ACE2 maybe serve as a prognostic biomarker in breast invasive carcinoma.
Breast cancer is a frequently occurring malignant tumor in women. Angiotensin-converting enzyme 2 (ACE2) is widely expressed in most organs; however, the association of ACE2 with prognosis and immune infiltration in breast invasive carcinoma (BRCA) remains elusive. We explored the expression level and prognostic value of ACE2 in patients with BRCA using a series of online bioinformatics analysis databases encompassing Oncomine, UALCAN, Kaplan-Meier plotter, TIMER, LinkedOmics, and GEO. qRT-PCR was performed to verify our findings. Angiotensin-converting enzyme 2 mRNA and protein expression levels were decreased in BRCA tissues, and patients with low ACE2 expression levels had a poor prognosis. DNA promoter methylation of ACE2 significantly downregulated ACE2 expression in BRCA, while the expression of this protein was positively linked to immune infiltration of B cells, CD8+ and CD4+ T cells, neutrophils, and dendritic cells in BRCA tissues. The high expression level of ACE2 in enriched basophils, CD8+ T cells, and type-2 helper T cells, which showed decreasing levels, indicated a better prognosis for BRCA. Enrichment analyses revealed that NF-κB, IL-17, and TNF signaling pathways were highly correlated to ACE2 in BRCA. Verification study revealed that downregulation of ACE2 was associated with a better prognosis in BRCA. Univariate and multivariate analysis confirmed ACE2 expression and clinical stage as independent prognostic factors for breast cancer. Angiotensin-converting enzyme 2 may be a potential prognostic biomarker and target for BRCA. Nevertheless, future investigations are needed for validating our findings and promoting the clinical application of ACE2 in BRCA.


Notch in T Cell Differentiation: All Things Considered.
Differentiation of naïve T cells into effector cells is required for optimal protection against different classes of microbial pathogen and for the development of immune memory. Recent findings have revealed important roles for the Notch signaling pathway in T cell differentiation into all known effector subsets, raising the question of how this pathway controls such diverse differentiation programs. Studies in preclinical models support the therapeutic potential of manipulating the Notch pathway to alleviate immune pathology, highlighting the importance of understanding the mechanisms through which Notch regulates T cell differentiation and function. We review these findings here, and outline both unifying principles involved in Notch-mediated T cell fate decisions and cell type- and context-specific differences that may present the most suitable points for therapeutic intervention.


Fluorescence quenching of tryptophan and related compounds by hydrogen peroxide.
The fluorescence of tryptophan and some related derivatives was found to be quenched by hydrogen peroxide. The quenching mechanism was shown to be essentially dynamic in nature, without any ground-state complex formation, and it is interpreted as resulting through an electron transfer from the excited indole ring to hydrogen peroxide.


Contemporary comparison of infective endocarditis caused by Candida albicans and Candida parapsilosis: a cohort study.
Among 1655 consecutive patients with infective endocarditis treated from 1998 to 2020 in three tertiary care centres, 16 were caused by Candida albicans (CAIE, n = 8) and Candida parapsilosis (CPIE, n = 8). Compared to CAIE, CPIE were more frequently community-acquired. Prosthetic valve involvement was remarkably more common among patients with CPIE. CPIE cases presented a higher rate of positive blood cultures at admission, persistently positive blood cultures after antifungals initiation and positive valve cultures. All patients but four underwent cardiac surgery. Urgent surgery was more frequently performed in CPIE. No differences regarding in-hospital mortality were documented, even after adjusting for therapeutic management.


Statistical analysis and a case study of tropical cyclones that trigger the onset of the South China Sea summer monsoon.
This paper addresses whether a tropical cyclone can trigger the onset of the South China Sea (SCS) summer monsoon (SM). We conducted a statistical analysis of tropical cyclones (TCs) generated over the western North Pacific (WNP) between late-April and May. The results showed that there were cases in which TCs were generated before the onset of the SCSSM, accounting for 43.2% of the TCs generated during this season. This study examined a representative case, Super Typhoon Chanchu (0601), which was determined to be influential in the onset of the SCSSM. With a northwestward track, Chanchu brought strong convection and westerly winds to the SCS on 12 May, which triggered the intrusion of the southwesterly winds from the Bay of Bengal and the eastward retreat of the western Pacific subtropical high. Super Typhoon Chanchu provides an example in which a TC triggered the onset of the SCSSM. The negative correlation between the onset date of the SCSSM and the number of TCs generated over the WNP used to be interpreted as the influence of the monsoon trough on TC genesis. This work provides a supplementary illustration that this relationship also includes the impact of TCs on the onset of the SCSSM.


Link between structural risk factors for adverse impacts of COVID-19 and food insecurity in developed and developing countries.
COVID-19 has had serious consequences for world food security; lockdowns and social distancing have led to changes in global food value chains, primarily affecting the poorest of the planet. The aim of this research is to analyse the relationship between food insecurity and the structural risk factors for adverse impacts of COVID-19. To that end, 12 contingency tables are constructed to identify the association between the pillars of the food insecurity index and the INFORM COVID-19 Risk Index. We use the Gamma coefficient as a measure of association. In addition, this paper proposes a synthetic index produced by applying the TOPSIS method, using the pillars of the two aforementioned indices (criteria) to establish a ranking of 112 countries (alternatives) ordered from highest to lowest risk faced in the key year of the pandemic, 2020. The results show that the two problems are connected, indicating to international organizations that countries with worse food insecurity will suffer more serious consequences from extreme situations such as the one experienced during the pandemic. The ranking established directs international organizations' attention to countries such as Haiti, Zambia and Burundi, highlighting their greater need for an injection of financial aid than other emerging economies. Conversely, Switzerland is the country with the lowest combined risk.


Herophilus, Erasistratus, Aretaeus, and Galen: ancient roots of the Bell-Magendie Law.
Since the early 19th century, significant controversy has persisted over the competing claims of two men, Charles Bell and François Magendie, to a pivotal discovery: that the dorsal spinal roots subserve sensation, whereas the ventral spinal roots subserve motion. However, the foundations of neuroanatomy on which Bell and Magendie built their research was formed two millennia in advance. Exploration of the work of four ancient scholars--Herophilus, Erasistratus, Aretaeus, and Galen--reveals a remarkable early appreciation of the separate neural pathways (if not the correct physiology) responsible for sensory and motor control.


Organization of the nuclear pore complex in Saccharomyces cerevisiae.
Fractions enriched for nuclear pore complexes (NPCs) have been isolated from Saccharomyces cerevisiae. The sequential extraction of nuclei with detergent, nucleases, and salt reveals an organization of the yeast NPC similar to other eukaryotes. Yeast NPCs contain a 30-nm "ring" structure not previously described in other organisms. This structure appears to organize 10-nm filaments into an assembly which exhibits an eight-fold rotational symmetry. Some proteins in the NPC fraction are capable of forming intermediate-sized filaments. These studies suggest that some component of the nuclear pore complex organizes an interaction between nuclear and cytoplasmic networks of intermediate filaments.


Colorectal stenting for malignant obstruction: an 8-year clinical experience.
A substantial percentage of patients with colorectal cancer present with obstructive symptoms. In such patients, surgery is often required and is associated with significant morbidity and mortality. Colorectal stenting is an increasingly commonplace alternative with potentially fewer risks than open surgery. We present our clinical experience over an 8-year period with colorectal stenting in a major tertiary Australian hospital. From 2000 to 2008, patients undergoing colorectal stenting were identified via medical records. Clinical data collected included patient demographics, tumour type, extent of metastatic disease, stent characteristics, technical and clinical success, acute and chronic complications, and long-term follow-up status. Thirty-five patients (69 ± 13 years, 25 male) received a total of 39 stents. Technical success was achieved in 37 (95%), and clinical relief of obstruction was achieved in 34 (89%). One case was complicated by perforation at the time of procedure and three cases experienced delayed perforation. Reintervention was required in 17% of patients, all of whom had less than 50% hepatic volume replacement by metastatic disease. Colorectal stenting is a feasible and safe alternative for patients presenting with obstructive symptoms but the benefit may be restricted to patients with a short expected survival.


Aesthetic Considerations in Orthofacial Surgery.
Currently, the wish to optimize facial esthetics-in the context of a dysfunctional occlusion or not-has become the main motivation for orthognathic surgery in many cases. In this context, considering that protrusive faces are advised more attractive and that the lack of skeletal support accelerates the aging process, orthognathic surgery will mostly involve a forward movement of the maxillamandibular complex..


Do plexiglass barriers reduce the risk for transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)?
Barriers are commonly installed in workplace situations where physical distancing cannot be maintained, but their effectiveness in decreasing viral transmission is unknown. In simulations, physical barriers with no openings were effective in reducing contamination with an aerosolized benign virus or fluorescent microspheres, but barriers with openings were not.


Antibacterial activity of the pancreatic fluid.
The antibacterial activity of canine pancreatic fluid was investigated in an attempt to understand the resistance of this organ, when intact, to ascending bacterial infections. The pancreatic fluid demonstrated bactericidal activity against Escherichia coli, Shigella species, Salmonella species, and Klebsiella pneumoniae; bacteriostatic activity against coagulase-positive and coagulase-negative staphylococci and Pseudomonas aeruginosa; and fungistatic activity against Candida albicans. There was no demonstrable antibacterial activity against Bacteroides fragilis and Streptococcus faecalis. The antibacterial activity was dialyzable and pH dependent, but independent of heat, the activity of several digestive pancreatic enzymes, and the bacterial inoculum. Electron micrographs of Escherichia coli exposed to pancreatic fluid did not demonstrate changes in the bacterial cell wall. Tracer studies of susceptible bacteria demonstrated decreased leucine uptake when briefly exposed to pancreatic fluid. The antibacterial activity was found by column chromatography to be a small molecular peptide. It is likely that pancreatic antibacterial factors protect the pancreas from ascending bacterial infections and operate along with other factors in the homeostasis of the upper small bowel flora.


Mesenchymal stem cells in peripheral blood of severely injured patients.
Mesenchymal stem cells (MSCs) are primarily stromal cells present in bone marrow and other tissues that are crucial for tissue regeneration and can be mobilized into peripheral blood after different types of organ damage. However, little is known about MSC appearance in blood in the setting of polytrauma. We conducted a monocentered and longitudinal observational clinical study in 11 polytraumatized patients with an injury severity score (ISS) ≥ 24 to determine the numbers of MSCs in peripheral blood. Blood was collected from healthy volunteers and patients after polytrauma in the emergency room and 4, 12, 24, 48 h, 5 and 10 day later, and cells carrying MSC-surface markers (negative for CD45, positive for CD29, CD73, CD90, CD105, and CD166 in different combinations also employing the more stringent markers STRO1 and MSCA1) were detected and characterized using flow cytometry. Relative numbers of MSC-like cells were correlated with clinical parameters to evaluate if specific injury patterns had an influence on their presence in the blood cell pool. We were able to detect MSC marker-positive cells in both cohorts; however, the percentage of those cells present in the blood of patients during the first 10 day after injury was mostly similar to healthy volunteers, and significantly lowers starting at 4 h post trauma for one marker combination when compared to controls. Furthermore, the presence of a pelvis fracture was partly correlated with reduced relative numbers of MSC-like cells detectable in blood. Polytrauma in humans was associated with partly reduced relative numbers of MSC-like cells detected in peripheral blood in the time course after injury. Further studies need to define if this reduction was due to lower mobilization from the bone marrow or to active migration to the sites of injury.


On design of plasma jet reactor for non-oxidative methane conversion.
Non-oxidative methane coupling in an atmospheric pressure plasma jet reactor with an internal diameter of 3.0 mm has been studied. The jet reactor consisted of a quartz tube surrounded by a copper ring and a stainless-steel tube, which were separated by a variable distance. The stainless-steel tube (inner diameter: 1.0 mm, outer diameter: 1.5 mm) served as high voltage electrode and gas inlet. The jet characteristics with different tip angles of the high voltage electrode were investigated using voltage-current waveforms and gas analysis at a constant methane flow rate of 100 ml min-1. The effect of the length of the ground electrode and the gap between the electrodes on conversion, C2 selectivity and energy efficiency has been studied. The methane conversion was nearly tripled with a sharp angle of the electrode (15°), while the energy consumption was reduced from 150 to 55 kJ molC2H y -1. The carbon deposition was also reduced.


Human Vγ2Vδ2 T cells limit breast cancer growth by modulating cell survival-, apoptosis-related molecules and microenvironment in tumors.
Innate immune system has been known to play an important role in inhibiting the malignant transformation, tumor progression and invasion. However, the mechanistic basis remains ambiguous. Despite polyclonality of human γδ T cells, Vγ2Vδ2 T cell subset was shown to recognize and limit the growth of various tumors at various degrees. The differential recognition of the tumor cells by Vγ2Vδ2 T cells are yet to be defined. Our study reveals that γδ T cells limit in vitro growth of most breast tumor cells, such as SkBr7 (HER2+), MCF7 (ER+) and MDA-MB-231 (ER-) by inhibiting their survival and inducing apoptosis, except BrCa-MZ01 (PR+) cells. To investigate detail mechanisms of antineoplastic effects, we found that cell death was associated with the surface expression levels of MICA/B and ICAM1. Molecular signaling analysis demonstrated that inhibition of cell growth by γδ T cells was associated with the lower expression levels of cell survival-related molecules such as AKT, ERK and concomitant upregulation of apoptosis-related molecules, such as PARP, cleaved caspase 3 and tumor suppressor genes PTEN and P53. However, opposite molecular signaling was observed in the resistant cell line after coculture with γδ T cells. In vivo, antineoplastic effects of γδ T cells were also documented, where tumor growth was inhibited due to the downregulation of survival signals, strong induction of apoptotic molecules, disruption of microvasculature and increased infiltration of tumor associated macrophages. These findings reveal that a complex molecular signaling is involved in γδ T cell-mediated antineoplastic effects.


The preventive effect of 5-hydroxytryptamine-3 receptor antagonist on blood pressure reduction and postoperative nausea and vomiting during general anesthesia induction: A double-blinded, randomized controlled trial.
Administering a 5-hydroxytryptamine-3 receptor (5-HT3) at anesthesia induction may aid in achieving hemodynamic stability during general anesthesia induced using opioids. Therefore, we aimed to evaluate the effect of ramosetron, a 5-HT3 antagonist, administered on hypotension at the induction of total intravenous anesthesia (TIVA) with propofol and remifentanil. Additionally, we aimed to compare the impact of ramosetron administration at anesthesia induction versus that at the end of the surgery on postoperative nausea and vomiting (PONV). Patients were randomly allocated to the Induction group (administration of ramosetron [0.3 mg/5 ml] at anesthesia induction and normal saline [5 ml] at the end of the surgery) or End group (administration of normal saline [5 ml] at anesthesia induction and ramosetron [0.3 mg/5 ml] at the end of the surgery). Hemodynamic status, PONV, and postoperative pain were assessed. Operating room, post-anesthetic care unit, and general ward. In total, 176 non-smoking patients without any past medical history undergoing laparoscopic gynecological surgeries under TIVA were included in the study. Blood pressure (BP), heart rate, PONV, visual analog scale (VAS). The Induction group exhibited significantly higher BP at anesthesia induction and required significantly lower doses of phenylephrine and ephedrine during anesthesia than the End group had. However, PONV and postoperative pain were similar between the two groups. Administering ramosetron at anesthesia induction resulted in significantly better hemodynamic stability with significantly lesser requirement of phenylephrine and ephedrine than administering at the end of the surgery did. Therefore, we recommend ramosetron administration at anesthesia induction rather than at the end of the surgery to prevent PONV and the decrease in the mean BP during TIVA with propofol and remifentanil.


Anti-tumor Necrosis Factor-alpha Exposure Impacts Vedolizumab Mucosal Healing Rates in Pediatric Inflammatory Bowel Disease.
Vedolizumab (VDZ) is effective for treating both adult and pediatric onset inflammatory bowel disease (IBD). Clinical outcomes, however, have been reported to be superior in patients naïve to anti-tumor necrosis factor (TNF). With the growing interest in endoscopic endpoints, we aimed to describe rates of mucosal healing in pediatric patients being treated with VDZ and examine the influence of anti-TNF on outcomes. We conducted a retrospective review of all IBD patients ≤21 years of age who initiated VDZ and underwent endoscopy. Primary outcome was mucosal healing (composite of endoscopic [SES-CD] and Mayo score UC) and histological remission [Nancy index-UC and Crohn disease (CD) histologic activity]. Descriptive statistics summarized the data. Comparisons were made for endpoints based on anti-TNF exposure using univariate testing. Sixty-eight patients were included in the final analysis; 35 with UC and 33 with CD. Thirty-two patients (22 UC and 10 CD) were anti-TNF-naïve and 36 patients (13 UC and 23 CD) were anti-TNF-exposed. The median duration on VDZ before endoscopic assessment was 49 (IQR 32-73) weeks. A total of 38% (25/66) of patients met the primary outcome of mucosal healing and did not differ between anti-TNF-naïve or anti-TNF-exposed. Endoscopic remission was achieved by 51% with significantly more anti-TNF naïve patients reaching this endpoint (66% vs 40%, P = 0.03). Histologic remission was achieved by 42% of patients with a nonsignificant trend towards improved histologic remission rates in anti-TNF-naïve patients (52% vs 33%, P = 0.13). VDZ is associated with mucosal healing in pediatric IBD. Anti-TNF exposure significantly impacted endoscopic remission, but not histologic remission in children on VDZ.


Anastigmatic tilted Mangin mirror for long-focus imaging systems.
A tilted Mangin mirror can be designed to be free of coma and astigmatism and to cancel the chromatic aberrations of refracting components.


Cancer Metabolic Subtypes and Their Association with Molecular and Clinical Features.
The alterations of metabolic pathways in cancer have been investigated for many years, beginning long before the discovery of the role of oncogenes and tumor suppressors, and the last few years have witnessed renewed interest in this topic. Large-scale molecular and clinical data on tens of thousands of samples allow us to tackle the problem from a general point of view. Here, we show that transcriptomic profiles of tumors can be exploited to define metabolic cancer subtypes, which can be systematically investigated for associations with other molecular and clinical data. We find thousands of significant associations between metabolic subtypes and molecular features such as somatic mutations, structural variants, epigenetic modifications, protein abundance and activation, and with clinical/phenotypic data, including survival probability, tumor grade, and histological types, which we make available to the community in a dedicated web resource. Our work provides a methodological framework and a rich database of statistical associations, which will contribute to the understanding of the role of metabolic alterations in cancer and to the development of precision therapeutic strategies.


Eosinophilic granuloma presenting with local osteolysis in an adult lumbar spine.
We report an adult patient with eosinophilic granuloma presenting as a local lytic lesion of a vertebral body in the lumbar spine. The patient was a 48-year-old man with a 2-month history of low back pain and numbness in both legs. On plain X-ray, a lytic lesion of the L2 vertebral body was noted. On MRI, the lesion exhibited low-intensity change on T(1)-weighted images, high-intensity change on T(2)-weighted images, and was homogeneously enhanced by gadolinium. The lesion was surgically treated by curettage and iliac bone grafting using a retroperitoneal approach. Histologically, a specimen obtained at the time of surgery was found to be eosinophilic granuloma. We present details of this extremely rare case and review the literature.


Assignment of absolute configuration using chiral reagents and NMR spectroscopy.
An overview of chiral reagents that are used to assign the absolute configuration of particular classes of compounds using NMR spectroscopy is presented. The use of chiral derivatizing agents, chiral solvating agents, metal complexes, and liquid crystals is described.


Age-related changes in the cholinergic components within the central nervous system of CW1 female mice. I. Structural analysis.
Histomorphometric analysis of age-related structural changes in the brain was performed in CW1 female mice, 3, 9, 24 and 32 months of age. Cholinergic regions, such as the hippocampus, NBM and the medial habenula (MH) were investigated in more detail focusing on morphological parameters. The thickness of the frontoparietal cortex (FPC), and the surface area of the dorsal hippocampus and the MH were found to decrease significantly from 9 to 24 months of age. Except for the unique appearance of pseudo-cysts within the FPC, the structural changes culminated by 24 months. Cells' degeneration, in the CA3 hippocampal subfield, was noted already by 9 months of age whereas in other regions the cells' surface area decreased only between 9 and 24 months. Lipofuscin accumulation was most pronounced in the large neurons of the cortex, hippocampus and NBM at 24 months of age.


The neurodevelopmental differences of increasing verbal working memory demand in children and adults.
Working memory (WM) - temporary storage and manipulation of information in the mind - is a key component of cognitive maturation, and structural brain changes throughout development are associated with refinements in WM. Recent functional neuroimaging studies have shown that there is greater activation in prefrontal and parietal brain regions with increasing age, with adults showing more refined, localized patterns of activations. However, few studies have investigated the neural basis of verbal WM development, as the majority of reports examine visuo-spatial WM. We used fMRI and a 1-back verbal WM task with six levels of difficulty to examine the neurodevelopmental changes in WM function in 40 participants, twenty-four children (ages 9-15 yr) and sixteen young adults (ages 20-25 yr). Children and adults both demonstrated an opposing system of cognitive processes with increasing cognitive demand, where areas related to WM (frontal and parietal regions) increased in activity, and areas associated with the default mode network decreased in activity. Although there were many similarities in the neural activation patterns associated with increasing verbal WM capacity in children and adults, significant changes in the fMRI responses were seen with age. Adults showed greater load-dependent changes than children in WM in the bilateral superior parietal gyri, inferior frontal and left middle frontal gyri and right cerebellum. Compared to children, adults also showed greater decreasing activation across WM load in the bilateral anterior cingulate, anterior medial prefrontal gyrus, right superior lateral temporal gyrus and left posterior cingulate. These results demonstrate that while children and adults activate similar neural networks in response to verbal WM tasks, the extent to which they rely on these areas in response to increasing cognitive load evolves between childhood and adulthood.


Evaluation of advanced methods and materials for construction of scintillation detector light guides.
New techniques for fabrication of optically clear structures (3D printing and casting) can be applied to fabrication of light guides, especially complex -shaped ones, for scintillation detectors. In this investigation, we explored the spectral transmissivity of sample light guides created with different fabrication methods and materials. A spectrophotometer was used to measure the transmissivity of the samples to determine their compatibility with a number of commonly used inorganic scintillators (NaI(Tl), BGO, LaBr3, LaCr3, CSI(Tl) and LYSO). These measurements showed that stereolithography with a Stratasys 3D printer using Somos WaterClear Ultra 10122® produced the most compatible light guide with common organic scintillators, especially LYSO (peak emission λ=420 nm) (a scintillator commonly used in positron emission tomography (PET) imaging). Additionally, Polytek Poly-Optic® 1730 clear urethane produced a cast light guide that was the most optically compatible with these scintillators. To demonstrate the ability to create a unique shaped scintillation detector using 3D-printing and casting methods, a small arc-shaped piece of LYSO was coupled to a 4 × 4 array of 4 mm2 silicon photomultipliers (SiPM) using light guides made from these materials. For comparative purposes, a light guide was also fabricated using standard acrylic, a material often used in current light guides. All detectors produced similar event position maps. The energy resolution for 18F (511 keV photopeak) was 13% for the acrylic light-guide-based detector, while it was 18% for the printed light-guide-based detector and 20% for the cast light-guide-based detector. Results from this study demonstrate that advanced fabrication methods have the potential to facilitate creation of light guides for scintillation detectors. Continued advancements in materials and methods will likely result in improved optical performance for 3D-printed structures.


Signaling reactions induced in human fibroblasts during adhesion to cementum-derived attachment protein.
Cementum-derived attachment protein (CAP) is a Mr 56,000 collagenous protein which promotes the adhesion and spreading of mesenchymal cell types. The CAP promotes the adhesion of osteoblasts and periodontal ligament cells better than gingival fibroblasts, while epithelial cells do not adhere to CAP-coated surfaces. To understand the mechanisms involved in CAP action, we have studied the signal transduction events induced by the CAP in human fibroblasts during cell adhesion. Human gingival fibroblasts were serum starved for 48 h, trypsinized, and added to non-tissue culture plastic plates previously coated with CAP. At various time points, attached cells were examined for induction of signaling reactions. Adherence of cells to plates coated with CAP caused tyrosine phosphorylation of proteins migrating on PAGE with molecular mass of 125-130, 85, 70, and 42-44 kDa. We identified focal adhesion kinase p125FAK and p130Cas as components of the 125-130 kDa protein band; however, p125FAK was the major phosphorylated component. ERK-1 and ERK-2 were detected in the 42-44 kDa protein band, but only the ERK-2, not ERK-1, was phosphorylated. Adhesion to CAP-stimulated mitogen-activated protein kinase (MAPK) activity and induced the expression of c-fos mRNA. Protein-tyrosine phosphorylation and c-fos mRNA expression were not induced in unattached cells, and adhesion was not abolished by the protein tyrosine kinase inhibitor, genestein. MAPK activity and c-fos mRNA expression were not induced in monolayer cultures, indicating that these reactions are induced by adhesion and not necessary for cell adhesion. The kinetics of MAPK activation were different from cells attaching on fibronectin (FN) or polylysine, and c-fos mRNA levels increased only half as much on FN and very little on polylysine. These data demonstrated that CAP and other adhesion molecules present in mineralized tissue matrices induce characteristic signaling events during adhesion, which may play a role in recruitment of specific cell types during wound healing and in mediating their specific biological functions.


Sex and day-night differences in opiate-induced responses of insular wild deer mice, Peromyscus maniculatus triangularis.
We examined the effects of mu and kappa opiate agonists on the day- and night-time nociceptive, locomotory and ingestive behaviors of an island population of wild male and female deer mice, Peromyscus maniculatus triangularis. The prototypical mu opiate agonist, morphine, had significant analgesic and locomotory effects, which were blocked by naloxone, and the specific delta opiate antagonist, ICI 154,129, respectively. The specific kappa opiate agonist, U-50,488, had significant analgesic actions and inhibitory effects on locomotor activity, as well as stimulating feeding. Significant day-night variations occurred in the analgesic and activity responses, with the mu and kappa opiate agonists having significantly greater effects at night. There were also prominent sex differences in responses; male deer mice displaying significantly greater levels of mu and kappa opiate-induced analgesia and alterations in activity than female animals. These sex differences in opiate-induced effects were most pronounced at night, female deer mice displaying reduced day-night rhythms of responsiveness. These results demonstrate the existence of significant day-night rhythms and sex differences in the mu and kappa opiate behavioral responses of a wild population of rodents.


KEYNOTE-033: Randomized phase 3 study of pembrolizumab vs docetaxel in previously treated, PD-L1-positive, advanced NSCLC.
KEYNOTE-033 (NCT02864394) was a multicountry, open-label, phase 3 study that compared pembrolizumab vs docetaxel in previously treated, programmed death-ligand 1 (PD-L1)-positive, advanced non-small cell lung cancer (NSCLC), with most patients enrolled in mainland China. Eligible patients were randomized (1:1) to pembrolizumab 2 mg/kg or docetaxel 75 mg/m2 every 3 weeks. Primary endpoints were overall survival (OS) and progression-free survival and were evaluated sequentially using stratified log-rank tests, first in patients with PD-L1 tumor proportion score (TPS) ≥50% and then in patients with PD-L1 TPS ≥1% (significance threshold: P < .025, one-sided). A total of 425 patients were randomized to pembrolizumab (N = 213) or docetaxel (N = 212) between 8 September 2016 and 17 October 2018. In patients with a PD-L1 TPS ≥50% (n = 227), median OS was 12.3 months with pembrolizumab and 10.9 months with docetaxel; the hazard ratio (HR) was 0.83 (95% confidence interval [CI]: 0.61-1.14; P = .1276). Because the significance threshold was not met, sequential testing of OS and PFS was ceased. In patients with a PD-L1 TPS ≥1%, the HR for OS for pembrolizumab vs docetaxel was 0.75 (95% CI: 0.60-0.95). In patients from mainland China (n = 311) with a PD-L1 TPS ≥1%, HR for OS was 0.68 (95% CI: 0.51-0.89). Incidence of grade 3 to 5 treatment-related AEs was 11.3% with pembrolizumab vs 47.5% with docetaxel. In summary, pembrolizumab improved OS vs docetaxel in previously treated, PD-L1-positive NSCLC without unexpected safety signals; although the statistical significance threshold was not reached, the numerical improvement is consistent with that previously observed for pembrolizumab in previously treated, advanced NSCLC.


A long-term survival case of tracheal agenesis: management for tracheoesophageal fistula and esophageal reconstruction.
Tracheal agenesis is a very rare disorder which leads to severe respiratory disorders immediately after birth. Reports are very limited on long-term survival cases. We report here a long-term survival case with Floyd's type I tracheal agenesis. During the neonatal stage, the patient underwent abdominal esophageal banding to substitute esophagus for trachea and transection at the cervical esophagus with esophagostomy. Subsequently, airway management was difficult due to a fragile tracheoesophageal fistula, but the fistula was conservatively treated and stabilized with the patient's growth. This patient is a very rare case in whom oral feeding was achieved after esophageal reconstruction using a gastric tube. For this case, we describe mainly (1) the management method of the tracheoesophageal fistula and (2) esophageal reconstruction without thoracotomy.


Electrocardiographic abnormalities in childhood spinal muscular atrophy.
Tremors of the isoelectric line in routine electrocardiograms have been described in patients with spinal muscular atrophy and have been interpreted as fasciculations of denervated muscles. In order to evaluate this phenomenon, 13 patients with spinal muscular atrophy have been studied (average age: 37.3 months). A first electrocardiogram was recorded routinely; a second tracing was then recorded with double sensitivity and double speed. In addition, all patients were evaluated clinically and had M-mode and cross-sectional echocardiography. Regular and constant spikes on the isoelectric electrocardiographic line were recorded in 12 patients (93.4%); their frequency ranged from 39 to 48 cycles/sec (average: 42.08 +/- 2.64). Contrary to previous reports, we found an "abnormal" electrocardiogram in all our patients with severe spinal muscular atrophy. The only patient with a normal electrocardiogram had a mild and clinically stable form of spinal muscular atrophy. We did not find any significant structural cardiac abnormality by clinical and echocardiographic evaluation. We conclude that continuous tremor on the isoelectric line of electrocardiogram represents a characteristic of spinal muscular atrophy in these patients. It is a result of muscle fasciculations and does not imply any abnormality of the heart.


Optimization of fermentation upstream parameters and immobilization of Corynebacterium glutamicum MH 20-22 B cells to enhance the production of L-lysine.
L-Lysine is an essential amino acid with high commercial importance, as it has to be available in sufficient quantities in animal and human feeds to meet their nutritional requirement. As there is constant increase in L-lysine demand every year, to meet the increasing demand it is necessary to produce L-lysine in large scale. Generally, L-lysine is produced by batch fermentation. In the present investigation, different fermentation process parameters such as fermentation time, pH, temperature, glucose concentration, airflow rate and aeration rate were studied to optimize the production of L-lysine by Corynebacterium glutamicum MH 20-22 B in a 5 L laboratory-scale stirred tank bioreactor. A comparative study of L-lysine production with free cells and immobilized cells of C. glutamicum MH 20-22 B was also investigated to determine whether free cells or immobilized cells were advantageous for production of L-lysine. In this way, optimized fermentation upstream parameters which produced the maximum yield of L-lysine were developed and it was also concluded from the present study that immobilized cells of C. glutamicum MH 20-22 B were more advantageous for L-lysine production as they yield more L-lysine compared to free cells of C. glutamicum MH 20-22 B. It was observed in the present study that the optimum values of fermentation time, pH, temperature, glucose concentration, airflow rate and aeration rate were 96 h, 7.5, 30 °C, 90 g/l, 1.0 vvm and 200 rpm, respectively, by immobilized cells, whereas in case of free cells the optimum values were 72 h, 7.5, 30 °C, 80 g/l, 1.25 vvm and 300 rpm. Immobilized C. glutamicum MH 20-22 B cells exhibited greater L-lysine production of 31.58 g/l than free cells which produced 26.34 g/l of L-lysine.


Risk Factors Such as Male Sex, Smoking, Metabolic Syndrome, Obesity, and Fatty Liver Do Not Justify Screening Colonoscopies Before Age 45.
Recently, many studies have reported that male sex, smoking, fatty liver, metabolic syndrome (MetS), and obesity are risk factors for colorectal neoplasia (CRN). However, current guidelines recommend that persons at average risk of colorectal cancer begin screening colonoscopy at age 50 years without consideration of those risk factors. To investigate an appropriate time to start screening colonoscopies in persons with risk factors for CRN. We performed a cross-sectional study on 27,894 Korean aged ≥30 years who underwent a first colonoscopy as part of a health screening program. To compare the efficacy of colonoscopic screening for the detection of advanced CRN among age groups with risk factors, we calculated the number needed to screen (NNS) to identify 1 patient with advanced CRN. The NNS for those 30-39 years old with all risk factors, male gender, smoking (≥10 pack-years), MetS, obesity, and fatty liver, was higher than that for ≥50-year-old female subjects (55.4 vs. 26.4). The NNS for those 40-44 years old with all risk factors (37.1) was also higher than that for ≥50-year-old female subjects. However, the NNS for those 45-49 years old with risk factors (16.9-22.9) was lower than that for ≥50-year-old women. The efficacy of colonoscopic screening in people 30-44 years old with multiple risk factors is lower than that in ≥50-year-old women. Risk factors such as male sex, smoking, MetS, obesity, and fatty liver do not justify starting screening colonoscopies before age 45.


Cardiovascular Disease in Women Update: Ischemia, Diagnostic Testing, and Menopause Hormone Therapy.
This update will address 3 areas specifically that are essential to improving cardiovascular outcomes for women. The current literature has been reviewed and three important areas of cardiovascular care in women are highlighted. First is that even though women and men share many traditional risk factors for ischemic heart disease, several of these risk factors affect women disproportionately when it comes to CVD risk and events. There are also unique sex-specific risk factors for women and risk factors that are more common in women than in men. Adverse outcomes of pregnancy and hypertensive disorders of pregnancy are associated with an increased long-term risk of CVD and events. At menopause, cardiovascular risks increase, and lipids become unfavorable. Second is that diagnostic testing for ischemic heart disease presents different specificities and sensitivities between men and women and testing should be determined according to what is best and safest for women. Third is that currently, menopause hormone therapy is approved by the U.S. Food and Drug Administration for the treatment of vasomotor and genitourinary symptoms, prevention of osteoporosis, and estrogen replacement in the setting of surgical menopause, hypogonadism, or premature ovarian insufficiency. It is not recommended for the primary or secondary prevention of CVD and not recommended for women with high atherosclerotic CVD risk. Cardiovascular disease (CVD) remains the most common cause of death in women in the United States despite tremendous improvements in cardiovascular care for men and women. The prevention of CVD in women with early detection and implementation of preventive therapies before atherosclerotic CVD develops is critical to improving outcomes for women.


Pharmacotherapy for Cancer Treatment-Related Cardiac Dysfunction and Heart Failure in Childhood Cancer Survivors.
The number of childhood cancer survivors is increasing rapidly. According to American Association for Cancer Research, there are more than 750,000 childhood cancer survivors in the United States and Europe. As the number of childhood cancer survivors increases, so does cancer treatment-related cardiac dysfunction (CTRCD), leading to heart failure (HF). It has been reported that childhood cancer survivors who received anthracyclines are 15 times more likely to have late cancer treatment-related HF and have a 5-fold higher risk of death from cardiovascular (CV) disease than the general population. CV disease is the leading cause of death in childhood cancer survivors. The increasing need to manage cancer survivor patients has led to the rapid creation and adaptation of cardio-oncology. Cardio-oncology is a multidisciplinary science that monitors, treats, and prevents CTRCD. Many guidelines and position statements have been published to help diagnose and manage CTRCD, including those from the American Society of Clinical Oncology, the European Society of Cardiology, the Canadian Cardiovascular Society, the European Society of Medical Oncology, the International Late Effects of Childhood Cancer Guideline Harmonization Group, and many others. However, there remains a gap in identifying high-risk patients likely to develop cardiomyopathy and HF in later life, thus reducing primary and secondary measures being instituted, and when to start treatment when there is echocardiographic evidence of left ventricular (LV) dysfunctions without symptoms of HF. There are no randomized controlled clinical trials for treatment for CTRCD leading to HF in childhood cancer survivors. The treatment of HF due to cancer treatment is similar to the guidelines for general HF. This review describes the latest pharmacologic therapy for preventing and treating LV dysfunction and HF in childhood cancer survivors based on expert consensus guidelines and extrapolating data from adult HF trials.


Pathogenic E. coli HPI upregulate the expression of inflammatory factors in porcine small intestinal epithelial cells by ubiquitin proteasome pathway.
To investigate the effects of pathogenic Escherichia coli high pathogenicity island (HPI) on the expression of inflammatory factors via ubiquitin proteasome pathway. Firstly, the UBC-sus-263 shRNA plasmid was successfully established and transfected into porcine small intestine epithelial cells (IPEC-J2) by liposome to silence the ubiquitinntion gene. Then the IPEC-J2 was infected with E. coli HPI+ and HPI- strains, respectively. Finally, the mRNA of intracellular NF-κB and IκB-α,and the protein levels of NF-κB, IκB-α, TNF-α and IL-1 in IPEC-J2 cell line transfected with UBC-sus-263 shRNA (Ub-shRNA) were detected. The results showed that the Ub-shRNA was effectively inhibited ubiquitination pathway in the IPEC-J2 cell. After infected with HPI+, the mRNA and protein levels of NF-κB and IκB-α were dramatically decreased in Ub-hsRNA transfected IPEC-J2 cells compared to the control and HPI--infected groups. Consistently, the production of downstream cytokines such as TNF-α and IL-1 were highly expressed after HPI+-infection than that of HPI--infected groups. However, whether the HPI+ or HPI-, both could induce increasingly expression of NF-κB and IκB-α and its downstream cytokines in normal IPEC-J2 cells. Thus, the E. coli HPI can upregulate the expression of IκB-α to promote the releasing of TNF-α and IL-1 via the ubiquitination pathway.


Assessment of human exposure to polychlorinated biphenyls and polybrominated diphenyl ethers in Japan using archived samples from the early 1980s and mid-1990s.
Persistent organic pollutants have been linked to various adverse effects on human health. We conducted a retrospective exposure assessment for 11polychlorinated biphenyl (PCB) congeners and 4 polybrominated diphenyl ether (PBDE) congeners. We analyzed paired samples of blood and food duplicate portions collected in the 1980s (1980 survey, N=40) and the mid-1990s (1995 survey, N=40) from females (five participants from each of eight sites per survey) living throughout Japan, from Hokkaido to Okinawa. The study populations in the 1980 and 1995 surveys were different but had lived in the same community. We measured PCBs and PBDEs in serum and PCBs in diet. Total serum PCBs (ng/g lipid) [geometric mean (geometric standard deviation)] were similar in the 1980 [163.0 (1.7)] and the 1995 [142.6 (2.0)] surveys. In contrast, dietary intake (ng/day) between 1980 and 1995 decreased significantly, from 522.8 (2.5) to 165.9 (3.3), respectively, (P<0.05). We classified the participants by birth year-before 1941 (older generation) and equal to or after 1941 (younger generation). Serum PCB levels decreased significantly in the younger generation, from 179.1 (1.8) in the 1980 survey to 115.4 (2.0) in the 1995 survey (P<0.05). However, in the older generation, serum levels (ng/g lipid) did not change: 150.4 (1.6) in the 1980 survey and 180 (1.8) in the 1995 survey. Total PBDE serum levels (ng/g lipid) increased significantly during the 15 years, from 0.5 (3.5) to 1.8 (3.7) (P<0.05). At the Shimane site, PBDE serum levels (ng/g lipid) increased 20-fold, from 1.3 (4.8) to 26.0 (5.0). The serum levels of PCBs decreased in the younger generation but not in the older, although levels in daily intakes decreased significantly. Exposure levels of PBDEs appear to be increasing in an area-specific manner.


Gallbladder wall perforation secondary to empyema in Mirizzi's syndrome: An unseen complication. A case report.
Mirizzi's syndrome is a rare but potential complication of long standing gallstone disease, particularly cholecystolithiasis. Being described is a case of a 42 year old patient who presented with right upper quadrant pain. Initially sent home as the pain settled but was diagnosed as Mirrizi's syndrome on readmission and was managed accordingly. This case report is being presented with the aim of highlighting the importance of Mirizzi's syndrome and the potential consequences it may bear. Due to lack of symptom specificity, this entity remains undiagnosed preoperatively in majority of the cases. Although safe in expert hands, minimally invasive approach (in selected types) can be challenging and bears the risk of bile duct injuries, with a high probability of conversion. Delays in targeted management may lead to dire consequences ranging from empyema gallbladder to gangrene of gall bladder wall, perforation and frank sepsis. A thorough clinical history and physical examination and assessment in light of clinical investigations can lead to a timely diagnosis and management.


Metabolic Disease Therapies.
In anticipation of our upcoming Cell Symposium on Metabolic Disease Therapies in San Diego, CA, on October 15th-17th (http://cell-symposia.com/metabolic-therapies-2017/), the speakers and organizers share their perspectives on why now, more than ever, cutting-edge research is needed to support effective therapies to combat metabolic disease.


Reduced likelihood of cancer screening among women in urban areas and with low socio-economic status: a multilevel analysis in Japan.
To elucidate socio-economic predictors of participation in cancer screening in Japanese women, paying attention to regional variations. In a nationally representative sample of women aged 40--64 years (n=15,224) in Japan, the relationships of self-reported attendance at screening for stomach, colon, uterine and breast cancers with individual characteristics (marital status, occupation and household income) and regional variables (living in a metropolitan area or not, and per capita income) were examined using multilevel analysis. The participation rate ranged from 21.6% for colon cancer to 32.5% for uterine cancer. Being married, employed and having a higher household income were significantly associated with a higher likelihood of cancer screening for all types of cancer: the adjusted odds ratio in the lowest income quintile ranged from 0.45 for uterine cancer to 0.53 for colon cancer compared with the highest income quintile. There was significant regional variance, and living in a metropolitan area and per capita income were associated with a reduced likelihood of cancer screening. Women with lower socio-economic status and living in urban areas are less likely to participate in cancer screening in Japan. Cancer screening should be encouraged in urban areas, taking account of the socio-economic inequalities.


Rapid transneuronal destruction following peripheral nerve transection in the medullary dorsal horn is enhanced by strychnine, picrotoxin and bicuculline.
The effects of systemic administration of strychnine (1 mg/kg), picrotoxin (0.5 mg/kg) and bicuculline (2 mg/kg) on acute transsynaptic destruction of medullary dorsal horn neurons following transection of the inferior alveolar nerve were assessed in rats. Single intraperitoneal injections of the above drugs were given without, 1 min before or 1 min after the nerve transection. The effect of transection without drug administration was also examined. Eighteen hours after nerve transection without drug, approximately 7 dark neurons were found in a single toluidine blue stained 1 micron section of the rostral medullary dorsal horn ipsilateral to the nerve transection. Administration of the drugs 1 min before the nerve transection significantly increased the number of dark neurons in a single section to about 17 (strychnine), 46 (picrotoxin) and 20 (bicuculline). These dark neurons were found mainly in the dorsal half of medullary dorsal horn. Delivery of any of the drugs 1 min after the nerve transection did not increase the number of dark neurons. The data thus indicate that the transneuronal effect of transection of the nerve was enhanced by antagonism of glycinergic and GABAergic inhibition of dorsal horn neurons. In view of the short latency and duration of transsynaptic destructive activity, a massive injury discharge of primary afferent neurons and the subsequent release of excitatory neurotransmitters appear to be the direct cause of convulsant-enhanced rapid transsynaptic destruction which follows the peripheral nerve transection.


Effects of buprenorphine on motor activity of the sphincter of Oddi in man.
Buprenorphine, (Temgesic), a N-cyclopropylmethyl derivative of oripavine, is both an agonist and antagonist of morphine. Its effect on the motility of the sphincter of Oddi (SO) in humans have been investigated by endoscopic manometry (EM). Buprenorphine leads to a significant decrease in the amplitude of SO contraction waves without altering other parameters. Thus, it has no morphine-like effect on SO motility, but it does act like a partial antagonist of morphine in reducing the amplitude of SO contraction waves.


Delirium among elderly persons admitted to a psychiatric hospital: clinical course during the acute stage and one-year follow-up.
Seventy elderly patients meeting the DSM-III criteria for delirium were examined during the acute stage and followed up to one year. The mean age of the patients was 75 years (range 60-88), their delirium lasted on average 20 days (range 3-81) and the psychiatric hospitalization on average 30 days (range 8-365). The most common etiologies for delirium were stroke, infections and metabolic disorders. For 57 cases (81%) a predisposing structural brain disease was found. During the index admission, the cognitive dysfunction associated with delirium ameliorated significantly (the mean +/- SD Mini-Mental State Examination score 9.7 +/- 6.6 at admission and 13.9 +/- 7.2 at discharge; P less than 0.001), but during the one-year follow-up progression of the basic central nervous system disease was seen together with declining cognition and deterioration of functions of daily living.


Coupling of size-exclusion chromatography to a continuous assay for subtilisin using a fluorescence resonance energy transfer peptide substrate: testing of two standard inhibitors.
Liquid chromatography (LC) was coupled on-line to a homogeneous continuous-flow protease assay using fluorescence resonance energy transfer (FRET) as a readout for the screening of inhibitors of an enzyme (e.g., Subtilisin Carlsberg). The inhibitors aprotinin (a protein of approximately 6500 g/mol) and 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF, 240 g/mol) were mixed with other, non-active compounds and separated on a size-exclusion chromatography column. After the separation, the analytes were eluted to the postcolumn reactor unit where the enzyme solution and subsequently the FRET peptide substrate were added; by measuring the fluorescence intensity the degree of inhibition was monitored on-line. As expected, only the two inhibitors caused a change in the FRET response. Detection limits for aprotinin were 5.8 microM in the flow injection analysis (FIA) mode and 12 microM in the on-line LC mode. System validation was performed by determining IC50 values for aprotinin for the FIA mode (19 microM) and the on-line mode (22 microM). These IC50 values were in line with the value determined in batch experiments (25 microM). With this system, chemical information (i.e., chromatographic retention time) and biological information (i.e., enzyme inhibition) can be combined to characterize mixtures.


TIMP-1 as candidate gene for embryo survival in two divergent lines selected for uterine capacity in rabbits.
Selection on uterine capacity has been used in animal breeding as a way to improve the litter size. A divergent selection experiment for uterine capacity was performed in rabbits during ten generations. After the first generations of selection, large differences in number of implanted embryos were obtained between high and low lines. The major part of the differences between lines was due to embryo survival. A segregation analysis suggested the presence of a major gene affecting the reproductive traits. The objective of this work was to test the TIMP-1 gene as a candidate gene for embryo survival in rabbits since it stands up as a target for the investigation of reproductive problems in humans. We have analyzed the parental generation of a F2 cross which consists of 8 and 14 animals from the high and low uterine capacity lines, respectively. The rabbit TIMP-1 gene structure and sequence has been determined, including the proximal promoter region. Despite of the absence of polymorphism between lines in the screened regions (CDS, proximal promoter, exon 1, intron 1, and exon 2), a real-time RT-PCR quantification of the TIMP-1 mRNA in oviduct has shown significant differences between high and low lines at 62 hr of gestation, just when rabbit embryos are located in the oviduct, postulating TIMP-1 as an interesting candidate gene to be involved in the phenotypic differences between the two rabbit lines.


High-throughput screening strategies for space-based radiation countermeasure discovery.
As humanity begins to venture further into space, approaches to better protect astronauts from the hazards found in space need to be developed. One particular hazard of concern is the complex radiation that is ever present in deep space. Currently, it is unlikely enough spacecraft shielding could be launched that would provide adequate protection to astronauts during long-duration missions such as a journey to Mars and back. In an effort to identify other means of protection, prophylactic radioprotective drugs have been proposed as a potential means to reduce the biological damage caused by this radiation. Unfortunately, few radioprotectors have been approved by the FDA for usage and for those that have been developed, they protect normal cells/tissues from acute, high levels of radiation exposure such as that from oncology radiation treatments. To date, essentially no radioprotectors have been developed that specifically counteract the effects of chronic low-dose rate space radiation. This review highlights how high-throughput screening (HTS) methodologies could be implemented to identify such a radioprotective agent. Several potential target, pathway, and phenotypic assays are discussed along with potential challenges towards screening for radioprotectors. Utilizing HTS strategies such as the ones proposed here have the potential to identify new chemical scaffolds that can be developed into efficacious radioprotectors that are specifically designed to protect astronauts during deep space journeys. The overarching goal of this review is to elicit broader interest in applying drug discovery techniques, specifically HTS towards the identification of radiation countermeasures designed to be efficacious towards the biological insults likely to be encountered by astronauts on long duration voyages.


Chemoradiotherapy in squamous cell carcinoma of the anal canal: a single institution experience.
We reviewed the treatment outcomes and prognostic factors for patients with anal canal carcinoma who were treated with curative intent chemoradiotherapy (CRT) at Severance Hospital from 2005 to 2011. Data for 38 eligible patients treated during this period were reviewed. All patients were treated with curative intent using radiotherapy (RT) with (n = 35) or without concomitant chemotherapy (n = 3). Among 35 patients who received CRT, most of the chemotherapeutic regimens were either 5-fluorouracil (5-FU) plus mitomycin C (23 patients) or 5-FU plus cisplatin (10 patients). Recurrence-free survival (RFS), colostomy-free survival (CFS), overall survival (OS), and locoregional control (LRC) rates were calculated using the Kaplan-Meier method and survival between subgroups were compared using the log-rank test. Cox's proportional hazard model was used for multivariate analysis. Over a median follow-up period of 44 months (range, 11 to 96 months), 3-year RFS, CFS, OS, and LRC were 80%, 79%, 85%, and 92%, respectively. In multivariate analysis, tumor size >4 cm was an independent predicting factor for poorer RFS (hazard ratio [HR], 6.35; 95% confidence interval [CI], 1.42 to 28.5; p = 0.006) and CFS (HR, 6.25; 95% CI, 1.39-28.0; p = 0.017), while the presence of external iliac lymph node metastasis was an independent prognosticator for poorer OS (HR, 9.32; 95% CI, 1.24 to 70.3; p = 0.030). No treatment-related colostomies or deaths occurred during or after treatment. Curative intent CRT resulted in excellent outcomes that were comparable to outcomes in previous randomized trials. No severe treatment-related toxicities were observed.


New concepts and new design of permanent maglev rotary artificial heart blood pumps.
According to tradition, permanent maglev cannot achieve stable equilibrium. The authors have developed, to the contrary, two stable permanent maglev impeller blood pumps. The first pump is an axially driven uni-ventricular assist pump, in which the rotor with impeller is radially supported by two passive magnetic bearings, but has one point contact with the stator axially at standstill. As the pump raises its rotating speed, the increasing hydrodynamic force of fluid acting on the impeller will make the rotor taking off from contacting point and disaffiliate from the stator. Then the rotor becomes fully suspended. The second pump is a radially driven bi-ventricular assist pump, i.e., an impeller total artificial heart. Its rotor with two impellers on both ends is supported by two passive magnetic bearings, which counteract the attractive force between rotor magnets and stator coil iron core. The rotor is affiliated to the stator radially at standstill and becomes levitated during rotation. Therefore, the rotor keeps concentric with stator during rotation but eccentric at standstill, as is confirmed by rotor position detection with Honeywell sensors. It concludes that the permanent maglev needs action of a non-magnetic force to achieve stability but a rotating magnetic levitator with high speed and large inertia can maintain its stability merely with passive magnetic bearings.


Models for the cross-correlation between retinal ganglion cells.
Neighboring ganglion cells in the vertebrate retina not only respond to the same stimuli but also display cross-correlated activity on a millisecond time scale. Recent studies of this cross-correlation have indicated that simple linear addition of common variability to each ganglion cell signal does not account for the observations (Levine 1997). In this report, Monte Carlo simulations of various linear and nonlinear models are presented that confirm the earlier speculations. Models in which common variability alters the leakages of a pair of leaky integrate-and-fire neurons account for the data and predict the cross-correlogram lag without invoking temporal delay lines.


Significance of radical resection for pilomyxoid astrocytoma of the cerebellum: a case report and review of the literature.
Pilomyxoid astrocytoma (PMA) was recently classified as a variant of pilocytic astrocytoma (PA) with significantly more aggressive clinical features than those of PA. Like PAs, PMAs frequently arise in the chiasmatic/hypothalamic regions. The cerebellum is also a common site of occurrence for PAs but not for PMAs. We present the case of a 31-month-old boy with cerebellar PMA that showed rapid regrowth during the 3 months following the first subtotal resection. Gross total resection was achieved in the second surgery, followed by radiation to the tumor bed. During follow-up over the next 12 years, there has been no evidence of recurrence on magnetic resonance imaging. Although the prognosis of cerebellar PMAs remains unknown because of the paucity of cases, the relevant literature reports a more favorable outcome for cerebellar PMAs than for PMAs occurring at other locations. The results of this case study and a review of the relevant literature advocate radical resection, sometimes involving multiple surgeries, for cerebellar PMAs because gross total or near total resection is more feasible in the cerebellum than in other locations.


Differential deficits in regional brain growth induced by postnatal alcohol.
Neonatal rats were exposed to alcohol during a period of brain development equivalent to part of the human third trimester. Rat pups were fed a milk formula containing either alcohol (9.8 g/kg/day) or isocaloric maltose/dextrin using artificial rearing techniques from postnatal days 4-10. Blood alcohol concentrations reached 345.8 +/- 15.6 mg/dl on postnatal day 6. All animals, including a group of normally reared suckle controls, were sacrificed on postnatal day 10, and the brains were perfused and processed for the Timm histochemical technique. Significant microencephaly (30% reduction in brain growth) was found in the alcohol-exposed animals. Growth deficits also were found in specific brain regions of the alcohol-exposed rats. The overall area of the hippocampus proper at a midtemporal level was reduced by 26.1% compared to controls. Sublaminae within the hippocampus were stunted as much as 40.5%. An overall reduction of 14.5% was found in the midsagittal (vermal) cerebellum. In contrast, growth of the dentate gyrus appeared much less affected (6.8% deficit) by the alcohol exposure. These data indicate that not all regions of the brain are affected equally by alcohol exposure during the third trimester equivalent.


CEST2022: Amide proton transfer-weighted MRI improves the diagnostic performance of multiparametric non-contrast-enhanced MRI techniques in patients with post-treatment high-grade gliomas.
New or enlarged lesions in malignant gliomas after surgery and chemoradiation can be associated with tumor recurrence or treatment effect. Due to similar radiographic characteristics, conventional-and even some advanced MRI techniques-are limited in distinguishing these two pathologies. Amide proton transfer-weighted (APTw) MRI, a protein-based molecular imaging technique that does not require the administration of any exogenous contrast agent, was recently introduced into the clinical setting. In this study, we evaluated and compared the diagnostic performances of APTw MRI with several non-contrast-enhanced MRI sequences, such as diffusion-weighted imaging, susceptibility-weighted imaging, and pseudo-continuous arterial spin labeling. Thirty-nine scans from 28 glioma patients were obtained on a 3 T MRI scanner. A histogram analysis approach was employed to extract parameters from each tumor area. Statistically significant parameters (P < 0.05) were selected to train multivariate logistic regression models to evaluate the performance of MRI sequences. Multiple histogram parameters, particularly from APTw and pseudo-continuous arterial spin labeling images, demonstrated significant differences between treatment effect and recurrent tumor. The regression model trained on the combination of all significant histogram parameters achieved the best result (area under the curve = 0.89). We found that APTw images added value to other advanced MR images for the differentiation of treatment effect and tumor recurrence.


Voicing narratives of structural violence in interpersonal firearm violence research and prevention in the United States.
Violence is defined as "the intentional use of physical force or power, threatened or actual, against oneself, another person, or against a group or community, that either results in or has a high likelihood of resulting in injury, death, psychological harm, maldevelopment, or deprivation." Encompassed in this definition are multiple, interrelated forms of violence, including interpersonal firearm death and injury, but also the systems, policies, and practices enacted by those with power to advantage some groups while depriving others of meaningful opportunities for meeting their basic needs-known as "structural violence". Yet dominant violence prevention narratives too often ignore or deemphasize the deeply intertwined threads of structural violence with other forms of violence, leading to policies and practices that are frequently insufficient, and often harmful, for reducing interpersonal firearm violence and building community safety, particularly in minoritized and structurally marginalized communities. We highlight ways in which limited scrutiny of structural violence, the omission of its defining characteristics-power and deprivation-from functional characterizations and frameworks of interpersonal firearm violence, and the inadequate distribution of power and resources to those most impacted by violence to self-determine narratives of and solutions to interpersonal firearm violence grossly impacts how interpersonal firearm violence is collectively conceived, discussed, and addressed. Expanding dominant narratives of interpersonal firearm violence, guided by the wisdom and determination of those most impacted, such that the goal of prevention and intervention efforts is not merely the absence of violence but rather the creation of a community safety and health ecosystem is essential to meet this critical moment in firearm violence research and prevention.


Epithelioid trophoblastic tumor that requires fertility preservation: A case report and review of literature.
Epithelioid trophoblastic tumor (ETT) is very rare and few cases have been published in the English literature. Hysterectomy is the recommended treatment, due to the high rate of recurrence and mortality. The objective of this article is to present a rare case of ETT with fertility-preserving treatment and review published similar cases. We report the case of ETT in a 19-year-old Chinese woman, who had a strong desire of fertility preservation. She presented with vaginal spotting and hysteroscopy showed an isolated solid mass (2.0 × 1.5 × 1.5 cm) at the right corner of the uterine cavity. Serum β-human chorionic gonadotropin (β-HCG) persisted at low level elevation about 100 IU/L. We treated her with a lesionectomy and 3 cycles EP-EMA (etoposide, cisplatin/etoposide, methotrexate and actinomycin) chemotherapy regimen. The patient is now in stable condition, without any signs of recurrence during 20 months of follow-up. Fertility-preserving surgery would probably be a feasible and safe strategy for the patients whose lesions can be completely removed.


Delirium and IL-6 added to clinical scores improves their performance: a prospective analysis of CALL, PREDI-CO, MRS score applied to a population of patients admitted to internal medicine ward.
This study aimed to evaluate the effectiveness of various scoring systems in predicting in-hospital mortality for COVID-19 patients admitted to the internal medicine ward. We conducted a prospective collection of clinical data from patients admitted to the Internal Medicine Unit at Santa Maria Nuova Hospital in Florence, Italy, with confirmed pneumonia caused by SARS-CoV-2. We calculated three scoring systems: the CALL score, the PREDI-CO score, and the COVID-19 in-hospital Mortality Risk Score (COVID-19 MRS). The primary endpoint was in-hospital mortality. : A total of 681 patients were enrolled in the study, with a mean age of 68.8 ± 16.1 years, and 54.8% of them were male. Non-survivors had significantly higher scores in all prognostic systems compared to survivors (MRS: 13 [12- 15] vs. 10 [8-12]; CALL: 12 [10-12] vs. 9 [7-11]; PREDI-CO: 4 [3-6] vs. 2 [1-4]; all p<0.001). The receiver operating characteristic (ROC) analysis yielded the following area under the curve (AUC) values: MRS 0.85, CALL 0.78, PREDI-CO 0.77. The addition of Delirium and IL6 to the scoring systems improved their discriminative ability, resulting in AUC values of 0.92 for MRS, 0.87 for CALL, and 0.84 for PREDI-CO. The mortality rate increased significantly across increasing quartiles (p<0.001). In conclusion the COVID-19 in-hospital Mortality Risk Score (MRS) demonstrated reasonable prognostic stratification for patients admitted to the internal medicine ward with SARS-CoV-2-induced pneumonia. The inclusion of Delirium and IL6 as additional prognostic indicators in the scoring systems enhanced their predictive performance, specifically in determining in-hospital mortality among COVID-19 patients.


Unique Circulating MicroRNA Profiles in HIV Infection.
MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression. We aimed to determine the association between extracellular miRNAs and HIV infection. Single-center, cross-sectional study. We analyzed the expression of 192 plasma-derived miRNAs in 69 HIV-infected individuals and 24 uninfected controls using TaqMan miRNA assays and a high-throughput Real-Time PCR instrument (Fluidigm). False discovery rate (FDR) was applied. HIV-infected individuals and controls were similar in age, sex, and traditional risk factors. Among those with HIV, 72.5% were on antiretroviral therapy (ARVs) and 64% had an undetectable viral load. Twenty-nine miRNAs were differentially expressed in the plasma of HIV-infected individuals compared with controls (P < 0.05, FDR < 0.15). Nineteen miRNAs were differentially expressed among HIV+ subjects on ARVs, HIV+ subjects not on ARVs, and HIV- subjects (P < 0.05 and FDR < 0.15). Thirty-four miRNAs were differentially expressed between HIV- subjects and elite controllers (ie, suppressed viral loads despite the absence of ARVs; P < 0.05 and FDR < 0.15). These 34 miRNAs included miRs-29c, 146b, 223, and 382, which were previously reported to have intracellular roles in HIV latency, as well as miRs-126, 145, and let-7, which were previously shown to be differentially expressed in coronary artery disease among uninfected individuals. We demonstrate a unique expression profile of 29 miRNAs in HIV+ subjects and 34 miRNAs in elite controllers as compared to HIV- subjects. These miRNA signatures may be useful in further elucidating mechanisms of viral and immunological control and may have diagnostic or prognostic value in HIV-associated coronary artery disease.


Bloodless esophageal replacement in children with corrosive esophageal strictures--report of two cases.
Esophageal replacement is major procedure with high risk for perioperative allogeneic blood transfusion (ABT), especially in pediatric patients due to nutritive deficiency, anemia, small body weight and blood volume. Autologous blood policy is particularly important in female children. We present treatment strategy with the aim of avoiding ABT, that have been applied in two female pediatric patients with caustic stricture of thoracic esophagus. The patients were 7 and 8 years old, with body weight 34 and 23.5 kg, respectively. Protocol was based on the stimulation of haematopoetic system with erythropoietin, iron therapy and preoperative autologous blood donation (PABD). In the first patient, with a history of previous retrosternal bypass esophagocoloplasty and extraction of necrotic colonic graft, delayed reconstruction--transhiatal subtotal esophagectomy and gastric pull-up with cervical anastomosis were performed. In the second patient, repeated ineffective dilatations of esophageal stricture were reason for retrosternal left colon interposiotion and exclusion of native esophagus. No adverse events were attributed to preoperative blood donation period. No allogenic blood products were used during perioperative period. Both patients had uneventful postoperative course. In specialized institutions for esophageal surgery, PABD with administration of erythropoietin and iron therapy, enable bloodless esophageal replacement, even in children.


HIV-associated cystic lesions of the parotid gland.
We present two cases of an HIV-associated parotid gland cyst. One case was a 36-year-old HIV infected woman. She was diagnosed with HIV infection and presented with slowly enlarged parotid gland cysts together with elevation of HIV viral RNA copies/mL in her serum. She was performed parotid gland biopsy under the general anesthesia. The histopathologic analysis revealed negative HIV p24-antigen in her parotid gland tissue. The other case was a 43-year-old man found his parotid gland swelling shortly after highly active antiretroviral therapy (HAART). He was diagnosed with HIV infection 2 years previously. He had started HAART several days before. He showed exceeding elevation of IgE in his serum. We treated him with medication using anti-histamic drugs for his cyst. A computed tomography scan revealed a complete response of his parotid gland cyst 4 weeks after the medication. His serum IgE level was decreased to half of the level before the medication. These findings suggested that the parotid gland swelling associated with HIV was due to various factors including immune reconstitution inflammatory syndrome (IRIS). In case such a parotid gland swelling, we could avoid invasive treatments.


[Spanish implantable cardioverter-defibrillator registry. Seventh official report of the spanish society of cardiology working group on implantable cardioverter-defibrillators (2010)].
The authors summarize the findings of the Spanish Implantable Cardioverter-Defibrillator Registry for 2010 compiled by the Spanish Society of Cardiology Working Group on Implantable Cardioverter-Defibrillators. Members of the Spanish Society of Cardiology were prospectively surveyed; data were recorded voluntarily by each implantation team on one-page questionnaires. In total, 4627 device implantations were reported, comprising 85.6% of the overall estimated number of implantations. The reported implantation rate was 100.61 per million population and the estimated total implantation rate was 117.50 per million. The proportion of first implantations was 73.87%. We collected data from 143 hospitals (9 more than in 2009). The majority of the implantable cardioverter-defibrillator implantations were performed in men (81%). The mean age was 62.5 ± 13 years. Most of the patients had severe or moderate-to-severe ventricular dysfunction and were in New York Heart Association functional class II. Ischemic heart disease was the most frequent underlying cardiac condition, followed by dilated cardiomyopathy. The number of implantable cardioverter-defibrillator implantations indicated for primary prevention increased over the previous year and now accounts for 65.6% of first implantations. In all, 76.1% of the implantable cardioverter-defibrillator implantations were performed by cardiac electrophysiologists. The 2010 Spanish Implantable Cardioverter-Defibrillator Registry includes data on almost 86% of all the implantable cardioverter-defibrillator implantations performed in Spain. Although the number has continued to increase, it still remains far lower than the European average. There has been a significant increase in the number of implantations indicated for primary prevention.


Evaluation of the relationship between vitamin D level and adropin, IL-1β, IL-6, and oxidative status in women.
Vitamin D, adropin, proinflammatory cytokines, and oxidative stress closely related with metabolic homeostasis and endothelial dysfunction. The aim of the present study is to investigate how vitamin D levels affect serum adropin, IL-1ß, IL-6, and oxidative stress. A total of 77 female subjects were divided into 3 groups according to vitamin D levels. Biochemical parameters, adropin, IL-1ß, IL-6, oxidative stress markers were studied in these groups, and the results were compared statistically. Serum adropin, IL-1ß, IL-6, total oxidant status (TOS) and total antioxidant status (TAS) and oxidative stress index (OSI) levels differed significantly between the vitamin D groups (p < 0.05). A significant positive correlation was detected between vitamin D, and adropin and TAS (r = 0.807; p < 0.001, r = 0.814; p < 0.001, respectively). A significant negative correlation was detected between vitamin D, and IL-1ß, IL-6, TOS, OSI (r = -0.725; p < 0.001, r = -0.720; p < 0.001, r = -0.238; p = 0.037, r = -0.705; p < 0.001, respectively). Vitamin D could show its effects through vitamin D receptors on tissues or on the ENHO gene in adropin secreting tissues via direct or indirect mechanisms. Proinflammatory cytokines, oxidative stress, and adropin targeted studies could contribute to the prevention and treatment of diseases associated with vitamin D deficiency in future.


Is population frequency a useful criterion to assign pathogenicity to newly described mitochondrial DNA variants?
Population frequency has been one of the most widely used criteria to help assign pathogenicity to newly described mitochondrial DNA variants. However, after sequencing this molecule in thousands of healthy individuals, it has been observed that a very large number of genetic variants have a very low population frequency, which has raised doubts about the utility of this criterion. By analyzing the genetic variation of mitochondrial DNA-encoded genes for oxidative phosphorylation subunits in 195,983 individuals from HelixMTdb that were not sequenced based on any medical phenotype, we show that rare variants are deleterious and, along with other criteria, population frequency is still a useful criterion to assign pathogenicity to newly described variants.


Co-administration of 5-HT6 receptor antagonists with clozapine, risperidone, and a 5-HT2A receptor antagonist: effects on prepulse inhibition in rats.
Some novel antipsychotics manifest antagonistic activity at serotonin-6 receptors; however, little is known about the role of 5-HT6 receptors in ameliorating sensory gating deficits. We evaluated the effects of the combined administration of the 5-HT6 receptor antagonist SB 271046 with clozapine and haloperidol, as well as the co-administration of SB 271046 or SB 399885 with risperidone and the 5-HT2A antagonist M100907, to overcome the deficits induced by MK-801 in the prepulse inhibition (PPI) test. MK-801 (0.1 mg/kg) produced reliable PPI deficits. Administration of SB 271046 (6 and 9 mg/kg), SB 399885 (3 and 6 mg/kg), clozapine (2.5 mg/kg), haloperidol (0.1 and 0.2 mg/kg), risperidone (0.25-1 mg/kg), and M100907 (0.5 and 1 mg/kg) did not affect the MK-801-induced deficits, but the administration of clozapine (5 mg/kg) did reverse the effects of MK-801. In MK-801-treated rats, the co-administration of inactive doses of clozapine (2.5 mg/kg) and SB 271046 (6 mg/kg) reversed the PPI impairments compared to animals that were administered inactive doses of either clozapine or SB 271046 alone. Co-administration of risperidone (1 mg/kg) or M100907 (0.5 mg/kg) with SB 271046 (6 mg/kg) or SB 399885 (3 mg/kg) also attenuated the MK-801-induced PPI deficits. In contrast, joint administration of haloperidol and SB 271046 had no effect on the PPI deficit. The present results suggest that the 5-HT6 receptors may play adjunctive roles in antipsychotic drug action, and that the combination of 5-HT2A and 5-HT6 antagonism may represent an important element in the pharmacological profile of antipsychotic drugs.


[Clinical presentation and complications of Plasmodium falciparum malaria in two populations: travelers and immigrants].
Plasmodium falciparum malaria is the most aggressive form of this disease, with 90% of cases occurring in Africa. Only natives of malaria-endemic areas can acquire a certain degree of immunity to the disease. It is not known whether immunity is lost when contact with the parasite is discontinued. Retrospective study of cases of falciparum malaria imported from Africa, performed in Hospital Clinic, Barcelona (Spain), from 1999 to 2005. Clinical, epidemiological and laboratory parameters were compared between travelers and African immigrants. Among 187 patients, 85 were immigrants from an endemic area who had been living in a non-endemic area for more than 5 years. These patients presented fewer complications than travelers. These data may point to a certain persistence of immunity in previously semi-immune persons who migrate to non-endemic areas.


Treatment Outcome of metastatic lesions from renal cell carcinoma underGoing Extra-cranial stereotactic body radioTHERapy: The together retrospective study.
stereotactic body radiation therapy (SBRT) use has increased overtime for the management of metastatic renal cell carcinoma (mRCC) patients, with a likely good control of irradiated lesions. We planned a retrospective multicenter Italian study, with the aim of investigating the outcome of treatment with SBRT for non-brain secondary lesions in mRCC patients. all consecutive metastatic non-brain lesions from mRCC that underwent SBRT at nine Italian institutions from January 2015 to June 2017 were considered. The primary endpoint of the study was the lesion-PFS, calculated from SBRT initiation to the local progression of the irradiated lesion. 57 extracranial metastatic lesions from 48 patients with primary mRCC were treated with SBRT. At the median follow-up of 26.4 months, the median lesion-PFS was not reached (43 censored); 72.4% of lesions were progression-free at 40 months, with significantly better lesion-PFS for small metastatic lesions (<14 mm). SBRT was safe and the 1-year local disease control was 87.7%. After SBRT, 18 patients (37.5%) permanently interrupted systemic therapy. consistently with the previous literature, our findings support the use of SBRT in selected mRCC patients.


Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia.
Nelarabine is effective in inducing remission in patients with relapsed and refractory T-cell acute lymphoblastic leukemia (T-ALL) but has not been fully evaluated in those with newly diagnosed disease. From 2007 to 2014, Children's Oncology Group trial AALL0434 (ClinicalTrials.gov identifier: NCT00408005) enrolled 1,562 evaluable patients with T-ALL age 1-31 years who received the augmented Berlin-Frankfurt-Muenster (ABFM) regimen with a 2 × 2 pseudo-factorial randomization to receive escalating-dose methotrexate (MTX) without leucovorin rescue plus pegaspargase (C-MTX) or high-dose MTX (HDMTX) with leucovorin rescue. Intermediate- and high-risk patients were also randomly assigned after induction to receive or not receive six 5-day courses of nelarabine that was incorporated into ABFM. Patients who experienced induction failure were nonrandomly assigned to HDMTX plus nelarabine. Patients with overt CNS disease (CNS3; ≥ 5 WBCs/μL with blasts) received HDMTX and were randomly assigned to receive or not receive nelarabine. All patients, except those with low-risk disease, received cranial irradiation. The 5-year event-free and overall survival rates were 83.7% ± 1.1% and 89.5% ± 0.9%, respectively. The 5-year disease-free survival (DFS) rates for patients with T-ALL randomly assigned to nelarabine (n = 323) and no nelarabine (n = 336) were 88.2% ± 2.4% and 82.1% ± 2.7%, respectively (P = .029). Differences between DFS in a four-arm comparison were significant (P = .01), with no interactions between the MTX and nelarabine randomizations (P = .41). Patients treated with the best-performing arm, C-MTX plus nelarabine, had a 5-year DFS of 91% (n = 147). Patients who received nelarabine had significantly fewer isolated and combined CNS relapses compared with patients who did not receive nelarabine (1.3% ± 0.63% v 6.9% ± 1.4%, respectively; P = .0001). Toxicities, including neurotoxicity, were acceptable and similar between all four arms. The addition of nelarabine to ABFM therapy improved DFS for children and young adults with newly diagnosed T-ALL without increased toxicity.


White clover clones as a cost-effective indicator of phytotoxic ozone: 10 years of experience from central Italy.
Data collected at one site in central Italy using the NC-S/NC-R clover (Trifolium repens) biotype system during 1997-2007 were analysed in order to assess: (a) its performance under Mediterranean conditions; (b) variations of ozone damage linked with meteorological conditions; (c) if critical level approach is a good predictor of ozone risk on vegetation. NC-S dry biomasses were systematically lower than those of NC-R, the mean ratio being 0.7. Relevant relationship between ozone visible injury and cumulated values of AOT40 were also reported. Temperature and number of rainy days were the most important factors associated with ozone presence and, as a consequence, with leaf injury index. Photosynthetic gas exchange properties indicate that NC-S has higher values of stomatal conductance.


[Manual afterloading applicators for intracavitary brachytherapy].
A technical description of uterovaginal and rectal applicator system of manual afterloading is described. A simple solution while using domestic materials covering the requirements of present-day brachytherapy. The applicators proved to be suitable for gamma radiation sources as well as for gamma-neutron radiation of 252Cf sources.


Involvement of APOE in Incidence of Revascularization in Patients Affected by Peripheral Arterial Disease: A Prospective Study from Southern Italy.
Atherosclerosis is a complex multifactorial disease and apolipoprotein E (APOE) polymorphism has been associated with cardiovascular events. The APOE gene, located on chromosome 19q13.2, has an important role in lipid metabolism, in particular on circulating cholesterol levels, implying further pleiotropic effects; from its polymorphism are derived three alleles (ε2, ε3 and ε4), which induce different phenotypes, while its impact on carotid and femoral atherosclerosis is still controversial. The aim of the study is to investigate the relationship between APOE genotypes and peripheral revascularization in a cohort of patients affected by advanced peripheral arterial disease (PAD) at a prolonged follow-up. Some 332 patients (259 males and 73 females; mean age 70.86 ± 7.95 years) with severe PAD were enrolled in a longitudinal study, with a 90.75 ± 32.25 month follow-up, assessing major adverse cardiovascular events (MACE). As compared with ε3/ε3, in ε4 patients we observed a significant higher incidence of carotid (13.2% vs. 5.6%; HR = 2.485, 95% CI 1.062-5.814; p = 0.036) and lower limb (11.8% vs. 4.3%; HR = 2.765, 95% CI 1.091-7.008; p = 0.032) revascularizations and, accordingly, a higher incidence of total peripheral revascularizations (13.5% vs. 9.5%; HR = 2.705, 95% CI 1.420-5.151; p = 0.002). HR remained statistically significant even when adjusted for classic cardiovascular risk factors. In our observational study, we confirm that the ε4 allele is associated with higher total peripheral revascularization in patients with advanced atherosclerotic vascular disease at prolonged follow-up.


Is FOLFOXIRI alone or combined with targeted therapy administered as first-line treatment a reasonable choice for most patients with mCRC? Systematic review and network meta-analysis.
Whether the intensive administration of folinic acid, 5-fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI) alone or combined with target therapy as first-line treatment could improve the prognosis of metastatic colorectal cancer (mCRC) patients is controversial. PubMed, the Cochrane Collaboration Central Register of Controlled Clinical Trials, Cochrane Systematic Reviews, ClinicalTrials.gov, the databases of conferences were queried to identify RCTs evaluating the efficacies and toxicities of intensive therapies used for first-line treatment of mCRC patients. The search included articles dated from the inception of these resources until March 31, 2017. We estimated HRs for OS and PFS and RRs for ORR, the R0 resection rate, and toxicities. Ten RCTs comprising 2,506 patients were included in this network meta-analysis. The PFS of patients administered FOLFOXIRI plus target therapy experienced prolonged PFS and OS and improved ORRs compared with FOLFOX/FOLFIRI plus target therapy (PFS: HR 0.71, 95% CI 0.59-0.86; OS: HR 0.81, 95% CI 0.69-0.94; ORR: RR 1.66, 95% CI 0.96-2.88; R0 resection rate: RR 2.66, 95% CI 1.86-3.82). There were no significant differences between PFS, OS, ORRs, or R0 resection rates and toxicities of patients administered FOLFOXIRI and FOLFOX/FOLFIRI plus target therapy. Further, FOLFOXIRI plus target therapy did not increase toxicities compared with FOLFOX/FOLFIRI plus target therapy. FOLFOXIRI plus target therapy when administered as first-line treatment of patients with mCRC is the best choice and did not increase toxicities. The patients with RAS/BRAF mutations could benefit from FOLFOXIRI plus Bev. FOLFOXIRI is as effective as FOLFOX/FOLFIRI plus target therapy.


Microtechnologies for membrane protein studies.
Despite the rapid and enormous progress in biotechnologies, the biochemical analysis of membrane proteins is still a difficult task. The presence of the large hydrophobic region buried in the lipid bilayer membrane (transmembrane domain) makes it difficult to analyze membrane proteins in standard assays developed for water-soluble proteins. To handle membrane proteins, the lipid bilayer membrane may be used as a platform to sustain their functionalities. Relatively slow progress in developing micro total analysis systems (microTAS) for membrane protein analysis directly reflects the difficulty of handling lipid membranes, which is a common problem in bulk measurement technologies. Nonetheless, researchers are continuing to develop efficient and sensitive analytical microsystems for the study of membrane proteins. Here, we review the latest developments, which enable detection of events caused by membrane proteins, such as ion channel current, membrane transport, and receptor/ligand interaction, by utilizing microfabricated structures. High-throughput and highly sensitive detection systems for membrane proteins are now becoming a realistic goal. Although most of these systems are still in the early stages of development, we believe this field will become one of the most important applications of microTAS for pharmaceutical and clinical screenings as well as for basic biochemical research.


Perceived Economic Uncertainty and Fertility Intentions in Couples: A Dyadic Extension of the Theory of Planned Behaviour.
By adopting a dyadic extension of the Theory of Planned Behavior (Ajzen, 1991), this study examined whether perceived economic uncertainty affects fertility intentions. Three-hundred thirty one heterosexual couples living in Italy participated in a randomized between-group experimental study, in which we manipulated perceived economic uncertainty (low vs. high vs. control). The participants subsequently completed a questionnaire measuring their attitudes, subjective norms, perceived behavioral control, and fertility intentions. We employed Structural Equation Modelling in estimating the Actor-Partner Interdependence Model. The model showed a good fit to the data. Women's attitudes, subjective norms, and perceived behavioral control were influenced by the high economic uncertain scenario, whereas among men these variables were affected only by the positive economic scenario. Attitudes and perceived behavioral control were significant predictors of fertility intentions for both sexes. Significant partner effects were observed as well. These findings suggest that fertility plans should be examined by adopting a dyadic perspective, as individuals' intentions are affected not only by their own beliefs, but also by those of their partners.


A time-resolved electron spin resonance study of the oxidation of ascorbic acid by hydroxyl radical.
Time-resolved electron spin resonance (ESR) spectroscopy for the study of radicals produced by pulse radiolysis is illustrated by a study of the oxidation of ascorbic acid by OH radical in aqueous solution. In basic solution, the direct oxidation product, the ascorbate mono-anion radical, is formed within less than 2 mus of the radiolysis pulse. In acid solutions (pH 3(-4.5), N(2)O:saturated) three radicals are initially formed, the ascorbate mono-anion radical, an OH adduct seen also in steady-state ESR experiments, and an OH adduct at C2 with the main spin density at C3 of the ring. The first OH adduct decays with an initial half-life of about 100 mus, probably by biomolecular reaction. The second OH adduct, which shows one hyperfine splitting about a(H) = 24.4 +/- 0.3 G and g = 2.0031 +/- 0.0002, decays with a half-life of about 10 mus. On this same time scale the concentration of the ascorbate radical approximately doubles. It is concluded that the adduct at C2, but not the other adduct, loses water rapidly to form the ascorbate radical.


Second-order advantage achieved by modeling excitation-emission fluorescence matrices affected by inner filter effects using a strategy which combines standardization and calibration: reducing experimental and increasing analytical sensitivity.
A methodology based on second-order data (excitation emission matrices) modeling with one of most popular algorithms presenting the second-order advantage, parallel factor analysis (PARAFAC), combined with transference of calibration is proposed to predict the analyte concentration when significant inner filter effects occur, even in the presence of unexpected sample components. The quantitation of phenylephrine hydrochloride (PHE) in water samples (concentrations ranged between 250 and 750 ng mL(-1)) in the presence of ibuprofen, acetyl salicylic acid and paracetamol (which produce inner filter effect across the useful wavelength range) was achieved. The strategy allows reducing the experimental work and increasing the analytical sensitivity in the determination of the analyte of interest in the presence of unexpected compounds and matrix effect caused by inner filter, avoiding the preparation of a large number of solutions and maintaining acceptable figures of merit. Recoveries between 97 and 102% for validation and real spiked water samples, respectively, and a relative prediction error of 5% were achieved. Results were compared with those obtained after the application of the classical standard addition method combined with PARAFAC, carrying out five additions to each sample, in triplicate. The presented methodology constitutes a simple and low-cost method for the determination of PHE in water samples with a considerable reduction in standard handling and time. This methodology can be extended to other systems presenting matrix effect and, consequently, can become in a useful tool to know the amount of pharmaceuticals in the aquatic environment and to evaluate the effect of conventional wastewater treatment plants in the elimination of pharmaceutical compounds.