Utilizing patient advocates in Parkinson's disease: A proposed framework for patient engagement and the modern metrics that can determine its success.
The wide application of patient engagement and its associated benefits has increased across government, academic and pharmaceutical research. However, neither an identified standard practice for the process of engagement, nor utilization of common metrics to assess associated outcomes, exists. Parkinson's Foundation developed a patient engagement framework and metrics to assess engagement within the academic research and drug development sectors. This approach was developed over the course of several years through assessing the literature, acquiring feedback from researchers and people with Parkinson's disease and adapting practices to be relevant and generalizable across patient engagement projects. This framework includes the: 1) creation of a scope of work, 2) establishment of guiding principles, 3) selection and training of participants, 4) co-determination of project metrics, 5) execution of the project and 6) dissemination of project findings. Parkinson's Foundation has also worked with academic, government and pharmaceutical stakeholders to identify metrics that assess both the quality of patient engagement and outcomes associated with patient engagement on projects. By improving patient engagement project methodologies and metrics, global clinical trials can have access to evidence-based patient engagement practices to more efficiently capture the needs of, and potentially benefit, the patient community.


Origin of the central pit in hemimicelles of semifluorinated alkanes: How molecular dipoles and substrate deformation can determine supra-molecular morphology.
Semifluorinated alkanes amphiphiles spontaneously form highly monodispersed hemimicelles at the surface of water. The origin of the formation and complex structure of these surprising supramolecular aggregates were only recently clarified using molecular dynamics simulations (MD). The existence of a pit at the center of these aggregates made up of almost 3000 molecules was indeed reproduced by the MD simulations, but not understood. A careful strategy of atomistic MD simulations comparing non-electrostatic force fields with force fields that include electrostatic forces, thus bearing an implicit or explicit dipole, allowed demonstrating the roles of dipolar interactions and interactions with the liquid subphase on the morphology of the aggregates. The simulation results clearly show that within the hemimicelles the strong molecular dipoles located at the CH2-CF2 junctions tend to align, leading to a collective shift of the PFAA molecules relatively to each other. This shift is responsible for the curvature of the hemimicelles and originates the central pit, provided the possibility of deforming the surface of the water sub-phase. Comparisons with non-electrostatic force field results further contribute to understand the origin of the self-assembling process. The results directly connect for the first time a molecular property with a mesoscopic structural feature. Given the molecular simplicity of these "primitive" amphiphiles compared to the common hydrophilic/hydrophobic surfactants, the results contribute to understand self-assembly in general.


Effectiveness of influenza vaccination in preventing influenza-like illness among community-dwelling elderly: population-based cohort study in Japan.
A population-based cohort study was conducted during the 2003-2004 season to examine the effectiveness of influenza vaccine among community-dwelling elderly. The subjects consisted of 4787 elderly, ranging from 65 to 79 years. We either interviewed the elderly directly or their families regarding acute febrile illness, hospital visits, hospitalization and death by telephone every month. The vaccination status and physician-diagnosed clinical influenza (hereinafter referred as clinical influenza) were determined based on data obtained from the city office and hospitals, respectively. Influenza-like illness (ILI) was defined as an acute febrile illness (> or = 38.5 degrees C) during the epidemic period. After adjusting for confounders, vaccination decreased ILI significantly (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.17-0.85), but not clinical influenza (OR, 0.76; 95% CI, 0.28-2.06). The results were inconclusive for preventing hospitalization for influenza or pneumonia (OR, 0.37; 95% CI, 0.09-1.47) and death (OR, 3.68; 95% CI, 0.75-18.12), due to the inadequate sample size. In conclusion, the influenza vaccination was thus found to be associated with a decreased ILI during the epidemic period in community-dwelling elderly.


Empirical study of an adaptive multiscale model for simulating cardiac conduction.
We modify and empirically study an adaptive multiscale model for simulating cardiac action potential propagation along a strand of cardiomyocytes. The model involves microscale partial differential equations posed over cells near the action potential upstroke and macroscale partial differential equations posed over the remainder of the tissue. An important advantage of the modified model of this paper is that, unlike our original model, it does not require perfect alignment between myocytes and the macroscale computational grid. We study the effects of gap-junctional coupling, ephaptic coupling, and macroscale grid spacing on the accuracy of the multiscale model. Our simulations reveal that the multiscale method accurately reproduces both the wavespeed and the waveform, including both upstroke and recovery, of fully microscale models. They also reveal that perfect alignment between myocytes and the macroscale grid is not necessary to reproduce the dynamics of a traveling action potential. Further, our simulations suggest that the macroscale grid spacing used in an adaptive multiscale model need not be much finer than the spatial width of an action potential. These results are demonstrated to hold under high, low, and zero gap-junctional coupling regimes.


Diminished femoral head-neck offset and the restricted hip range of motion suggesting a possible role in ACL injuries.
Femoroacetabular impingement may be associated with anterior cruciate ligament (ACL) injuries. The purpose of this study was to determine the head-neck offset, as measured by 45° Dunn's view alpha angles, in patients with ACL injuries compared to control subjects. In this retrospective study, 140 consecutive non-professional athletes with primary ACL ruptures confirmed with knee arthroscopy and 100 consecutive patients with non-ACL injury were enrolled. Hip range of motion was assessed in lower extremities in all participants, and alpha angle was calculated according to 45° Dunn's view radiographs. There is not any difference in age, gender distribution, height, weight, and BMI between groups. Internal rotation, abduction, and adduction of the hip were significantly decreased in ACL-injured patients comparing with control subjects (p < 0.001). ACL-injured patients had also a significantly higher alpha angle comparing to the control individuals (p < 0.001). The mean of alpha angle in the ACL-injured patients was 56.1 (SD 10.1) and in the non-ACL-injured group was 49.3 (SD 9.4). The patients in ACL-injured group showed a significant restriction in hip range of motion and also a diminished femoral head-neck offset suggesting a possible role of these findings in the outcome assessed. III.


Congenital atresia of the foramen of Monro.
Two cases of congenital atresia of the foramen of Monro are described, one 8 days old and the other 2 months old. Both are associated with a parieto-occipital paraventricular diverticulum and spontaneous ventriculostomy with the passing of the cerebrospinal fluid to the posterior fossa and the formation of a cyst in the supracerebella region which compressed and displaced the structures of the posterior fossa.


Effect of beta-blockers on heart failure severity in patients with heart failure with preserved ejection fraction: a meta-analysis of randomized controlled trials.
Patients with heart failure with preserved ejection fraction (HFpEF) are often elderly and likely to have cardiac comorbidities such as coronary artery disease (CAD) and atrial fibrillation (AF). The primary chronic symptom of HFpEF patients is severe exercise intolerance. The inability to adequately increase heart rate during exercise is commonly present in HFpEF patients and contributes to their exercise intolerance. Although beta-blockers are frequently used for the treatment of myocardial ischemia and tachycardia in HFpEF patients, there is a concern that slowing heart rate by beta-blockers may worsen chronotropic incompetence and further exacerbate their symptoms. Although the effect of beta-blockers on heart failure severity in HFpEF patients has been examined in randomized controlled trials (RCTs), results are inconsistent due partly to limited power. We aimed to conduct a meta-analysis of RCTs on the effect of beta-blockers on heart failure severity in HFpEF patients. The search of electronic databases identified 5 RCTs including 538 patients. In pooled analyses, beta-blockers did not significantly change the New York Heart Association (NYHA) class, exercise capacity expressed as metabolic equivalents, or plasma B-type natriuretic peptide (BNP) levels compared with control but with substantial heterogeneity across trials. In meta-regression analyses, the higher proportion of CAD or AF in the included trials was associated with a decrease in NYHA class and BNP levels and with an increase in exercise capacity. Thus, we found no clear beneficial effect of beta-blockers on heart failure severity in HFpEF patients. However, beta-blockers may be beneficial in HFpEF patients with CAD or AF.


Long-term outcome of inactive and active, low viraemic HBeAg-negative-hepatitis B virus infection: Benign course towards HBsAg clearance.
The difference between the long-term outcome of low-viraemic (HBV-DNA≤20 000-IU/mL, LV-AC) and inactive HBsAg carriers (HBV-DNA≤2000-IU/mL, IC) remains to be defined. We studied prospectively 153 HBeAg-negative HBsAg-carriers with baseline HBV-DNA≤20 000-IU/mL and normal transaminases. IC, LV-AC or chronic hepatitis B (CHB) (HBV-DNA persistently ≤2000-IU/mL, ≤20 000-IU/mL or >20 000-IU/mL respectively) were diagnosed after 1-year, 3-monthly monitoring. Thereafter IC and LV-AC were followed-up for additional 57.2 (8.5-158.3) months. HBV-DNA, HBsAg, HBV"core-related"Antigen (HBcrAg) and total-anti-HBc were quantified at baseline. After the 1st year diagnostic follow-up CHB [higher HBV-DNA (P=.005), total-anti-HBc (P=.012), ALT (P=.007) and liver-stiffness (P=.021)] was identified in 20 (13.1%) carriers; baseline HBsAg≤1000IU/HBV-DNA≤2000IU/mL excluded the presence of CHB (NPV-100%). Thereafter, during the long-term follow-up none of 87 IC reactivated, 19 (21.8%) cleared HBsAg [older-age (P=.004), lower HBsAg (P<.001), higher yearly HBsAg decline (P<.001)]. Twenty-five of 46 (54.3%) LV-AC remained stable, 20 (43.5%) became IC and 1 (2.2%) developed CHB. The best single-point CHB and IC diagnostic-accuracies were total-anti-HBc (84.2%, NPV-98.2%) and HBV-DNA/total-anti-HBc/HBcrAg combination (89.5%, 93%-sensitivity, 84.8%-specificity) respectively. Viraemia persistently ≤20 000-IU/mL predicts a benign clinical outcome: it was associated with transition to IC in 43% of LV-AC and to Occult HBV Infection in 20% of IC within 5-years. Nevertheless, 13.1% of individuals with low viraemia at presentation develops CHB within 1 year: 1-year HBV-DNA monitoring resulted the most accurate diagnostic approach that can be limited to at least a half of cases by the single point HBV-DNA/HBsAg quantification. The IC-diagnostic-accuracy combining HBV-DNA/total-anti-HBc/HBcrAg needs to be confirmed in further studies.


Resection of liver tumors: technical aspects.
The resection of primary and secondary liver tumors has become accepted as the only curative therapy that can be offered to patients with these cancers. Technical advances made over the last two decades have improved the ability of the surgeon to perform these procedures with decreased morbidity. This article reviews hepatic anatomy, the preoperative evaluation of patients and various technical aspects involved in liver resections. The latter includes the role of intraoperative ultrasound and techniques of vascular occlusion and hepatic parenchymal dissection.


Guanine nucleotides stimulate NADPH oxidase in membranes of human neutrophils.
In the chain of events by which chemotactic peptides stimulate NADPH oxidase-catalyzed superoxide formation in human neutrophils, the involvements of a pertussis toxin-sensitive guanine nucleotide-binding protein (N-protein), mobilization of intracellular calcium and protein kinase C stimulation have been proposed. Superoxide formation was studied in membranes from human neutrophils; NADPH oxidase was stimulated by arachidonic acid in the presence of neutrophil cytosol. Fluoride and stable GTP analogues, such as GTP gamma S and GppNHp, which all activate N-proteins, enhanced NADPH oxidase activity up to 4-fold. GDP beta S inhibited the effect of GTP gamma S. These data suggest that NADPH oxidase is regulated by an N-protein, independent of an elevation of the cytoplasmic calcium concentration.


Does treatment affect the levels of serum interleukin-6, interleukin-8 and procalcitonin in diabetic foot infection? A pilot study.
To investigate about serum PCT, IL-6 and IL-8 levels and how they are affected by the treatment in diabetic foot patients. Fifty patients' blood samples were taken to study ESR and CRP, IL-6, IL-8 and PCT before and at the 14th day of the treatment. The pretreatment results of the 50 patients showed positive correlations between PCT and either ESH (r=0.49, p<0.001), or CRP (r=0.56, p<0.001). Similarly, there was a positive correlation between IL-6 and ESH (r=0.46, p=0.001), just like as it was between IL-6 and CRP (r=0.54, p<0.001). At the 14th day, the levels of ESR (70 ± 30.2 and 58.4 ± 26.2, p=0.02), CRP (63.8 ± 73.1 and 18.1 ± 19.7, p<0.001) and PCT (0.6 ± 2.1 and 0.05 ± 0.02, p=0.007) were significantly decreased while IL-6 was decreased at a close range to statistical significancy at healing patients (97.5 ± 147.2 and 47.1 ± 77.6; p=0.05), but they did not at nonhealing patients. IL-8 levels were not changed anyhow. PCT was significantly decreased such as ESR and CRP were in the early phase of healing; IL-6 and IL-8 levels were also decreased by the treatment, but not statistically significantly. IL-6 and PCT were affected in correlation with the other inflammatory parameters in the beginning, but IL-8 was not. PCT and IL-6 may be useful like CRP and ESR in the diagnosis and follow up of diabetic foot infection, but IL-8 is not. Further investigation is needed.


Inhibitor screening of proprotein convertases using positional scanning libraries.
Proprotein convertases represent an important class of biosynthetic enzymes that are increasingly viewed as targets for therapeutic approaches to infection, cancer, and potentially endocrine disorders. The identification of potent inhibitors can be accomplished by screening synthetic combinatorial libraries containing thousands of small molecules to millions of peptides. In this chapter, the screening of positional scanning libraries is described for the identification of PC1/3 and PC2 inhibitors.


Oral supplementation of nicotinamide riboside alters intestinal microbial composition in rats and mice, but not humans.
The gut microbiota impacts systemic levels of multiple metabolites including NAD+ precursors through diverse pathways. Nicotinamide riboside (NR) is an NAD+ precursor capable of regulating mammalian cellular metabolism. Some bacterial families express the NR-specific transporter, PnuC. We hypothesized that dietary NR supplementation would modify the gut microbiota across intestinal sections. We determined the effects of 12 weeks of NR supplementation on the microbiota composition of intestinal segments of high-fat diet-fed (HFD) rats. We also explored the effects of 12 weeks of NR supplementation on the gut microbiota in humans and mice. In rats, NR reduced fat mass and tended to decrease body weight. Interestingly, NR increased fat and energy absorption but only in HFD-fed rats. Moreover, 16S rRNA gene sequencing analysis of intestinal and fecal samples revealed an increased abundance of species within Erysipelotrichaceae and Ruminococcaceae families in response to NR. PnuC-positive bacterial strains within these families showed an increased growth rate when supplemented with NR. The abundance of species within the Lachnospiraceae family decreased in response to HFD irrespective of NR. Alpha and beta diversity and bacterial composition of the human fecal microbiota were unaltered by NR, but in mice, the fecal abundance of species within Lachnospiraceae increased while abundances of Parasutterella and Bacteroides dorei species decreased in response to NR. In conclusion, oral NR altered the gut microbiota in rats and mice, but not in humans. In addition, NR attenuated body fat mass gain in rats, and increased fat and energy absorption in the HFD context.


Sustained Low Incidence of Severe and Fatal COVID-19 Following Widespread Infection Induced Immunity after the Omicron (BA.1) Dominant in Gauteng, South Africa: An Observational Study.
We conducted an epidemiologic survey to determine the seroprevalence of SARS-CoV-2 anti-nucleocapsid (anti-N) and anti-spike (anti-S) protein IgG from 1 March to 11 April 2022 after the BA.1-dominant wave had subsided in South Africa and prior to another wave dominated by the BA.4 and BA.5 (BA.4/BA.5) sub-lineages. We also analysed epidemiologic trends in Gauteng Province for cases, hospitalizations, recorded deaths, and excess deaths were evaluated from the inception of the pandemic through 17 November 2022. Despite only 26.7% (1995/7470) of individuals having received a COVID-19 vaccine, the overall seropositivity for SARS-CoV-2 was 90.9% (95% confidence interval (CI), 90.2 to 91.5) at the end of the BA.1 wave, and 64% (95% CI, 61.8 to 65.9) of individuals were infected during the BA.1-dominant wave. The SARS-CoV-2 infection fatality risk was 16.5-22.3 times lower in the BA.1-dominant wave compared with the pre-BA.1 waves for recorded deaths (0.02% vs. 0.33%) and estimated excess mortality (0.03% vs. 0.67%). Although there are ongoing cases of COVID-19 infections, hospitalization and death, there has not been any meaningful resurgence of COVID-19 since the BA.1-dominant wave despite only 37.8% coverage by at least a single dose of COVID-19 vaccine in Gauteng, South Africa.


Choroidal blood flow in diabetic retinopathy.
The ocular hemodynamics in diabetic patients with increasingly severe retinopathy have been evaluated using a non-invasive computerized methodology. In a group of 19 healthy volunteers the mean ophthalmic arterial pressure and the ocular pulsatile blood flow were 83 +/- 2.4 mmHg and 648 +/- 42 microliters min-1 respectively. Nine diabetics with no apparent retinopathy had ophthalmic pressures and pulsatile blood flows similar to those in the control subjects. In 11 diabetic patients with background retinopathy the mean pulsatile blood flow was 471 +/- 70 microliters min-1. Thirteen diabetics with proliferative retinopathy had a pulsatile blood flow of 210 +/- 37 microliters min-1 and abnormally low ophthalmic arterial pressures. The results provide evidence that the choroidal blood flow decreases with the severity of the retinopathy in diabetes due to increased vascular resistance and a decreased ocular perfusion pressure.


Assessing the pollution level of a subtropical lake by using a novel hydrogen sulfide fluorescence technology.
Hydrogen sulfide (H2S) is an important environmental toxin with bi-directional biological effects on organisms. In natural waters, H2S complexes with heavy metal ions in an anaerobic environment influence heavy metals' bioavailability and induce phosphorus release and eutrophication in water columns. Traditional detection techniques, such as colorimetric, electrochemical, and chromatographic, cannot simultaneously detect H2S and pollution assessment of subtropical lakes. To address these technical defects, we developed small-molecule fluorescent probes to evaluate the pollution level in natural water bodies. This method relies on the combination of the probes' response signals to raw water and the water quality index, thereby enhancing the accuracy and reliability of water quality assessments. Furthermore, this novel material has a large Stokes shift. It can detect complex levels of H2S concentrations in natural water bodies by correlating the degree of contamination and fluorescence signals. The development of this visual research tool for detecting environmental H2S levels in natural water bodies is expected to have meaningful, practical applications.


From GWAS variant to function: A study of ∼148,000 variants for blood cell traits.
Genome-wide association studies (GWASs) have identified hundreds of thousands of genetic variants associated with complex diseases and traits. However, most variants are noncoding and not clearly linked to genes, making it challenging to interpret these GWAS signals. We present a systematic variant-to-function study, prioritizing the most likely functional elements of the genome for experimental follow-up, for >148,000 variants identified for hematological traits. Specifically, we developed VAMPIRE: Variant Annotation Method Pointing to Interesting Regulatory Effects, an interactive web application implemented in R Shiny. This tool efficiently integrates and displays information from multiple complementary sources, including epigenomic signatures from blood-cell-relevant tissues or cells, functional and conservation summary scores, variant impact on protein and gene expression, chromatin conformation information, as well as publicly available GWAS and phenome-wide association study (PheWAS) results. Leveraging data generated from independently performed functional validation experiments, we demonstrate that our prioritized variants, genes, or variant-gene links are significantly more likely to be experimentally validated. This study not only has important implications for systematic and efficient revelation of functional mechanisms underlying GWAS variants for hematological traits but also provides a prototype that can be adapted to many other complex traits, paving the path for efficient variant-to-function (V2F) analyses.


Slovenian experience from diagnostic angiography to interventional radiology.
The purpose of writing this article is to document the important events and people in the first 50 years of diagnostic angiography and interventional radiology in Slovenia. During this period not only did the name of the institutions and departments change, but also its governance. This depicted the important roles different people played at various times in the cardiovascular divisions inside and outside of the diagnostic and interventional radiology. Historical data show that Slovenian radiology has relatively immediately introduced the new methods of interventional radiology in clinical practice.


Bone Substitute Effect on Vascularization and Bone Remodeling after Application of phVEGF165 Transfected BMSC.
VEGF (vascular endothelial growth factor) promotes vascularization and remodeling of bone substitutes. The aim of this study was to examine the effect of distinct resorbable ceramic carriers on bone forming capacities of VEGF transfected bone marrow stromal cells (BMSC). A critical size defect of the radius in rabbits was filled either by a low surface scaffold called beta-TCP (tricalciumphsphate) or the high surface scaffold CDHA (calcium deficient hydroxy-apatite) loaded with autologous BMSC, which were either transfected with a control plasmid or a plasmid coding for phVEGF165. They were compared to unloaded scaffolds. Thus, six treatment groups (n = 6 in each group) were followed by X-ray over 16 weeks. After probe retrieval, the volume of new bone was measured by micro-CT scans and vascularization was assessed in histology. While only minor bone formation was found in both carriers when implanted alone, BMSC led to increased osteogenesis in both carriers. VEGF promoted vascularization of the scaffolds significantly in contrast to BMSC alone. Bone formation was increased in the beta-TCP group, whereas it was inhibited in the CDHA group that showed faster scaffold degradation. The results indicate that the interaction of VEGF transfected BMSC with resorbable ceramic carrier influences the ability to promote bone healing.


[The treatment and rehabilitation characteristics of osteoarthritis patients undergoing mineral baths, underwater horizontal traction of the legs and therapeutic gymnastics].
Balneotherapy, balneotraction therapy, balneokinesotherapy and balneotraction kinesotherapy in weak radon nitrogen mineral water (Tskhaltubo springs) were compared for efficacy in patients suffering from osteoarthritis of large joints stage I-IV with synovitis. Balneotraction was found most adequate. Balneotherapy is also beneficial, whereas balneokinesotherapy is indicated only in the second half of the treatment course.


Obstructive sleep apnea and inflammation.
The pathogenesis of cardiovascular complications in obstructive sleep apnea syndrome (OSAS) is not fully understood but is likely multifactorial in origin. Inflammatory processes play an important role in the pathogenesis of atherosclerosis, and circulating levels of several markers of inflammation have been associated with future cardiovascular risk. These include cell adhesion molecules such as intercellular adhesion molecule-1 and selectins, cytokines such as tumour necrosis factor alpha and interleukin 6, chemokines such as interleukin 8, and C-reactive protein. There is also increasing evidence that inflammatory processes play an important role in the cardiovascular pathophysiology of OSAS and many of the inflammatory markers associated with cardiovascular risk have been reported as elevated in patients with OSAS. Furthermore, animal and cell culture studies have demonstrated preferential activation of inflammatory pathways by intermittent hypoxia, which is an integral feature of OSAS. The precise role of inflammation in the development of cardiovascular disease in OSAS requires further study, particularly the relationship with oxidative stress, metabolic dysfunction, and obesity.


6-PGD types in the Polish population.
6-PGD types were examined in 467 adult, nonrelated subjects, inhabiting various regions of Poland. In the investigated sample three phenotypes were encountered: A, AB and B, having the following frequencies: 0.9191, 0.0878 and 0.0021, respectively. Frequencies of determining genes were calculated from distribution of the phenotypes with the following results: 6-PGDA = 0.954, 6-PGDB = 0.046.


Pathways of care the first year after moderate and severe traumatic brain injury-discharge destinations and outpatient follow-up.
To determine the pathways of care within the first year after traumatic brain injury (TBI) and to explore whether provided care is related to residual impairments. Retrospective study of 343 patients with moderate and severe TBI admitted to a Level-1 trauma centre. Discharge destinations from hospital to home and frequency of outpatient visits were determined. Outcome was defined 1 year after injury by the Extended Glasgow Outcome Scale and Return to Work. Most (94%) patients had returned home 1-year after injury despite cognitive (76%), behavioural (67%) and physical (55%) impairments. One in four patients was severely disabled and 32% had resumed work on a previous level. Two-thirds of all patients went home as secondary discharge destination and 50% needed inpatient rehabilitation. Almost half of patients needed outpatient care, mostly for behavioural and cognitive impairments. One in 10 patients consulted a psychiatrist, with 55% unfavourable outcome. Of those patients initially discharged to home without follow-up, eventually 10% needed outpatient rehabilitation. One-year after injury most patients had returned home with residual impairments and frequent medical consultations. This finding warrants further investigation to define appropriate aftercare by various medical specialists aimed at long-term community integration.


Technical Note: Impact of impurities on Yttrium-90 glass microsphere activity quantitation.
Glass 90 Y microspheres are produced with known radionuclide impurities. These impurities are not independently monitored. Clinical instruments, including ionization chamber dose calibrators and positron emmission tomography (PET) cameras, can be much more sensitive in detecting signals from these impurities than to signals from 90 Y itself. The "typical" levels of 90 Y impurities have been studied to assess their impact on dosimetry during internal implantation, and for the management of waste. However, unaccounted-for decay spectra of impurities can also have an impact on dose calibrator and PET readings. Thus, even what might be considered negligibly small impurity fractions, can in principle cause substantial overestimates of the amount of 90 Y activity present in a sample. To our knowledge, quantitative effects of radionuclide impurities in glass microspheres on activity measurements have not been documented in the field. As activity quantitation for dosimetry and its correlations with outcome becomes more prevalent, the effects of impurities on measurements may remain unaccounted for in dosimetry studies. In this letter, we review theoretical and physical considerations that will result in asymmetric errors in quantitation from 90 Y impurities and estimate their typical and potential impact on clinical utilization. Among the common impurities 88 Y is of particular concern for its impact on 90 Y dose measurements because of its decay characteristics, along with other isotopes 91 Y and 46 Sc which can also impact measurements. The typical level of 88 Y impurities reported by the manufacturer should only cause small errors in dose calibrator and PET measurements made within the 12-day label-specified use-by period, up to 2.0% and 1.6%, respectively. However, the product specification max allowable impurity levels, specified by the manufacturer, leave open the potential for much greater bias from within the 12-day use-by period, potentially as high as 13.2% for dose calibrator measurements and 10.6% for PET from the 88 Y impurities. While typical levels of impurities appear to have acceptable impact on patient absorbed dose, it should be noted that they can have adverse effects on 90 Y radioactivity measurements. Furthermore, there is currently minimal independent verification and/or monitoring of impurity levels within the field.


Right heart and pulmonary thromboembolism from extensive splanchnic vein thrombosis after splenectomy for myeloproliferative disease.
Splenectomy is a risk factor for both portal-vein and chronic thromboembolic pulmonary hypertension. The underlying mechanism is unclear, but may involve a hypercoagulable state. We describe 1 patient with polycythemia vera who developed extensive portal thrombosis of the portal, suprahepatic, and inferior cava veins, leading to right heart thromboembolism, with a resultant pulmonary embolism subsequent to splenectomy despite heparin prophylaxis. In this patient, several mechanisms may have played a role, including perioperative stress, thrombocytosis, thrombophilia, and associated chronic liver disease. Nevertheless, combined treatment with intravenous heparin and thrombolysis and the myeloproliferative inhibitor hydroxyurea was associated with a favorable outcome. The risk of pulmonary thromboembolic complications and their management after splenectomies for hematologic disease warrant further study.


Classical MHC expression by DP thymocytes impairs the selection of non-classical MHC restricted innate-like T cells.
Conventional T cells are selected by peptide-MHC expressed by cortical epithelial cells in the thymus, and not by cortical thymocytes themselves that do not express MHC I or MHC II. Instead, cortical thymocytes express non-peptide presenting MHC molecules like CD1d and MR1, and promote the selection of PLZF+ iNKT and MAIT cells, respectively. Here, we report an inducible class-I transactivator mouse that enables the expression of peptide presenting MHC I molecules in different cell types. We show that MHC I expression in DP thymocytes leads to expansion of peptide specific PLZF+ innate-like (PIL) T cells. Akin to iNKT cells, PIL T cells differentiate into three functional effector subsets in the thymus, and are dependent on SAP signaling. We demonstrate that PIL and NKT cells compete for a narrow niche, suggesting that the absence of peptide-MHC on DP thymocytes facilitates selection of non-peptide specific lymphocytes.


Long-term follow-up of a prospective phase 2 clinical trial of extended treatment with rituximab in patients with B cell post-transplant lymphoproliferative disease and validation in real world patients.
The purpose of this report is to provide long-term follow-up of 38 patients diagnosed of post-transplant lymphoproliferative disease (PTLD) included in a phase 2 clinical trial of first line therapy with rituximab and to evaluate the same therapy in a real world cohort of 21 consecutive patients treated once the trial was closed. Eligible patients were ≥ 18 years of age with a biopsy-proven CD20 positive B cell PTLD and treatment naive except for reduction of immunosuppression. Treatment consisted in four weekly infusions of rituximab at the standard dose of 375 mg/m2. Patients in complete remission (CR) were followed without further treatment, and those in partial remission (PR) were treated with another four cycles of weekly rituximab. Median follow-up in the clinical trial was 13.0 years. Disease-specific survival (DSS) at 10 years was 64.7% [95% confidence interval (CI) 48.2-81.2%]. For those patients who achieved CR (61%), DSS at 5 and 10 years was 94.4% (95% CI 83.8-100%) and 88.1% (95% CI 72.6-100%), respectively, and only 1 patient progressed beyond 5 years. The median follow-up of the real world patients was 6.5 years. DSS at 5 years was 75.2% (95% CI 56.4-94.0%). DSS at 5 years of patients who achieved CR (38%) was 87.5% (95% CI 64.6-100%). In conclusion, PTLD patients in CR after rituximab have an excellent long-term outcome. These results not only apply in the clinical trial setting but are also reproducible in the real world. However, those patients who do not respond represent an unmet clinical need and should be included in prospective clinical trials.


Lumevis ™: a new medical device to prepare patients for esophagogastroduodenoscopy. Experimental clinical study.
Esophagogastroduodenoscopy (EGDS) is the gold standard exam for upper gastrointestinal diseases. EGDS is very important in Early Gastric Cancer diagnosis and treatment but it is an operator-dependent exam and there are lots of factors that reduce its visibility (mucus, bubbles and foam). The aim of our study is to evaluate if the use of Lumevis™ improves mucosa visualization during EGDS without increasing the examination time and complications' rate and comparing the differences in patients prepared with water or no intervention. we recruited 50 patients from 01/08/2020 to 31/08/2020 who came to our observation for epigastric pain, dyspepsia and gastroesophageal reflux (GERD). For each patient we evaluate the satisfaction of the procedure, vision quality, EGDS duration and the presence of bubbles following the administration of: nothing (group 1); 50 ml of water alone (W) (group 2); W + simethicone (S) 150 mg+N-acetylcysteine (NAC) 250 mg+10% acetic acid 2.5 ml (group 3); W+S 100 mg + NAC 300 mg + 10% acetic acid 2 ml (group 4); W + S 100 mg + NAC 200 mg + 10% acetic acid 1.5 ml (group 5). Our results suggest that the lesion detection rate improves with the use of simethicone, acetylcysteine and acetic acid prior to EGDS, although this needs to be studied prospectively. Lumevis™ is proposed as a new product in the routine preparation of all patients who have to undergo an EGDS, raising the level in the quality of the exam.


Species differences in sodium o-phenylphenate induction of urinary bladder lesions.
The effects of sodium o-phenylphenate (Na-OPP) treatment on urinary bladder epithelium were examined in male F344 rats, B6C3F1 mice, Syrian golden hamsters and Hartley guinea pigs. Na-OPP was incorporated into diet at a dose of 2% and administered for 4, 8, 12, 24, 36 or 48 weeks. Simple and papillary or nodular (PN) hyperplasias were evident on light microscopy and pleomorphic microvilli demonstrated by scanning electron microscopy were only observed in rats, the lesions becoming more advanced with continued chemical feeding. In mice, hamsters and guinea pigs, proliferative lesions relating to Na-OPP administration were not observed. No significant differences in urinary pH, osmolality or crystal formation were apparent between the various animal species. Since carcinogenicity has been demonstrated for Na-OPP in rats but not in mice, the present findings suggest that Na-OPP might not exert urinary bladder carcinogenic potential in hamsters and guinea pigs.


IgG4 paratesticular fibrous pseudotumor: Case presentation and literature review.
PFP with IgG-4 immunostaining is a rare paratesticular tumour. Pre-operative ultrasound scan and MRI usually confirm the benign nature of the paratesticular mass avoiding the need for radical orchiectomy. The final diagnosis is based on histology of the removed paratesticular tumour. FDG PET scan plays an important role in ruling out systematic IgG4-related disease (IgG4-RD). We describe a case of multiple paratesticular fibrous pseudotumors with IgG4 immunostaining, not associated with systemic IgG4 related disease.


Usefulness of the daily defined dose method to estimate trends in the consumption, costs and prevalence of the use of home enteral nutrition.
To analyse the trends in consumption and costs of home enteral nutrition (HEN) products in Andalusia (Spain) and estimate the prevalence of HEN from 2000 to 2007. Using the defined daily dose (DDD) method, we assigned a DDD to each type of diet, grouped as whole diets, supplements, modules and thickeners. The number of cases/10(6) inhabitants/day (CID) was calculated. The number of persons receiving HEN rose notably, from 66.4 CID in 2000 to 1315.4 in 2007. The number of persons with home enteral tube feeding has remained stable since 2003, at around 220 CID. HEN with oral nutritional supplements (ONS) increased exponentially, with a prevalence of 910 CID in 2007. The prevalence of HEN in 2007 was similar to that of other European countries. The costs associated with HEN rose from 1.3 million euros in 2000 to over 37 million euros in 2007, due to the progressive increase in the number of persons being prescribed HEN, especially ONS, and the incorporation of more expensive organ-specific formulas. DDD is useful to indirectly estimate the prevalence of HEN and evaluate long-term trends in the prescription and costs of various HEN products.


Risk of peritonitis and fatal septicaemia and the need to defunction the low anastomosis.
The aim of this study was to investigate the need to defunction the low anastomosis after anterior resection of the rectum with total mesorectal excision for rectal cancer. Two hundred consecutive patients (125 defunctioned, 75 non-defunctioned) undergoing low anterior resection for carcinoma were included in the study. Peritonitis requiring emergency laparotomy occurred in 8 per cent of the patients who did not have a defunctioning stoma compared with less than 1 per cent of those patients who had a defunctioning stoma (P less than 0.01). There was no mortality related to closure of the stoma but seven patients developed a faecal fistula and ten developed an incisional hernia. Despite current trends to avoid the defunctioning stoma, these results suggest that after total mesorectal excision the faecal stream should be temporarily diverted away from the anastomosis that is 6 cm or less from the anal verge to protect against potentially life-threatening anastomotic leakage.


Effects of 35% hydrogen peroxide solution containing hydrated calcium silicate on enamel surface.
The objectives of this study were to develop a novel bleaching material containing hydrated calcium silicate (hCS) particles and investigate the effects of hCS on the bleaching efficacy, microhardness, and surface morphology of bovine enamel. To prepare the hCS particles, white Portland cement was mixed with distilled water and ground into a fine powder. The particles in various proportions were then mixed with 35% hydrogen peroxide solution (HP), while HP without hCS was used as a control (HP), and teeth whitening gel was used as a commercial control (CC). Following the thrice application of experimental and control solutions on the discolored bovine enamel surface for 15 min, color change (n = 10), microhardness (n = 10), and micromorphology (n = 2) of the enamel surface were analyzed. The Δ E* of the enamel surface treated with the experimental solution containing hCS was significantly higher than that of the CC, but there were no significant differences between the different hCS contents. The experimental solution containing hCS reduced the percentage of microhardness loss on the enamel surface, and the percentage of microhardness loss significantly decreased as the content of hCS increased (p < 0.05). The erosion pattern was only observed on enamel surfaces treated with HP and CC. This study suggests that HP containing hCS is effective in bleaching efficacy. In addition, hCS could also minimize the microhardness loss of tooth structure caused by HP and maintain enamel surface morphology. This novel bleaching material is promising for inhibiting demineralization and promoting the remineralization of teeth during bleaching treatment in dental clinics.


Effect of hairy vetch cover crop on maize nitrogen supply and productivity at varying yield environments in Southern Brazil.
Cover crops play a critical role on conservation and sustainable agriculture due to their well-documented benefits on both soil and crop productivity. Inclusion of legumes (e.g., hairy vetch, Vicia villosa Roth) in the farming system can reduce the nitrogen (N) fertilizer needs for cereals such as maize (Zea mays L.) crop while maintaining or increasing its productivity. The aims of this research study were to quantify the effect of hairy vetch as a cover crop on: i) successor maize yield under varying yield environments (YEs) and fertilizer N rates, and ii) maize N status [N uptake, N nutritional index (NNI), and N fertilizer replacement value (NFRV)] at flowering time. Two field studies were carried out in Southern Brazil under varying YEs. The factors investigated were: YE (low, medium, and high), hairy vetch cover crop (with and without), and fertilizer N rate (0, 60, 120, 180, and 240 kg N ha-1). Under the combination of low YE and low fertilizer N rates (0-60 kg ha-1) with previous vetch, maize displayed the largest yield response and an improvement in its N status. The NNI determined at maize flowering was an efficient index of the vetch effect, increasing delta maize yield response (yield with- minus without-vetch) as the NNI reduced, with more than 10% delta yield response with NNI below 0.85. The NFRV of the hairy vetch represents potential N savings of 151 kg N ha-1 for the LYE, 95 kg N ha-1 for the MYE and from 59 to 45 kg N ha-1 for the HYE depending on the tested fertilizer N rate. The N coming from the legume cover crop in addition to the N fertilization was critical for supplying N to maize and boosting productivity across all YEs.


Clinical outcomes of polymer-free, paclitaxel-coated stents vs stent grafts in peripheral arterial disease patients with femoropopliteal artery lesions.
Zilver PTX polymer-free, paclitaxel-coated stents and Viabahn stent grafts are effective for the treatment of femoropopliteal lesions. The aim of this study was to compare clinical outcomes between the two devices in patients with symptomatic peripheral arterial disease in real-world settings. This multicenter, retrospective study concerned a clinical database of 445 patients with symptomatic peripheral arterial disease (Rutherford categories 1-6) who underwent either Zilver PTX or Viabahn implantation for a femoropopliteal lesion of 10 cm or longer with reference vessel diameters of 4.0 to 7.5 mm between 2012 and 2018 at five hospitals in Japan. Outcome measures were primary patency, freedom from stent thrombosis, freedom from any target lesion reintervention, limb salvage, and overall survival. After propensity score matching, these clinical outcomes were compared between patients treated with the Zilver PTX and those treated with the Viabahn. Also assessed were the interaction effects of baseline characteristics on the association of the Zilver PTX and Viabahn with restenosis and stent thrombosis. In total, 271 patients were treated with the Zilver PTX, and 174 patients were treated with the Viabahn. Propensity score matching extracted 133 patient pairs with no major intergroup differences in baseline characteristics. The Zilver PTX group had a lower rate of 3-year primary patency (59.5%; [95% confidence interval (CI), 53.0%-66.2%] vs 69.6% [95% CI, 59.3%-79.4%]; P = .005), but a higher rate of 3-year freedom from stent thrombosis (93.6% [95% CI, 90.0%-96.3%] vs 82.4% [95% CI, 74.5%-89.0%], P = .038). There was no significant difference in overall survival, limb salvage, or freedom from reintervention (all P > .05). An interaction analysis showed that the restenosis risk of the Zilver PTX was significantly higher vs the Viabahn in patients with no or one below-the-knee runoff vessel and in those with intravascular ultrasound use than in patients with two or three below-the-knee runoff vessels and in those without intravascular ultrasound use, respectively (P for interaction = .046 and .010, respectively), whereas the stent thrombosis risk of the Zilver PTX was significantly smaller vs the Viabahn in patients not on dialysis than in those on dialysis (P for interaction = .034). Compared with Viabahn stent grafts, Zilver PTX stents have a lower rate of primary patency but a higher rate of freedom from stent thrombosis.


Effect of potent endomorphin degradation blockers on analgesic and antidepressant-like responses in mice.
The biological effects of endomorphins (EMs) are short-lasting due to their rapid degradation by endogenous enzymes. Competing enzymatic degradation is an approach to prolong EM bioavailability. In the present study, a series of tetra- and tripeptides of similar to EMs structure was synthesized and tested in vitro and in vivo for their ability to inhibit degradation of EMs. The obtained results indicated that, among the series of analogs, the tetrapeptide Tyr-Pro-d-ClPhe-Phe-NH(2) and the tripeptide Tyr-Pro-Ala-NH(2), which did not bind to the μ-opioid receptors, were potent inhibitors of EM catabolism in rat brain homogenate. In vivo, these two peptides significantly prolonged the analgesic and antidepressant-like effects, induced by exogenous EMs, by blocking EM degrading enzymes. These new potent inhibitors may therefore increase the level and the half life of endogenous EMs and could be used in a new therapeutic strategy against pain and mood disorders, based on increasing of EM bioavailability.


Cytotoxicity and genotoxicity of nanosilver in stable GADD45α promoter-driven luciferase reporter HepG2 and A549 cells.
The intense commercial application of silver nanoparticles (AgNPs) has been raising concerns about their potential adverse health effects to human. This study aimed to explore the potency of AgNPs to induce GADD45α gene, an important stress sensor, and its relationships with the cytotoxicity and genotoxicity elicited by AgNPs. Two established HepG2 and A549 cell lines containing the GADD45α promoter-driven luciferase reporter were treated with increasing concentrations of AgNPs for 48 hours. After the treatment, transcriptional activation of GADD45α indicated by luciferase activity, cell viability, cell cycle arrest, and levels of genotoxicity were determined. The uptake and intracellular localization of AgNPs, cellular Ag doses as well as Ag+ release were also detected. AgNPs could activate GADD45α gene at the transcriptional level as demonstrated by the dose-dependent increases in luciferase activity in both the reporter cells. The relative luciferase activity was greater than 12× the control level in HepG2-luciferase cells at the highest concentration tested where the cell viability decreased to 17.0% of the control. These results was generally in accordance with the positive responses in cytotoxicity, cell cycle arrest of Sub G1 and G2/M phase, Olive tail moment, micronuclei frequency, and the cellular Ag content. The cytotoxicity and genotoxicity of AgNPs seems to occur mainly via particles uptake and the subsequent liberation of ions inside the cells. And furthermore, the GADD45α promoter-driven luciferase reporter cells, especially the HepG2-luciferase cells, could provide a new and valuable tool for predicting nanomaterials genotoxicity in humans.


Problems with repeated arthroscopic surgery in the discoid meniscus.
To identify the main causes of repeated arthroscopic surgery of the knee joint and to find out the points of therapeutic approaches, we evaluated 139 patients who underwent arthroscopic meniscectomy in our department and in affiliated hospitals between 1983 and 1987. Two or more arthroscopic surgeries were needed in 9 knees of 8 patients (6.5%). In 5 knees with no known injuries, the primary reason for repeated surgery was horizontal tears of remnant meniscus after partial resection of lateral discoid meniscus. The most appropriate initial treatment for lateral discoid menisci in cases without tear should be observation of the clinical course with minimal treatment using diagnostic arthroscopy.


Draft genome sequence data of Rhodosporidium toruloides VN1, a strain capable of producing natural astaxanthin.
Rhodosporidium toruloides strain VN1 is of special interest because of its capability for high astaxanthin production. Here, we report the draft genome sequence of R. toruloides VN1, which comprises 20.01 Mb in 424 contigs with an overall G + C content of 61.8%. This whole-genome shotgun project has been deposited at DDBJ/EMBL/GenBank under the accession number SJTE00000000.


A Newton-like iterative method implemented in the DelPhi for solving the nonlinear Poisson-Boltzmann equation.
DelPhi is a popular scientific program which numerically solves the Poisson-Boltzmann equation (PBE) for electrostatic potentials and energies of biomolecules immersed in water via finite difference method. It is well known for its accuracy, reliability, flexibility, and efficiency. In this work, a new edition of DelPhi that uses a novel Newton-like method to solve the nonlinear PBE, in addition to the already implemented Successive Over Relaxation (SOR) algorithm, is introduced. Our tests on various examples have shown that this new method is superior to the SOR method in terms of stability when solving the nonlinear PBE, being able to converge even for problems involving very strong nonlinearity.


5-Aza-2-deoxycytidine alleviates the progression of primary biliary cholangitis by suppressing the FoxP3 methylation and promoting the Treg/Th17 balance.
Primary biliary cholangitis (PBC) is a common autoimmune liver disease manifested by the infiltration of CD4+ T cells, and the subsequent targeted injury of biliary epithelial cells (BECs). As important components of CD4 subsets, the Treg/Th17 axis maintains an immunological balance between self-tolerance and inflammation in the liver microenvironment. However, the role and regulatory mechanism of the Treg/Th17 axis in PBC remain unclear. In this study, we examined the Treg/Th17 axis in PBC patients and found that the Treg/Th17 axis was imbalanced in PBC at both the transcriptional and cellular levels, with Treg being a weak candidate, which correlates with the PBC progression. This imbalanced Treg/Th17 axis was likely to be affected by the FoxP3 hypermethylation, which was related to the increase of DNA methyltransferase. Furthermore, the effect of 5-Aza-2-deoxycytidine (DAC)-mediated FoxP3 demethylation on PBC mice was investigated. We verified that DAC significantly suppressed the FoxP3 methylation and rebuilt the Treg/Th17 balance, resulting in the alleviation of liver lesions and inflammation. Taken together, our data indicate that DAC plays a positive role in alleviating the progression of PBC through the inhibition of DNA methylation of FoxP3 to rebuild the balanced Treg/Th17 axis. DAC could be considered as a potential candidate for the development of new anti-inflammation strategies in the treatment of PBC.


Correction to: Transmission of the frequency components of the vibrational signal of the glassy-winged sharpshooter, Homalodisca vitripennis, within and between grapevines.
Unfortunately, Fig. 3 was incorrectly published in the original publication. The correct version of Fig. 3 is updated here.


Ca2+ homeostasis in permeabilized human neutrophils. Characterization of Ca2+-sequestering pools and the action of inositol 1,4,5-triphosphate.
The regulation of Ca2+ transport by intracellular compartments was studied in digitonin-permeabilized human neutrophils, using a Ca2+-selective electrode. When incubated in a medium containing ATP and respiratory substrates, the cells lowered within 6 min the ambient [Ca2+] to a steady state of around 0.2 microM. A vesicular ATP-dependent and vanadate-sensitive non-mitochondrial pool maintained this low [Ca2+] level. In the absence of ATP, a higher Ca2+ steady state of 0.6 microM was seen, exhibiting the characteristics of a mitochondrial Ca2+ "set point." Both pools were shown to act in concert to restore the previous ambient [Ca2+] following its elevation. Thus, the mitochondria participate with the other pool(s) in decreasing [Ca2+] to the submicromolar range whereas only the nonmitochondrial pool(s) lowers [Ca2+] to the basal level. The action of inositol 1,4,5-triphosphate (IP3) which has been inferred to mediate Ca2+ mobilization in a few cell types was studied. IP3 released (detectable within 2 s) Ca2+ accumulated in the ATP-dependent pool(s) but had no effect on the mitochondria. The response was transient and resulted in desensitization toward subsequent IP3 additions. Under experimental conditions in which the ATP-dependent Ca2+ influx was blocked, the addition of IP3 resulted in a very large Ca2+ release from nonmitochondrial pool. The results strongly suggest that IP3 is a second messenger mediating intracellular Ca2+ mobilization in human neutrophils. Furthermore, the nonmitochondrial pool appears to have independent influx and efflux pathways for Ca2+ transport, a Ca2+ ATPase (the influx component) and an IP3-sensitive efflux component activated during Ca2+ mobilization.


[Iodine, carbohydrate and protein metabolism in rats receiving insufficient amount of iodine in the feed].
Significant changes in the iodine, carbohydrate and protein metabolism are observed under conditions of prolonged iodine deficiency in the rat ration. The reason-consequent correlations between the main links of iodine metabolism are shown. Indices of protein and carbohydrate metabolism are stated to depend on the concentration of protein-bound iodine in blood.


Post-translational modifications of tight junction transmembrane proteins and their direct effect on barrier function.
Post-translational modifications (PTMs) such as phosphorylation, ubiquitination or glycosylation are processes affecting the conformation, stability, localization and function of proteins. There is clear evidence that PTMs can act upon tight junction (TJ) proteins, thus modulating epithelial barrier function. Compared to transcriptional or translational regulation, PTMs are rapid and more dynamic processes so in the context of barrier maintenance they might be essential for coping with changing environmental or external impacts. The aim of this review is to extract literature deciphering PTMs in TJ proteins directly contributing to epithelial barrier changes in permeability to ions and macromolecules. It is not intended to cover the entire scope of PTMs in TJ proteins and should rather be understood as a digest of TJ protein modifications directly resulting in the tightening or opening of the epithelial barrier.


Perceptions of transitional care needs and experiences in pediatric heart transplant recipients.
Survival following pediatric heart transplantation (HTx) continues to improve. The transition from pediatric to adult care is becoming a pivotal stage in the ongoing medical management of this population. Published data support enhanced outcomes for adolescent patients with increased attention to transitional care. The purpose of this study was to explore the 'transition experience' of adolescent HTx recipients and families. All teens (12-18 years) and parents at a single-center HTx program were invited to participate in semistructured interviews. Qualitative, phenomenological methodology was used to build theoretical knowledge and guided the data collection and analysis. The study population included 14 patients (7 males) with a mean age of 15.7 +/- 1.8 years (11.7-17.8 years) and at a mean of 4.1 +/- 3.3 years post-HTx (0.3-9.2 years) at the time of study participation. Major themes identified included: (i) adolescent disinterest and apathy regarding transition to adult care versus parental anxiety about their child's eventual departure from the pediatric transplant center, (ii) perceived differences in pediatric versus adult care and (iii) identification of strategies described as helpful in facilitating the transition. Understanding the experiences and perceptions of adolescent HTx recipients and their parents is crucial to planning effective transitional care and necessary for evidenced-based practice.


Effectiveness of message-framing to improve oral health behaviors and dental plaque among pregnant women.
Oral health is considered a prominent factor that contributes to quality of life. Hormonal changes during pregnancy can influence oral health. Message framing can play an important role in oral health. The aim of the present study was to investigate the effect of message framing on oral health and dental plaque among pregnant women. The study was conducted in 2017 on 108 pregnant women in Izeh county, Iran. Participants were randomly assigned to gain-framed, loss-framed, and control groups. The research instrument included a two part questionnaire containing demographic information and oral health knowledge, attitude, behavioral intention, self-efficacy, practice, and dental plaque index. Gain-and loss-framed messages were sent to the intervention groups via cell phone texts, but the control group did not receive any messages. Participant dental plaque was clinically assessed. Analysis of covariance with follow-up tests were performed using SPSS version, 23.0 with p-value set at 0.01 for significance. Intervention groups had better oral health (knowledge, atttitude, intention, efficacy, practices and plaque) scores compared to the control group (p < 0.001), but intervention (gain- vs loss-framed) groups did not differ on outcomes. Text message intervention improved knowledge, attitude, behavioral intention, self-efficacy, practice, and dental plaque among pregnant women. While differences between control and both intervention groups indicated text messaging had an impact on oral health outcomes, message framing (i.e., gain vs loss) had no discernable impact on oral health outcomes.


Prevalence of Escherichia coli O157:H7 and Salmonella in beef steers consuming different forage diets.
To compare the prevalence of faecal shedding of Escherichia coli O157:H7 and Salmonella in growing beef cattle consuming various forages. In Experiment I, faecal samples were collected from steers grazing either endophyte-infected (E+) tall fescue or common bermudagrass (CB). Steers grazing E+ tall fescue were confined to a dry-lot pen and fed CB hay ad libitum for 10 days. In Exp. II, faecal samples were collected from steers grazing either E+ or novel endophyte-infected (NE) tall fescue and treated with one of two anthelmintics: ivermectin (I) or fenbendazole (F). In Exp. I, prevalence of E. coli O157:H7 was less in E+ tall fescue steers fed CB hay than steers grazing CB. More I-treated steers shed Salmonella than F-treated steers at 42-day postanthelmintic treatment but shedding of Salmonella was similar between anthelmintics at day 63 in Exp. II. Faecal shedding of pathogenic bacteria was not affected by grazing E+ tall fescue. Alterations of forage diets may influence the prevalence of E. coli O157:H7, and anthelmintic treatment could affect faecal shedding of Salmonella. Knowledge of factors that influence shedding of pathogenic bacteria in cattle is necessary to develop on-farm intervention strategies aimed at reducing pathogen shedding.


Monitoring of osteoporosis therapy.
Over the past two decades, major advances have been made in the number and range of agents available for the treatment of osteoporosis, all with proven anti-fracture efficacy. Unfortunately, compliance with these treatments is not optimal, and a number of patients could be considered as non-responders. Consequently, monitoring anti-osteoporotic therapy could be part of successful osteoporosis management. Currently, no formal well-accepted clinical practice guidelines are available for monitoring anti-osteoporosis therapies. Changes in bone mineral density and bone turnover markers, while on therapy, have potential value in monitoring treatment but their assessment and, consequently, their benefits could be limited by metrological and clinical issues. Moreover, their effectiveness is probably drug dependant. Recommendation for the standardisation of the methodology when analysing the potential relevance of tools for the monitoring of osteoporosis therapy is needed.


Ex vivo specimen MRI and pathology confirm a rectosigmoid mesenteric waist at the junction of the mesorectum and mesocolon.
Continuity of the mesentery has recently been established and may provide an anatomical basis for optimal colorectal resectional surgery. Preliminary data from operative specimen measurements suggest there is a tapering in the mesentery of the distal sigmoid. A mesenteric waist in this area may be a risk factor for local recurrence of colorectal cancer. This study aimed to investigate the anatomical characteristics of the mesentery at the colorectal junction. In this cross-sectional study, 20 patients were recruited. After planned colorectal resection, the surgical specimens were scanned in a MRI system and subsequently dissected and photographed as per national pathology guidelines. Mesenteric surface area and linear measurements were compared between MRI and pathology to establish the presence and location of a mesenteric waist. Specimen analysis confirmed that a narrowing in the mesenteric surface area was consistently apparent at the rectosigmoid junction. Above the anterior peritoneal reflection, the surface area and posterior distance of the mesentery of the upper rectum initially decreased before increasing as the mesentery of the sigmoid colon. These anatomical properties created the appearance of a mesenteric 'waist' at the rectosigmoid junction. Using the anterior reflection as a reference landmark, the rectosigmoid waist occurred at a mean height of 23.6 and 21.7 mm on MRI and pathology, respectively. A rectosigmoid waist occurs at the junction of the mesorectum and mesocolon, and is a mesenteric landmark for the rectum that is present on both radiology and pathology.


Prediction model for successful induction of labor by cervical strain elastography diagnosed at late-term pregnancy in nulliparous women: a prospective cohort study.
The use of cervical strain elastography for nulliparous women during late-term pregnancy remains unclear. This study assesses the predictive value of late-term cervical strain elastography for successful induction of labor (IOL) in nulliparous women. This single-centered, prospective study included 86 patients undergoing IOL between January 2020 and March 2022. Univariate and multivariate analyses were conducted to identify predictive factors for successful IOL. The predictive values were assessed using the area under receiver operating characteristic (ROC) curves. IOL was successful in 58 patients. The hardness ratio and cervical length were significantly associated with successful late-term IOL in nulliparous women. The predictive value of the combination of hardness ratio and cervical length was higher than that of cervical length alone. The hardness ratio and cervical length assessed by cervical strain elastography during late-term pregnancy are predictors of the success of IOL in nulliparous women. The predictive value of the combination of hardness ratio and cervical length was higher than that of cervical length alone.


[Intercompartment soft tissue emphysema after arthroscopic meniscus resection. Case report and differential diagnosis].
Soft-tissue emphysema following surgical procedures needs prompt and accurate diagnosis in order not to miss severe infections, such as clostridial myonecrosis and necrotizing fasciitis. We report the case of a 32-year-old patient who developed massive crepitation of the right leg and thoracic wall after knee arthroscopy had been performed a few days earlier. He was readmitted under suspicion of gas gangrene. This could not be ruled out by preoperative examinations as a subacute infection existed in the range of the infrapatellar incision. A mini-arthrotomy was carried out to exclude necrotizing soft tissue infection and to rinse the joint. An intercompartment emphysema could be confirmed intraoperatively. The postoperative course was uneventful. The main differential diagnoses of benign soft Tissue emphysema are summarized and treatment options are recommended.


Lipid A Phosphoethanolamine Transferase: Regulation, Structure and Immune Response.
A wide variety of antibiotics are targeted to the bacterial membrane due to its unique arrangement and composition relative to the host mammalian membranes. By modification of their membranes, some gram-negative pathogens resist the action of antibiotics. Lipid A phosphoethanolamine transferase (EptA) is an intramembrane enzyme that modifies the lipid A portion of lipopolysaccharide/lipooligosaccharide by the addition of phosphoethanolamine. This modification reduces the overall net-negative charge of the outer membrane of some gram-negative bacteria, conferring resistance to polymyxin. This resistance mechanism has resulted in a global public health issue due to the increased use of polymyxin as last-resort antibiotic treatments against multi-drug-resistant pathogens. Studies show that, without EptA, pathogenic bacteria become more sensitive to polymyxin and to clearance by the host immune system, suggesting the importance of this target enzyme for the development of novel therapeutic agents. In this review, EptA will be discussed comprehensively. Specifically, this review will cover the regulation of eptA expression by the two component systems PmrA/PmrB and PhoP/PhoQ, the site of modification on lipid A, the structure and catalytic mechanism of EptA in comparison to MCR-1 and Escherichia coli alkaline phosphatase, and the host immune system's response to lipid A modification by EptA. The overarching aim of this review is to provide a comprehensive overview of polymyxin resistance mediated by EptA.


2-Carboranylquinazoline: The Path to an ABCG2 Inhibitor.
The role of ATP-binding cassette (ABC) transporter-mediated multidrug resistance (MDR) in anti-cancer therapy is often challenging, frequently leading to inefficiency of treatments. Cancer cells exploit efflux transporters, like the breast cancer resistance protein (BCRP, ABCG2), to secrete chemotherapeutic substances. In this study, an N-phenyl-2-carboranylquinazolin-4-amine (8) was designed as inorganic-organic hybrid BCRP inhibitor. In particular, the ABCG2-transporter inhibitor-prominent scaffold N-phenylquinazolin-4-amine was combined with a boron-carbon cluster (carborane) moiety. Introducing a carborane at 2-position of the quinazoline scaffold resulted in an increased inhibitory activity towards human ABCG2 (hABCG2) compared to its recently published regioisomer N-carboranyl-2-phenyl-quinazolin-4-amine. The carboranylquinazoline 8 further showed the ability to reverse hABCG2-mediated drug resistance in MDCKII-hABCG2 cells by lowering the IC50 value of the BCRP-substrate mitoxantrone, similar to the standard reference and strong inhibitor Ko143, without exhibiting intrinsic toxicity in the lower micromolar ranges. These results make compound 8 a promising scaffold for the design of further BCRP inhibitors.


Understanding anatomical plasticity of Argan wood features at local geographical scale in ecological and archaeobotanical perspectives.
The emergence of the Argan tree as an agricultural, pastoral, cultural, economic and ecological keystone species in Southern Morocco is considered to be linked to the settlement of agropastoral communities that favored its expansion. Nevertheless, the use and exploitation of Argan tree is documented by both few medieval written sources and archaeobotanical studies, from a single location, Îgîlîz (Toughmart, Morocco), a famous medieval site of the Anti-Atlas Mountains. Therefore, data remain scarce regarding the type of Argan communities exploited at this period. In order to document this question, a quantitative eco-anatomical approach aiming to understand variations of wood characters involved in sap conduction and reserve storage, is developed from modern samples collected in the area of Îgîlîz. Results show that diameter of branches and environmental factors are the major parameters explaining plasticity of wood anatomical characters. Quantitative eco-anatomical features of Argan archaeological charcoal confronted to two statistical models, allow assessing both the diameter of the branches from which it derives and the agro-ecological conditions of tree growth and development. This preliminary study may be considered as a relevant and pioneering work for the understanding of the eco-history of the Argan tree, and of its use and exploitation during the past.


Dermatology in Ancient Rome: Medical ingredients in Ovid's "Remedies for female faces".
In Roman medicine, face packs, plasters, unguents, and peelings were part of the therapy of dermatological diseases, but also served cosmetic purposes. Ancient medical textbooks inform us about the ingredients for these applications. Beyond medical literature, other genres contain information about dermatological applications. The Roman poet Ovid (43 BC-17 AD) wrote a didactic poem recording five recipes for topical applications for female faces (Medicamina faciei femineae). Researchers debate the relation of Ovid's poem to Roman medicine: Does the poem contain therapeutical or cosmetical information, or is it mere belles lettres? The objective of the paper is to conduct a medico-historical classification of Ovid's poem by determining whether the ingredients of Ovid's recipes were thought to be effective by the authors of Roman medical textbooks. First, translation and identification of the ingredients were carried out. Second, comparison of the ingredients' functions regarding the therapy of dermatological diseases in two important Roman medical textbooks was realized. For this purpose, several commentaries on the text of Ovid were used and a keyword search in Roman medical textbooks was performed. Ovid's five recipes contain 23 ingredients. All ingredients can be found in medical textbooks. We find that 14 of these ingredients serve cosmetic purposes, 17 serve the therapy of dermatological diseases, and 13 serve both. Ovid's recipes contain drugs that were considered effective by the authors of Roman medical textbooks. These drugs were recommended both for therapeutic and cosmetic purposes by the same authors. Therefore, Ovid's didactic poem is not mere belles lettres, but contains serious medical and cosmetical information. As far as we know, it is the first Roman text that contains dermatological recipes.


Using the Appropriate Formula for QT Measurement Can Save Lives.
CDK 4/6 inhibitors, in combination with endocrine therapy, are the standard of care for patients with endocrinesensitive advanced breast cancer. This class of drug, however, is associated with QT prolongation, which serves as a surrogate marker for Torsades de Pointes (TdP), a cause of life-threatening ventricular arrhythmias and sudden cardiac death. The ICH E14 guidance document uses the Bazett formula for reporting of cardio-dynamic and safety ECG data in clinical trials. While there is substantial familiarity with the Bazett (QTcB) formula (QT/(RR) 1/2), the Fridericia (QTcF) formula (QT/(RR) 1/3 ) is preferred in the cancer population as it is often more accurate at heart rate extreme. Accordingly, the Fridericia formula is currently the standard adopted by the FDA when submitting QT data for review. At the King Faisal Specialist Hospital and Research Center, a total of 82 patients with advanced breast cancer, had a baseline ECG on day 1 before the initiation of ribociclib based therapy. Of the enrolled 82 patients, 19 (23%) were initially excluded from receiving ribociclib based due to a prolonged QTc >450ms, however, when the QTc-interval was manually measured and recalculated using Fridericia and Framingham formulae using MDCalC (https://www.mdcalc.com),17 of 19 patients successfully received their treatment without any arrhythmogenic effects. Repeat ECG on day14, and day 1 of cycle 2 demonstrated that none of these patients had QTc exceeding 480 ms. Our data highlights the complexities of evaluating the QT interval in oncology patients and the utility of the Fridericia/Framingham formulae in this population. Given these findings, we recommend the adoption of the Fridericia or Framingham formulae for measurement of QTc in all cancer patients exposed to potentially QT-prolonging cancer therapy.


Application of induced pluripotent stem cells to model smooth muscle cell function in vascular diseases.
Vascular smooth muscle cells (SMC) play an essential role in remodeling the vasculature during disease progression. Induced pluripotent stem cells (iPSC) provide an attractive approach to obtain autologous SMC source for patient-specific disease modeling. Here we discuss the current methods to 1) derive functional SMC from iPSC, 2) model vascular diseases using SMC generated from patient-derived iPSC, and 3) modulate microenvironmental cues to enhance cellular differentiation and functionality and better mimic the physiological environment. We emphasize that continuous exploration of biomaterial technologies to engineer a more SMC-specific microenvironment will provide further insight on complex vascular diseases.


A general strategy to optimize the performance of aza-BODIPY-based probes for enhanced photoacoustic properties.
In this chapter, we describe a generalizable strategy to obtain a high PA output platform that is optimized for ratiometric imaging. Our approach entails conformationally restricting pendant aryl rings on the aza-BODIPY core to enhance orbital overlap which consequently increases the extinction coefficient. This strategy can potentially be applied to other dye platforms to enhance their signal intensity. We provide detailed protocols for the synthesis, in vitro characterization, and in vivo application.


The parathyroid glands and parathyroid hormone: Insights from PTH gene mutations.
Nine mutations have been discovered in the parathyroid hormone (PTH) gene since it was initially sequenced in 1983. An autosomal dominant C18R mutation in the signal peptide was first reported in 1990, followed by an exon skipping mutation, leading to loss of exon 2 in 1992; the latter mutation prevents PTH biosynthesis, as exon 2 contains the initiation codon. The S23P and S23X mutations affecting the same residue were reported in 1999 and 2012, respectively, while in 2008, the somatic mutation, R83X, was detected in a parathyroid adenoma tissue sample from a patient with overt hyperparathyroidism. In 2013, the heterozygous p.Met1_Asp6del mutation was discovered incidentally in a case-control study, while another heterozygous mutation, M14K, was detected in the signal peptide 4 years later. In 2015, a homozygous R56C mutation was reported, and was the first hypoparathyroidism-causing mutation identified that affects the mature bioactive portion of PTH; this mutation has significantly contributed to the understanding of the molecular mechanisms involved in signal transduction through the PTH receptor. Recently, a novel homozygous S32P mutation was identified, which is also situated in the bioactive portion of PTH. The discovery of these nine mutations in the PTH gene and determination of the molecular mechanisms underlying their effects has provided deep insights into the synthesis, processing, and secretion of PTH. Future attempts to discover other such mutations will help elucidate as yet unknown functions of PTH, with potential clinical implications.


Accuracy and precision of hemoglobin point-of-care testing during major pediatric surgery.
The aim of the study was to compare accuracy and reproducibility of four point-of-care testing (POCT) devices (GEM® Premier 3000, ABL 800 flex, GEM® OPL™, HemoCue® B-Hemoglobin) for hemoglobin (Hb) analyzes as compared with the reference laboratory method (Sysmex XE 2100) in children undergoing major surgery. Pediatric patients undergoing craniofacial, spine, hip, or cancer surgery were included. Blood samples for Hb testing were taken at several intraoperative time points and generally withdrawn from the arterial catheter, if accessible. A total of 256 blood samples were taken intraoperatively from 71 pediatric patients. All POCT devices showed very small bias (maximum -0.46 g/dL) to reference method as well as very good reproducibility (maximum coefficient of variation of 0.99%). However, in two cases (HemoCue), potential clinical relevant differences were observed beyond a range of 2 g/dL. All POCT devices tested and operated by trained staff for hemoglobinometry showed reliable test results. They all allow for simple, fast, and precise bedside determination of hemoglobin concentration in the intraoperative setting.


Response surface optimization of ultrasound assisted extraction of pectin from pomegranate peel.
Ultrasound assisted extraction of pectin from waste pomegranate peel was investigated and optimized using Box-Behnken response surface design coupled with numerical optimization technique. The individual and interactive effect of process variables (solid-liquid ratio, pH, extraction time and temperature) on the pectin yield was studied. The experimental data obtained were analyzed by Pareto analysis of variance (ANOVA) and second-order polynomial models were developed using multiple regression analysis. The models developed from the experimental design were predictive and good fit with the experimental data with high coefficient of determination (R(2)) value. The optimal extraction condition was found to be 1:17.52 g/ml of solid-liquid ratio, 1.27 of pH, 28.31 min of extraction time and 61.90 °C of extraction temperature respectively. Under the optimal conditions, experimental yield was very close to the predicted values.


The Number of Subgrain Boundaries in the Airfoils of Heat-Treated Single-Crystalline Turbine Blades.
In the present study, the dendrites deflection mechanism from the mold walls were subjected to verification regarding its heat-treated turbine rotor blades. The number of macroscopic low-angle boundaries created on the cross-section of the blades' airfoil near the tip was experimentally determined and compared to the number of low-angle boundaries calculated from a model based on the dendrites deflection mechanism. Based on the Laue patterns and geometrical parameters of airfoils, the number of low-angle boundaries occurring at the upper part of the blades airfoil after heat treatment was calculated. This number for the analyzed group of blades ranged from 5 to 9.


Interpersonal testosterone transfer after topical application of a newly developed testosterone gel preparation.
Transdermal testosterone gel treatment is an effective androgen substitution therapy with several advantages over conventional substitution therapies. Whereas side-effects due to overdosing of hypogonadal patients are unlikely, testosterone gel application without protection may cause severe side-effects in other subjects (partners, family members) by contamination. Therefore, the risk of testosterone transfer of a newly developed 2.5% testosterone gel preparation was evaluated. In two clinical randomized open single-centre studies on healthy male volunteers the percentage of testosterone remaining on the skin after gel application over time (n = 12) and the possibility of a transfer of testosterone to another person (n = 28) was evaluated. In the second study the endogenous testosterone production in the receiving subjects was suppressed by injecting 400 mg norethisterone enanthate (NETE). After 8 h approximately 60% of testosterone applied to the skin could be recovered. When the skin had been previously washed with water, only about 14% of applied testosterone could be recovered. After intense skin contact with a volunteer who had applied testosterone before on his forearm, no increase in testosterone serum levels could be found in NETE-suppressed men. Although considerable amounts of testosterone remain on the intact skin for several hours after evaporation of the alcohol vehicle, contamination of a second, especially female or prepubertal, subject causing side-effects seems very unlikely.


Targeting of highly conserved Dengue virus sequences with anti-Dengue virus trans-splicing group I introns.
Dengue viruses (DENV) are one of the most important viral diseases in the world with approximately 100 million infections and 200,000 deaths each year. The current lack of an approved tetravalent vaccine and ineffective insecticide control measures warrant a search for alternatives to effectively combat DENV. The trans-splicing variant of the Tetrahymena thermophila group I intron catalytic RNA, or ribozyme, is a powerful tool for post-transcriptional RNA modification. The nature of the ribozyme and the predictability with which it can be directed makes it a powerful tool for modifying RNA in nearly any cell type without the need for genome-altering gene therapy techniques or dependence on native cofactors. Several anti-DENV Group I trans-splicing introns (αDENV-GrpIs) were designed and tested for their ability to target DENV-2 NGC genomes in situ. We have successfully targeted two different uracil bases on the positive sense genomic strand within the highly conserved 5'-3' cyclization sequence (CS) region common to all serotypes of DENV with our αDENV-GrpIs. Our ribozymes have demonstrated ability to specifically trans-splice a new RNA sequence downstream of the targeted site in vitro and in transfected insect cells as analyzed by firefly luciferase and RT-PCR assays. The effectiveness of these αDENV-GrpIs to target infecting DENV genomes is also validated in transfected or transformed Aedes mosquito cell lines upon infection with unattenuated DENV-2 NGC. Analysis shows that our αDENV-GrpIs have the ability to effectively trans-splice the DENV genome in situ. Notably, these results show that the αDENV-GrpI 9v1, designed to be active against all forms of Dengue virus, effectively targeted the DENV-2 NGC genome in a sequence specific manner. These novel αDENV-GrpI introns provide a striking alternative to other RNA based approaches for the transgenic suppression of DENV in transformed mosquito cells and tissues.


Privileged structure-based ligands for melanocortin receptors-tetrahydroquinolines, indoles, and aminotetralines.
Substitution of the aryl sulfonamide moiety contained in MC4 agonist 1 with bicyclic heterocycles and aminotetralines produced compounds with MC4 activity. The heterocycles represent alternative privileged structures to that contained in 1. Compounds in which the polar group of the privileged structure was displayed in an endocyclic fashion were not as active as the parent agonist 1, while those with an exocyclic polar group afforded activity competitive with 1.


Connective Tissue Diseases in the Skin: Emerging Concepts and Updates on Molecular and Immune Drivers of Disease.
Cutaneous manifestations are common across the spectrum of autoimmune diseases. Connective tissue diseases manifesting in the skin are often difficult to classify and require integration of clinical, histopathologic, and serologic findings. This review focuses on the current understanding of the molecular and immune drivers involved in the pathogenesis of cutaneous lupus erythematosus, dermatomyositis, scleroderma/systemic sclerosis, and mixed connective tissue disease. Recent research advances have led to the emergence of new ancillary tools and useful diagnostic clues of which dermatopathologists should be aware to improve diagnostic accuracy for these diseases.


Apgar Score and Risk of Cerebral Palsy in Preterm Infants: A Population-Based Cohort Study.
A low Apgar score is associated with increased risk of cerebral palsy (CP) in term infants, while such association remains controversial in preterm neonates. The objective of this study was to assess association between 5-minute Apgar scores and CP in different subcategories of preterm birth based on gestational age. The Slovenian National Perinatal Information System was used to identify singleton children without congenital malformations live-born at 22 to 37 weeks of gestation between 2002 and 2010. Data were linked to the Slovenian Registry of Cerebral Palsy in children born between 2002 and 2010. CP was diagnosed at a minimum of 5 years of age. Of 11,924 children included, 241 (2.0%) died before discharge and 153 (1.3%) were diagnosed with CP. Five-minute Apgar scores <7 were significantly associated with higher risk of death or CP (compared with scores ≥9) at all preterm gestations. CP alone was associated with Apgar scores <7 only at moderately or late preterm gestation (32-36 weeks) (adjusted relative risk [aRR]: 8.27; 95% confidence interval [CI]: 1.87-36.64 for scores 0-4 and aRR: 4.96; 95% CI 1.89-13.06 for scores 5-6). In conclusion, a low 5-minute Apgar score was associated with combined outcome of neonatal death or CP in all preterm births, while in surviving preterm infants at >32 weeks a low 5-minute Apgar score was associated with CP.


Caspase-10 inhibits ATP-citrate lyase-mediated metabolic and epigenetic reprogramming to suppress tumorigenesis.
Caspase-10 belongs to the class of initiator caspases and is a close homolog of caspase-8. However, the lack of caspase-10 in mice and limited substrate repertoire restricts the understanding of its physiological functions. Here, we report that ATP-citrate lyase (ACLY) is a caspase-10 substrate. Caspase-10 cleaves ACLY at the conserved Asp1026 site under conditions of altered metabolic homeostasis. Cleavage of ACLY abrogates its enzymatic activity and suppresses the generation of acetyl-CoA, which is critical for lipogenesis and histone acetylation. Thus, caspase-10-mediated ACLY cleavage results in reduced intracellular lipid levels and represses GCN5-mediated histone H3 and H4 acetylation. Furthermore, decline in GCN5 activity alters the epigenetic profile, resulting in downregulation of proliferative and metastatic genes. Thus caspase-10 suppresses ACLY-promoted malignant phenotype. These findings expand the substrate repertoire of caspase-10 and highlight its pivotal role in inhibiting tumorigenesis through metabolic and epigenetic mechanisms.


CCHamide2-receptor regulates feeding behavior in the pea aphid, Acyrthosiphon pisum.
Neuropeptide CCHamide-2 is a recently discovered peptide presents in many arthropods and it is the ligand of the CCHamide-2 receptor (CCHa2-R), which is playing a regulatory role in diverse physiological processes, such as feeding, insulin production, lipid metabolism, growth and reproduction, however, the function of this gene in aphids is still unknown. Here, we characterized and determined the presumed role of CCHa2-R signaling in the wingless pea aphid, Acyrthosiphon pisum. Quantitative real-time reverse transcription-PCR (qRT-PCR) revealed the expression levels of CCHa2-R transcripts in different development stages and different tissues, which indicates that the CCHa2-R expression was high in the first instar as compared to the upcoming nymphal instars and adult and was predominantly high in the brain. The CCHa2-R transcript levels were significantly up-regulated in starved aphids as compared to fed aphids. Moreover, RNAi knockdown by the injection of dsRNA-CCHa2-R significantly reduced the expression and also reduced their food intake in adult aphids, as revealed by electrical penetration graphs (EPGs) results. CCHa2-R-silencing was also shown to reduce reproduction but not survival in A. pisum. These observations suggest a role for the CCHa2-R pathway in the response of wingless parthenogenetic aphids to their nutritional status, and this role involves the regulation of the expression of CCHa2-R. Overall, the results of these experiments indicate that CCHa2-R plays a dominant role in the regulation of feeding in A. pisum.


Factors deciding the assembly and thermostability of the DmrB cage.
Dihydromethanopterin reductase (DmrB), is a naturally occurring cage protein found in various archaeal and a few bacterial species. It exists as 24mer with cubic geometry where 8 trimeric subunits are present at the corners of each cube. Each trimer is made up of three monomeric units and six FMN, where two molecules of FMN are present at the interface of each monomer. DmrB is involved in the conversion of dihydromethanopterin to tetrahydromethanopterin using FMN as a redox equivalent. In the present study, we have used spectroscopic and biochemical techniques along with complementary bio-informatic work to understand the assembly principles of the DmrB. Our results show a concentration dependant self-assembly of DmrB which is mediated by ionic interactions. The co-factor FMN stabilizes and preserves the secondary and quaternary structure of DmrB against thermal insult, indicating that the higher order assembly of DmrB is very thermostable. Our work provides an interesting piece of information regarding the role of the co-factors in the thermostability of these classes of cage proteins. The understanding of the assembly and disassembly of this thermostable cage would enable the downstream usage of this system in various nano-biotechnological applications.


The crucial factors of soil fertility and rapeseed yield - A five year field trial with biochar addition in upland red soil, China.
Biochar has been used as an amendment to improve soil fertility and increase crop yield. However, the effects of biochar on soil properties and rapeseed yield in upland red soil have not been thoroughly investigated, and the factors crucial for rapeseed yield are not yet clear. A five-year field trial was conducted to investigate the effects the of biochar (biochar application rates of 0, 2.5, 5, 10, 20, 30, and 40 t ha-1, respectively) on soil physicochemical and microbial properties as well as rapeseed yield in upland red soil in Jiangxi Province, China. Results showed that biochar can significantly increase soil pH, available phosphorus, organic carbon, Ks, and water retention, however, the influences of biochar on these indexes declined over time. Soil total nitrogen increased significantly when the dose of biochar exceeded 5 t ha-1, and the content of total nitrogen in the 40 t ha-1 biochar treatment increased each year. While the application of biochar gradually increased the contents of NH4+-N, NO3--N and enhanced the soil microorganism and enzymatic activities during the first three years, they had returned nearly to their starting values by the end of this study. Rapeseed yield and yield components were significantly improved relative to the control for all biochar amendments in the first year, but the rapeseed yield in all biochar treatments decreased steadily after 2012. According to the principal components analysis and path analysis, the most responsive parameters in the upland red soil were soil acidity and hydraulic properties, meanwhile, soil acidity and hydraulic properties had greater impacts on rapeseed yield than did other indexes. Taken together, these results suggest that biochar can significantly improve soil fertility and rapeseed yield, but the improvements are not permanent. Soil acidity and hydraulic properties were the crucial factors that determined soil fertility and rapeseed yield in upland red soil.


PCDDs, PCDFs and dioxin-like PCBs in food of animal origin (Slovakia).
The levels of 17 toxic polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and 12 non-ortho and mono-ortho polychlorinated biphenyls (PCBs) in 73 foodstuff samples of animal origin collected from shops and small farms in selected districts of Slovak Republic are presented in this paper. The concentrations expressed as WHO-TEQ in analysed samples ranged for PCDDs/PCDFs from 0.25 pg/g fat in pork to 75 pg/g fat in cod liver. The TEQ concentrations of non-ortho PCBs were between 0.007 and 181 pg/g fat and mono-ortho PCBs between 0.0083 and 66.5 pg/g fat. The mean concentrations in freshwater fish and imported species of marine fish were 0.089 pg TEQ/g fresh weight for PCDDs/PCDFs, 0.17 pg TEQ/g fresh weight for non-ortho PCBs and 0.034 pg TEQ/g fresh weight for mono-ortho PCBs. The mean total concentration of PCDDs/PCDFs and dioxin-like PCBs in samples of infant milk formula imported from EU countries was 0.98 pg TEQ/g fat.


Construction and validation of an atomic model for bacterial TSPO from electron microscopy density, evolutionary constraints, and biochemical and biophysical data.
The 18 kDa protein TSPO is a highly conserved transmembrane protein found in bacteria, yeast, animals and plants. TSPO is involved in a wide range of physiological functions, among which the transport of several molecules. The atomic structure of monomeric ligand-bound mouse TSPO in detergent has been published recently. A previously published low-resolution structure of Rhodobacter sphaeroides TSPO, obtained from tubular crystals with lipids and observed in cryo-electron microscopy, revealed an oligomeric structure without any ligand. We analyze this electron microscopy density in view of available biochemical and biophysical data, building a matching atomic model for the monomer and then the entire crystal. We compare its intra- and inter-molecular contacts with those predicted by amino acid covariation in TSPO proteins from evolutionary sequence analysis. The arrangement of the five transmembrane helices in a monomer of our model is different from that observed for the mouse TSPO. We analyze possible ligand binding sites for protoporphyrin, for the high-affinity ligand PK 11195, and for cholesterol in TSPO monomers and/or oligomers, and we discuss possible functional implications.


Urge-tic associations in children and adolescents with Tourette syndrome.
Premonitory urges preceding tics are a cardinal feature of Gilles de la Tourette syndrome (GTS), a developmental disorder usually starting during middle childhood. However, the temporal relation between urges and tics has only been investigated in adults. In 25 children and adolescents with GTS (8-18 years), we assess urge-tic associations, including inter-individual differences, correlation to clinical measures, and in comparison to a previously reported sample of adult GTS patients. Group-level analyses confirmed positive associations between urges and tics. However, at the individual level, less than half of participants showed positive associations, a similar proportion did not, and in two participants, the association was reversed. Tic expression and subjective urge levels correlated with corresponding clinical scores and participants with more severe tics during the urge monitor exhibited stronger urge-tic associations. Associations between reported urge levels and instantaneous tic intensity tended to be less pronounced in children and adolescents than in adult GTS patients. The observed heterogeneity of urge-tic associations cast doubt on the notion that tics are directly caused by urges. More severe tics may facilitate anticipation of tics and thereby lead to more pronounced urge-tic associations, consistent with a hypothesis of urges as a byproduct of tics.


Acute pulpal-aleveolar cellulitis syndrome. I. Clinical study of bacterial isolates from pulps and exudates of intact teeth, with description of a specific culture technique.
A wide spectrum of microbes has been demonstrated as etiologic factors in the severest form of acute pulpal-alveolar infection; acute cellulitis. An appreciation of the pathogenic potential or oral microorganisms has been gained. Streptococci have been substantiated as the major group of microbes associated with acute odontogenic infection. Anaerobes, primarily gram-negative, are also significant factors. A culture technique for specific microbial growth has been demonstrated and discussed. A simple and economical procedure has been suggested for transport of culture and office study.


[Moqet, a tool for collecting clinical data].
Data collection is the preliminary and essential step in clinical nursing judgment. Certain theories and models of the nursing discipline are used in initial training to conduct this operation. Clinical nursing examination requires theoretical, methodological and experiential learning. The Moqet tool was created to help nursing students with this learning.