results indicate that nanoparticles of silver synthesized using catkin extract of P. longum can be exploited towards the development of potential antibacterial agents.


In vitro nail invasion by pathogenic and non-pathogenic fungi under different culture conditions.
Data from the literature suggest that the nutritional environment can modify major metabolic functions of fungi and possibly their aggressivity towards keratinous structures. Trichophyton rubrum (TR), Microsporum canis (MC), Scopulariopsis brevicaulis (SB), Aspergillus fumigatus (AF) and Penicillium spec. (P) were inoculated on media of different nutritional value, in presence of nail fragments. The activity of the fungi was evaluated at two and four weeks for intensity and depth of invasion of nail samples. Nail invasion was most pronounced by MC, especially when grown on rice agar or peptone agar. Nail invasion by the other fungi tested was less important, Sabourand glucose and rice agar were most favorable. Our results indicate that nutritional factors can, at least in some fungus species, alter their rate of nail invasion.


CON: Procalcitonin does not have clinical utility in children with community-acquired pneumonia.
Most clinical studies supporting procalcitonin (PCT)-guided management of lower respiratory tract infections have been performed in adults. There is a paucity of studies evaluating the clinical impact of PCT use in children and limited data informing age-appropriate PCT cut-offs; diagnostic accuracy in immunocompromised children; patient subgroups most likely to benefit from PCT testing; whether PCT adds value beyond available rapid molecular viral diagnostics; and optimal implementation strategies for PCT-guided treatment. At the present time there is little evidence to support routine use of PCT to aid management of paediatric pneumonia.


Anal canal carcinoma: experience from a single Korean institution.
The clinical features, treatment modality approaches in clinical practice, and prognostic factors for anal canal carcinoma patients were retrospectively analyzed. Between October 1994 and December 2005, 50 patients with anal canal cancer were treated at Samsung Medical Center, Seoul, Korea. After a median follow up of 37.8 months (range, 6.6-136.1 months), the 5-year and 10-year survival rates for the 38 patients with early and locally advanced squamous and cloacogenic carcinoma (squamous cell carcinoma and cloacogenic carcinoma) were 74.8% and 66.5%, respectively. The 5-year survival and disease-free survival rates (DFS) of the 31 patients who received chemoradiation therapy (CRT) were 83.6% and 74.3%, respectively. The overall and DFS could not be determined for the adenocarcinoma group due to the small number of cases (n=8). Univariate analysis showed that tumor size (p=0.04) and inguinal node status (p=0.04) significantly influenced patient survival in patients with squamous cell and cloacogenic carcinomas. Furthermore, univariate analysis also showed that, inguinal node status influenced patient survival in the adenocarcinoma group. Multivariate analysis showed that inguinal node metastasis is a single independent prognostic variable for survival (p=0.04) in patients with squamous cell and cloacogenic carcinomas. Combined CRT has been adopted as standard treatment with outcomes that are comparable to those reported in randomized clinical trials. Due to the rarity and complexity of anal canal carcinoma, interdepartmental cooperation is required for disease treatment. Thus, proper treatment of patients should incorporate a team-approach and should be available to as many patients as possible.


ECIL-3 classical diagnostic procedures for the diagnosis of invasive fungal diseases in patients with leukaemia.
Invasive fungal diseases (IFDs) continue to cause considerable morbidity and mortality in patients with haematological malignancy. Diagnosis of IFD is difficult, with the sensitivity of the gold standard tests (culture and histopathology) often reported to be low, which may at least in part be due to sub-optimal sampling or subsequent handling in the routine microbiological laboratory. Therefore, a working group of the European Conference in Infections in Leukaemia was convened in 2009 with the task of reviewing the classical diagnostic procedures and providing recommendations for their optimal use. The recommendations were presented and approved at the ECIL-3 conference in September 2009. Although new serological and molecular tests are examined in separate papers, this review focuses on sample types, microscopy and culture procedures, antifungal susceptibility testing and imaging. The performance and limitations of these procedures are discussed and recommendations are provided on when and how to use them and how to interpret the results.


Ligand-Controlled Palladium-Catalyzed Carbonylation of Alkynols: Highly Selective Synthesis of α-Methylene-β-Lactones.
The first general and regioselective Pd-catalyzed cyclocarbonylation to give α-methylene-β-lactones is reported. Key to the success for this process is the use of a specific sterically demanding phosphine ligand based on N-arylated imidazole (L11) in the presence of Pd(MeCN)2 Cl2 as pre-catalyst. A variety of easily available alkynols provide under additive-free conditions the corresponding α-methylene-β-lactones in moderate to good yields with excellent regio- and diastereoselectivity. The applicability of this novel methodology is showcased by the direct carbonylation of biologically active molecules including natural products.


Concurrent stone stabilization improves ultrasonic and pneumatic efficacy during cystolithopaxy: an in vitro analysis.
To identify whether stabilization of larger bladder stones would improve the efficacy of combination (ultrasonic/pneumatic) lithotripsy in a phantom bladder stone model for percutaneous cystolithopaxy. Using 1cm phantom Bego stones, a spherical model bladder was used to simulate percutaneous bladder access. A UroNet (US Endoscopy, USA) was placed alongside a Swiss Lithoclast probe through the working channel of a Storz 26Fr rigid nephroscope. Using a 30Fr working sheath, the stone was captured, and fragmented for 60 seconds. Resulting fragments and irrigation were filtered through a 1mm strainer, and recorded. Five trials were performed with and without the UN. Durability was then assessed by measuring net defects, and residual grasp strength of each instrument. Descriptive statistics (mean, standard deviations) were used to summarize the data, and Student's t-tests (alpha < 0.05) were used to compare trials. The mean time to stone capture was 12s (8-45s). After fragmentation with UN stabilization, there were significant improvements in the amount of residual stone (22% dry weight reduction vs 8.1% without UN, p < 0.001), number of fragments (17.5 vs 5.0 frag/stone, p=0.0029), and fragment size (3.6mm vs. 7.05 mm, p=0.035). Mesh defects were noted in all nets, ranging from 2-14 mm, though all but one net retained their original grip strength (36.8N). Bladder stone stabilization improved fragmentation when used in conjunction with ultrasonic/pneumatic lithotripsy. However, due to limitations in maneuverability and durability of the UN, other tools need to identified for this indication.


Alpha-2 adrenoceptor blockade and the response to intruder aggression in Long-Evans rats.
Alpha-2 adrenoceptor antagonists remove the presynaptic negative feed-back control of norepinephrine release, by this enhancing the naturally occurring adrenergic activation. Male Long-Evans rats were injected with 1 mg/kg CH-38083, an alpha 2 adrenoceptor blocker. Twenty minutes later a size matched Wistar or Long-Evans opponent, respectively, was introduced in their home cage for 15 min (the Wistar strain is more aggressive than the Long-Evans in these circumstances). The treatment increased the number of biting attacks several folds in both situations. The correlations existing between the behavior of the intruder and the aggressiveness of the resident (treated) rat led to the conclusion that the catecholaminergic treatment increased the sensitivity of the animals to the behavioral actions of the intruder. The treated animals responded in an exaggerated fashion compared to their saline treated counterparts. An increase in the corticosterone response of the treated rats paralleled the increase in attack frequency, and seemed not to depend on the challenge received from the intruder.


Better glycaemic control and risk reduction of diabetic complications in Type 2 diabetes: comparison with the DCCT.
To construct dose response curves relating the development of diabetic complications (retinopathy and microalbuminuria) to mean glycaemic exposure in a cohort of Type 2 patients followed over a period of several years. This allows a comparison with similar data on Type 1 subjects reported by the Diabetes Control and Complications Trial (DCCT) and provides a rational basis for deciding what levels of glycaemic control should be aimed for in advising individual patients and in setting guidelines for conducting health services. This was an analysis of data prospectively collected in our computerized data base for Type 2 patients who attended and were followed up at the Complications Assessment Service of our Diabetes Center. The initial development of retinopathy and microalbuminuria was analyzed with respect to the mean HbA1c during the follow up period. Statistical procedures identical to those employed in the DCCT were used to construct the dose response curve. A smooth relationship between the development of retinopathy with increasing hyperglycaemia was found. For every 10% decrease in HbA1c, there was a 24%) (confidence interval (CI): 16-32) reduction in relative risk, about 2/3 of that reported for insulin-dependent diabetes mellitus (IDDM) patients. The relationship between microalbuminuria and HbAc was more linear and less steep with a relative risk reduction of 9% (CI: -2-19%) for any 10% fall in HbA1c, about 1/3 of that reported for IDDM subjects. No threshold of HbA1c can be found for the relative risk of developing complications. However, more cases of complications are prevented by the same degree of improvement in glycaemic control at higher levels of HbA1c. The development of diabetic retinopathy in Type 2 subjects is also related to the magnitude of hyperglycaemia although the degree of dependence is less than that in Type 1. Glycaemic control has less influence on microalbuminuria in Type 2. In terms of relative risk, no threshold of 'safe HbA1c' can be found but in absolute terms more cases of diabetic complications can be prevented by improving the glycaemic control of the very hyperglycaemic patients.


Optical Control of Mitosis with a Photoswitchable Eg5 Inhibitor.
Eg5 is a kinesin motor protein that is responsible for bipolar spindle formation and plays a crucial role during mitosis. Loss of Eg5 function leads to the formation of monopolar spindles, followed by mitotic arrest, and subsequent cell death. Several cell-permeable small molecules have been reported to inhibit Eg5 and some have been evaluated as anticancer agents. We now describe the design, synthesis, and biological evaluation of photoswitchable variants with five different pharmacophores. Our lead compound Azo-EMD is a cell permeable azobenzene that inhibits Eg5 more potently in its light-induced cis form. This activity decreased the velocity of Eg5 in single-molecule assays, promoted formation of monopolar spindles, and led to mitotic arrest in a light dependent way.


Tentative identification of a second central nervous system myelin membrane autoantigen (M2) by a biochemical comparison with the basic protein (BP).
Two central nervous system myelin autoantigens, M2 and basic protein (BP), were examined, using complement-fixing antibodies against each autoantigen as markers on myelin. M2 activity was very labile and very insoluble, PB activity was very resistant. Trypsin reduced both activities an this reduction was greater after phospholipase treatment. Both activities were slightly solubilized in 8 M urea. It is known that BP is not present on the surface of myelin and is considered a peripheral membrane protein. M2 appears to be a surface and integral membrane protein, and as such resembles Folch Pi proteolipid protein. The relationship between M2 and BP requires further study.


Hepatic nodular lymphoid lesion with increased IgG4-positive plasma cells associated with primary biliary cirrhosis: a report of two cases.
The nodular lymphoid lesion of the liver known as reactive lymphoid hyperplasia or pseudolymphoma is rare and its pathogenesis is unknown. We report two cases of nodular lymphoid lesions of the liver with numerous IgG4-positive plasma cells in patients with primary biliary cirrhosis. Histologically, in both cases, the lesion showed a dense lymphoplasmacytic infiltrate with lymphoid follicles and granulomas. Fibrous tissue was scarce and without a storiform pattern. Obliterative phlebitis was not identified. The IgG4+ plasma cell counts were 82 and 76 per high power field, with an IgG4/IgG ratio of 75 and 64 %, respectively, which qualifies the lesions according to the diagnostic criteria for IgG4-related disease as « probable histological feature of IgG4-related disease ». There were no rearrangements of immunoglobulin heavy-chain genes and plasma cells had a polytypic pattern of kappa and lambda light-chain expression. The non-tumor liver showed primary biliary cirrhosis with destructive cholangitis without IgG4 plasma cells. In both cases, IgG4-related disease was not found in other organs neither at the time of diagnosis nor 3 years later. Serum IgG4 levels normalized after local ablation of the lesions. It seems unlikely that these lesions are a manifestation of IgG4-related disease. However, because the pathogenesis of both nodular lymphoid lesions and IgG4-related disease remains unclear, further studies are needed to elucidate a potential link between nodular lymphoid lesions of the liver and an increased number of IgG4 plasma cells. More definite conclusions will be possible when the pathogenesis of IgG4-related disease has been clarified.


New molecular bridge between RelA/p65 and NF-κB target genes via histone acetyltransferase TIP60 cofactor.
The nuclear factor-κB (NF-κB) family is involved in the expressions of numerous genes, in development, apoptosis, inflammatory responses, and oncogenesis. In this study we identified four NF-κB target genes that are modulated by TIP60. We also found that TIP60 interacts with the NF-κB RelA/p65 subunit and increases its transcriptional activity through protein-protein interaction. Although TIP60 binds with RelA/p65 using its histone acetyltransferase domain, TIP60 does not directly acetylate RelA/p65. However, TIP60 maintained acetylated Lys-310 RelA/p65 levels in the TNF-α-dependent NF-κB signaling pathway. In chromatin immunoprecipitation assay, TIP60 was primarily recruited to the IL-6, IL-8, C-IAP1, and XIAP promoters in TNF-α stimulation followed by acetylation of histones H3 and H4. Chromatin remodeling by TIP60 involved the sequential recruitment of acetyl-Lys-310 RelA/p65 to its target gene promoters. Furthermore, we showed that up-regulated TIP60 expression was correlated with acetyl-Lys-310 RelA/p65 expressions in hepatocarcinoma tissues. Taken together these results suggest that TIP60 is involved in the NF-κB pathway through protein interaction with RelA/p65 and that it modulates the transcriptional activity of RelA/p65 in NF-κB-dependent gene expression.


Effect of zero magnetic field on cardiovascular system and microcirculation.
The effects of zero magnetic field conditions on cardiovascular system of healthy adults have been studied. In order to generate zero magnetic field, the facility for magnetic fields modeling "ARFA" has been used. Parameters of the capillary blood flow, blood pressure, and the electrocardiogram (ECG) monitoring were measured during the study. All subjects were tested twice: in zero magnetic field and, for comparison, in sham condition. The obtained results during 60 minutes of zero magnetic field exposure demonstrate a clear effect on cardiovascular system and microcirculation. The results of our experiments can be used in studies of long-term stay in hypo-magnetic conditions during interplanetary missions.


Palaeontology: the 165-million-year itch.
New flea-like fossils from China provide a rare, tantalizing glimpse of bizarre insects in the Cretaceous and Jurassic. Possibly the oldest flea-like animals known, they provide a challenge to the functional morphologist to infer which animals they may have targeted.


Pancreatic Dysfunction and Reduction in Quality of Life Is Common After Pancreaticoduodenectomy.
Improvements in survival after pancreaticoduodenectomy has increased the number of patients potentially at risk of pancreatic insufficiency. We studied long-term (> 1 year) pancreatic functions (endocrine and exocrine) after pancreaticoduodenectomy and aimed to recognize the impact of various clinicopathological factors and postoperative complications on pancreatic functions. All patients who underwent pancreaticoduodenectomy at least 1 year prior were recruited from July 2020 to December 2021. Endocrine function was assessed using HbA1c, fasting blood sugar and postprandial blood sugar levels. Pancreatic exocrine function was assessed clinically with history of steatorrhea and objectively with quantitative estimation of fecal elastase-1 levels in stool samples. Volume of remnant pancreas, parenchymal thickness and duct diameter were assessed by computed tomography. Quality of life assessment was done using SF-36 questionnaire. Of the 106 patients assessed, 64 patients met the inclusion criteria. Endocrine insufficiency was noted in 51.6%, and 34.3% had new onset diabetes mellitus. The incidence of pancreatic exocrine insufficiency was 87.5% and severe insufficiency was found in 62.5% of patients. Twenty-nine (45.3%) patients had both exocrine and endocrine insufficiency. Patients with CRPOPF had higher risk of severe exocrine insufficiency (5 vs. 2, OR 1.57(0.28-8.81) p = 0.6). The SF-36 scores were lower than general population especially in role limitation due to physical health, role limitation due to emotional problems, energy/fatigue, general health perception and health change domains. Post-pancreaticoduodenectomy patients have a high frequency of pancreatic insufficiency and should be screened for same. The post-operative pancreatic fistula increases the risk of pancreatic exocrine insufficiency.


Hepatitis C Behind and Beyond Bars: Targeting the US Prison Population and Changing North Carolina Prisoner Health Policy.
Prisoners in the United States are disproportionately affected by hepatitis C. Addressing the disease behind bars is crucial for curtailing the epidemic in the greater population. Effective strategies for testing and treatment are elucidated here. Recommendations for changes in hepatitis C health care policy in North Carolina prisons are also described.


Confirmation of the low clinical effect of human herpesvirus-6 and -7 infections after renal transplantation.
Human herpesvirus-6 and -7 (HHV-6 and HHV-7) may lead to pathological manifestations in renal transplant recipients. The aim of this study was to investigate beta-herpesvirus infections in 50 adult kidney transplant recipients after transplantation to examine the effect, interactions, and pathogenic consequences of infection and the effect of immunosuppressive regimens and Human cytomegalovirus (HCMV) prophylaxis with VACV. Beta-herpesviruses loads in the blood of 50 adult kidney transplant recipients over a 6-month period after transplantation and 198 blood donors were determined using polymerase chain reaction. The rate of HHV-6 detection in peripheral mononuclear cells (PBMCs) was higher in patients with end-stage renal disease and during the post-transplantation follow-up than in healthy subjects (33% and 68% vs. 12%, respectively). The detection rate of HHV-7 in PBMCs was similar between patients, both before grafting and during the follow-up for transplant recipients (69% and 88%, respectively), and healthy subjects (78%), and correlated with the number of lymphocytes. HCMV in plasma was detected only in patients during the post-transplant period (24%). VACV prophylaxis had no negative effect on the replication of HHV-6 or HHV-7, and univariate analyses demonstrated associations between HHV-6 infection and acute graft rejection [Odds ratio (OR) = 2.94, 95% confidence interval (CI), 1.05-8.2, P = 0.04], and between HHV-7 infection and cholestasis [OR = 2.61 (95% CI, 1.08-6.3), P = 0.03]. Immunosuppressive regimens had no effect on beta-herpesviruses infections. This study revealed the differing behavior of HCMV, HHV-6, and HHV-7 in kidney transplant recipients, and confirmed the association of HHV-6 with graft rejection.


Multiple craniofacial surgical interventions during 25 years of follow-up in a case of giant fibrous dysplasia. Case report.
Fibrous dysplasia may affect the jaws as a monostotic lesion which most often ceases to be active at the end of normal bone growth. In some cases there is no stabilization on completion of normal skeletal growth. This may lead to severe malformation and functional disturbance to the face. In these cases, the patient must be followed regularly and resection of the deformed tissue must be performed repeatedly as the recurrences appear. Attention is also brought to the fact that fibrous dysplasia may be difficult to separate from chronic sclerosing osteomyelitis, a condition that should be treated differently.


A review of microalgae biofilm as an eco-friendly approach to bioplastics, promoting environmental sustainability.
In this comprehensive review, we delve into the challenges hindering the large-scale production of microalgae-based bioplastics, primarily focusing on economic feasibility and bioplastic quality. To address these issues, we explore the potential of microalgae biofilm cultivation as a sustainable and highly viable approach for bioplastic production. We present a proposed method for producing bioplastics using microalgae biofilm and evaluate its environmental impact using various tools such as life cycle analysis (LCA), ecological footprint analysis, resource flow analysis, and resource accounting. While pilot-scale and large-scale LCA data are limited, we utilize alternative indicators such as energy efficiency, carbon footprint, materials management, and community acceptance to predict the environmental implications of commercializing microalgae biofilm-based bioplastics. The findings of this study indicate that utilizing microalgae biofilm for bioplastic production offers significant environmental sustainability benefits. The system exhibits low energy requirements and a minimal carbon footprint. Moreover, it has the potential to address the issue of wastewater by utilizing it as a carbon source, thereby mitigating associated problems. However, it is important to acknowledge certain limitations associated with the method proposed in this review. Further research is needed to explore and engineer precise techniques for manipulating microalgae biofilm structure to optimize the accumulation of desired metabolites. This could involve employing chemical triggers, metabolic engineering, and genetic engineering to achieve the intended goals. In conclusion, this review highlights the potential of microalgae biofilm as a viable and sustainable solution for bioplastic production. While acknowledging the advantages, it also emphasizes the need for continued synthetic studies to enhance the efficiency and reliability of this approach. By addressing the identified drawbacks and maximizing the utilization of advanced techniques, we can further harness the potential of microalgae biofilm in contributing to a more environmentally friendly and economically feasible bioplastic industry.


Lifestyle multidomain intervention, omega-3 supplementation, or both for reducing the risk of developing clinically relevant depressive symptoms in older adults with memory complaints? Secondary analysis from the MAPT trial.
We tested the associations of a lifestyle multidomain intervention (MI), omega-3 supplementation (O3) or their combination with the change of clinically meaningful depressive symptoms in older adults. Secondary analysis of the 3-year Multidomain Alzheimer Preventive Trial (MAPT), in which 1679 people, ≥70 years with memory complaints were randomized into: MI, O3, MI + O3, or placebo. MI was composed of nutritional and physical activity counselling and cognitive training. O3 supplementation corresponded to a daily dose of 1000 mg of omega-3. Discrete-time cox regressions were performed for each outcome. Three binary variables of incidence of depressive symptoms were created from the 15-item geriatric depression scale (GDS-15): minimum clinically meaningful depressive symptoms (≥2-point increase in GDS-15), moderate depressive symptoms (GDS-15 ≥ 5), and severe depressive symptoms (GDS-15 ≥ 10) DS. Discrete-time cox proportional hazards have found no associations for all of the analysis. The incidence of severe depressive symptoms across groups were, respectively: 1.1, 2.4, 2.3 and 2.5 per 100 person year for MI + O3, for O3, for MI, for placebo. There was a trend for a decreased risk of developing severe DS compared to placebo in the MI + O3 group (p = 0.085 after adjustment). To conclude, we did not find any association of a lifestyle multidomain intervention with the onset of clinically depressive symptoms in older adults with memory complaints. A study with a more intensive multidomain intervention might bring further insights on this topic.


Drastic reduction in the growth temperature of graphene on copper via enhanced London dispersion force.
London dispersion force is ubiquitous in nature, and is increasingly recognized to be an important factor in a variety of surface processes. Here we demonstrate unambiguously the decisive role of London dispersion force in non-equilibrium growth of ordered nanostructures on metal substrates using aromatic source molecules. Our first-principles based multi-scale modeling shows that a drastic reduction in the growth temperature, from ~1000°C to ~300°C, can be achieved in graphene growth on Cu(111) when the typical carbon source of methane is replaced by benzene or p-Terphenyl. The London dispersion force enhances their adsorption energies by about (0.5-1.8) eV, thereby preventing their easy desorption, facilitating dehydrogenation, and promoting graphene growth at much lower temperatures. These quantitative predictions are validated in our experimental tests, showing convincing demonstration of monolayer graphene growth using the p-Terphenyl source. The general trends established are also more broadly applicable in molecular synthesis of surface-based nanostructures.