Twenty years of experience in revision cochlear implant surgery: signs that indicate the need for revision surgery to audiologists.
To report device failures, audiological signs and other reasons for revision cochlear implant surgery, and discuss indications for revision surgery. Revision procedures between November 1997 and August 2017 were retrospectively analysed. Over 20 years, 2181 cochlear implant operations were performed, and 114 patients underwent 127 revision operations. The revision rate was 4.67 per cent. The full insertion rate for revision cochlear implant surgery was 88.2 per cent. The most frequent reasons for revision surgery were: device failure (59 per cent), wound breakdown (9.4 per cent) and electrode malposition (8.7 per cent). The device failure rate was: 2.78 per cent for Advanced Bionics, 1.82 per cent for Cochlear and 5.25 per cent for Med-El systems. The number of active electrodes was significantly increased only for Med-El devices after revision surgery. The most common complaints among 61 patients were: gradually decreased auditory performance, sudden internal device shutdown and headaches. The most common reason for revision surgery was device failure. Patients should be evaluated for device failure in cases of: no hearing despite appropriate follow up, side effects such as facial nerve stimulation, and rejection of speech processor use in paediatrics. After revision surgery, most patients have successful outcomes.


Collision judgment of objects approaching the head.
Recent investigations have indicated that human perception of the trajectory of objects approaching in the horizontal plane is precise but biased away from straight ahead. This is remarkable because it could mean that subjects perceive objects that approach on a collision course as missing the head. Approach within the horizontal plane through the eyes and the fixation point (the plane of regard) is special, as general motions will also have a component of motion perpendicular to the plane of regard. Thus, we investigated three-dimensional motion perception in the vicinity of the head, including vertical components. Subjects judged whether an object that moved in the mid-sagittal plane was going to hit below or above a well-known reference point on the face like the center of the chin or the forehead (perceptual task). Tactile and proprioceptive information about the reference point significantly improved precision. Precision did not change with distance of the approaching target or with fixation direction. Bias was virtually absent for these vertical motions. When subjects pointed with their index finger to the perceived location of impact on their face (visuo-motor task), they overestimated (1.7 cm) the horizontal eccentricity of the point of impact (pointing task). Vertical bias, however, was again virtually absent. Interestingly, when trajectories intersected the plane of regard, higher precision was observed in the perceptual task regardless of the other conditions. In contrast, neither bias nor precision of the pointing task changed significantly when the trajectories intersected the plane of regard. When asked to point to the location where a trajectory intersected the plane of regard, subjects overestimated the depth component of this intersection location by about 3 cm. The absence of perceptual and pointing bias in the vertical direction in contrast to the clear horizontal bias suggests that different (combinations of) cues are used to judge these components of the trajectory of an approaching object. The results of our perceptual task suggest a role for somatosensory signals in the visual judgment of impending impact.


A Good Way to Reduce Screening for Retinopathy of Prematurity: Development of the ROP Model in a China Preterm Population.
Importance: Retinopathy of prematurity (ROP) is a preventable cause of blindness in children. Without treatment, more than 45% of eyes may suffer permanent vision loss. Current ROP screening guidelines, which include a range of birth weights (BWs) and gestational ages (GAs), may require screening many low-risk preemies who might develop severe ROP. Method: All high-risk infants in the neonatal intensive care unit (NICU) of the First Affiliated Hospital of Zhengzhou University from 2017 to 2021 were included in this retrospective cohort study. Each of the 27 candidate risk factors was evaluated in univariate analysis and adjusted for known risk factors (i.e., GA and BW). The significant results were analyzed in a backward selection multivariate logistic regression model. Receiver operating characteristic (ROC) curves and a nomogram were drawn. Results: The study included 2,040 infants who underwent ROP screening. The weight gain rate [OR, 2.65; 95% confidence interval (CI), 1.49-1.21 ≤ 12 g/d vs. > 18 g/d; P = 0.001], blood transfusion (OR, 2.03; 95% CI, 1.14-3.64; P = 0.017), invasive mechanical ventilation (OR, 1.74; 95% CI, 1.15-2.66; P = 0.009) and N-terminal segment of pro-B-type natriuretic peptide (NT-proBNP) ≥ 25,000 ng/L (OR, 1.51; 95% CI, 1.00-2.28; P = 0.048) were four new statistically independent risk factors in addition to GA and BW. The area under the curve (AUC) of the final multivariate model was 0.90 (95% CI, 0.88-0.92; P < 0.001). Conclusions and Relevance: These findings add to our understanding of ROP screening because they include all eligible infants rather than only high-risk infants, as in previous studies. Under the control of BW and GA, low weight gain rate, increased number of blood transfusion, invasive mechanical ventilation and NT-proBNP ≥ 25,000 ng/L were "new" statistically independent risk factors for ROP. The ROP risk can be calculated manually or represented by a nomogram for clinical use.


Inflammation of paranasal sinuses: the clinical pattern is age-dependent.
Acute rhinosinusitis (ARS) represents a common disorder, associated with consistent morbidity as well as with a large prescription of antibiotics. ARS has a significant impact on clinical practice; it usually presents with respiratory complaints persisting longer than 10 days and showing no signs of improvement. Throughout the evaluation of 256 pediatric patients (152 males and 135 females, aged between 2 and 15 yr), with ARS confirmed by nasal endoscopy, we have been able to provide evidence that age has a significant influence on clinical patterns in children with ARS.


Physicochemical Changes of Contaminated Titanium Discs Treated With Erbium-Doped Yttrium Aluminum Garnet (Er:YAG) Laser Irradiation or Air-Flow Abrasion: An In Vitro Study.
Introduction: Peri-implantitis is a common complication of dental implant treatment. A cause-and-effect relationship has been previously documented between microbial plaque and peri-implantitis and implant failure. A difference has been reported in the disinfection efficacy of erbium laser irradiation and air-flow abrasion for contaminated titanium surfaces. Also, the surface changes caused by lasers and air-flow abrasion have not been well studied. Thus, the purpose of this study was to compare the surface changes of contaminated titanium discs following decontamination by erbium-doped yttrium aluminum garnet (Er:YAG) laser irradiation and air-flow abrasion. Methods: Twenty-eight intact, sandblasted, and acid-etched (SLA) titanium discs were used. Twenty-four titanium discs were contaminated with Escherichia coli. Then, they were decontaminated by using Er:YAG laser irradiation and air-flow abrasion. Four discs remained intact. The mean and standard deviation of the contact angle and the weight percentage of aluminum, titanium, oxygen, carbon, phosphorus, and calcium were measured. Qualitative changes in surface topography of titanium discs were assessed by scanning electron microscopy (SEM). Results: The mean weight percentage of carbon in the air-flow abrasion group (4.98%) experienced a significant reduction compared with the contaminated (positive control) group (P=0.035). The contact angles were 46.54° and 38.67° in the laser and air-flow abrasion groups respectively, which were significantly lower than the value in the positive control group (75.15°) (P ≤0.001). SEM micrographs showed no significant change in the surface area in either technique. Conclusion: Air-flow abrasion was more successful in improving the surface characteristics of titanium discs with no alteration in surface topography or elements, compared with Er:YAG laser irradiation. Further studies regarding the safety of the Er:YAG laser for the decontamination of titanium surfaces are recommended.


The Boston marathon bombings: the early plastic surgery experience of one Boston hospital.
On April 15, 2013, at approximately 2:49 p.m. EDT, two improvised explosive devices detonated near the finish line of the 117th Boston Marathon. Patients were transported from the scene to several trauma centers, including the authors' institution. Plastic surgical assessment of patients began in the Emergency Department and then rapidly expanded as the scope of the incident became clear. Daily interdisciplinary meetings involving the acute care surgery, orthopedic surgery, plastic surgery, and nursing services were convened in order to coordinate operating room schedules and treatment plans. An interdisciplinary weekly clinic continued until all patient goals had been reached. Twenty-four patients were treated at Beth Israel Deaconess Medical Center within the first 24 hours of the Boston Marathon bombing. Seven were triaged directly to the operating room from the Emergency Department. The Division of Plastic Surgery was directly involved with the care of 11 patients, all of whom were treated surgically within 24 hours of the bombing. Patients were aged 23 to 50 years old. All 11 patients sustained lower extremity injuries with gross contamination. Four patients also sustained significant upper extremity trauma. Injuries included extremity amputations and fractures, soft-tissue loss, impaction of nails and other debris, burns, ocular injury, and ruptured tympanic membranes. Twenty-four patients received acute care at Beth Israel Deaconess Medical Center following the Boston Marathon bombing. Institution of dedicated interdisciplinary daily rounds, protected operating room block time, and joint follow-up clinic allowed for efficient early diagnosis and treatment of patients' injuries.


Harnessing Cerebrospinal Fluid Biomarkers in Clinical Trials for Treating Alzheimer's and Parkinson's Diseases: Potential and Challenges.
No disease-modifying therapies (DMT) for neurodegenerative diseases (NDs) have been established, particularly for Alzheimer's disease (AD) and Parkinson's disease (PD). It is unclear why candidate drugs that successfully demonstrate therapeutic effects in animal models fail to show disease-modifying effects in clinical trials. To overcome this hurdle, patients with homogeneous pathologies should be detected as early as possible. The early detection of AD patients using sufficiently tested biomarkers could demonstrate the potential usefulness of combining biomarkers with clinical measures as a diagnostic tool. Cerebrospinal fluid (CSF) biomarkers for NDs are being incorporated in clinical trials designed with the aim of detecting patients earlier, evaluating target engagement, collecting homogeneous patients, facilitating prevention trials, and testing the potential of surrogate markers relative to clinical measures. In this review we summarize the latest information on CSF biomarkers in NDs, particularly AD and PD, and their use in clinical trials. The large number of issues related to CSF biomarker measurements and applications has resulted in relatively few clinical trials on CSF biomarkers being conducted. However, the available CSF biomarker data obtained in clinical trials support the advantages of incorporating CSF biomarkers in clinical trials, even though the data have mostly been obtained in AD trials. We describe the current issues with and ongoing efforts for the use of CSF biomarkers in clinical trials and the plans to harness CSF biomarkers for the development of DMT and clinical routines. This effort requires nationwide, global, and multidisciplinary efforts in academia, industry, and regulatory agencies to facilitate a new era.


Treatment and clinical outcomes in anti-p200 pemphigoid: a systematic review.
Current treatment paradigms in anti-p200 pemphigoid rely on low levels of evidence, primarily originating from case reports and case series. To systematically review the utilized treatment modalities for anti-p200 pemphigoid and to synthesize the available clinical outcomes of treated patients. We conducted a systematic review of the literature using Ovid-Medline (1946-2018), Embase (1947-2018) and Web of Science (1900-2018) databases with a broad and inclusive search strategy along with a subsequent search of retrieved articles. All case reports and case series of patients with anti-p200 pemphigoid were included. Sixty-eight eligible studies comprising 113 anti-p200 pemphigoid patients with a mean age of 65.5 years were included in the qualitative synthesis. The clinical outcome of patients following treatment was reported for 91 (80.5%) patients, of whom 83 (91.2%) had achieved complete remission at least once. Complete remission on-therapy was observed in 51 (56.0%) and complete remission off-therapy in 12 (13.2%) patients. Thirty-six (39.6%) patients had experienced at least one flare during the duration of follow-up. A combination of systemic corticosteroids and adjuvant immunomodulatory agents was the leading therapeutic approach (63.0%) required for disease control. Systemic and topical corticosteroids as monotherapy were sufficient to control the disease in 19.6% and 13.0% of cases, respectively. Dapsone was the most commonly used (41.3%) adjuvant agent. The highest rates of complete remission were achieved in patients managed by systemic corticosteroids as monotherapy (100%) and in those managed by systemic corticosteroids with adjuvant agents (90.7%). Conversely, 45.5% of patients treated only by topical corticosteroids experienced at least one relapse during follow-up. The vast majority of patients had reached a complete remission during the course of the disease, whereas a considerable proportion of patients experienced at least one relapse. A combination of systemic corticosteroids and adjuvant immunomodulatory agents was the most frequently utilized therapeutic approach.


Chew on This: Not All First Finger Foods Are Created Equal.
The American Academy of Pediatrics (AAP) recommends when to start first finger foods (FFFs) and what types of foods to start with, but it is unclear whether products marketed as FFF comply with these recommendations. We evaluated FFF products for compliance with AAP recommendations and product safety using 41 adult product testers, who were asked to dissolve each product in their mouth. Product characteristics, comments pertaining to product safety, and time to dissolve each product were recorded. Only 2 products met all AAP criteria, and safety concerns were raised for an additional 2 products. One product showed a large change in dissolvability after being left out of original packaging. Consumers should not assume that products marketed for infant/toddler consumption comply with AAP recommendations. Also, products left out of original packaging may change consistency, presenting a choking hazard. Additional research is warranted to guide the development of regulations surrounding labeling and marketing of these foods.


Depleted uranium induces neoplastic transformation in human lung epithelial cells.
Depleted uranium (DU) is commonly used in military armor and munitions, and thus, exposure of soldiers and noncombatants is frequent and widespread. Previous studies have shown that DU has both chemical and radiological toxicity and that the primary route of exposure of DU to humans is through inhalation and ingestion. However, there is limited research information on the potential carcinogenicity of DU in human bronchial cells. Accordingly, we determined the neoplastic transforming ability of particulate DU to human bronchial epithelial cells (BEP2D). We observed the loss of contact inhibition and anchorage independent growth in cells exposed to DU after 24 h. We also characterized these DU-induced transformed cell lines and found that 40% of the cell lines exhibit alterations in plating efficiency and no significant changes in the cytotoxic response to DU. Cytogenetic analyses showed that 53% of the DU-transformed cell lines possess a hypodiploid phenotype. These data indicate that human bronchial cells are transformed by DU and exhibit significant chromosome instability consistent with a neoplastic phenotype.


Outbreak of unusual Salmonella enterica serovar Typhimurium monophasic variant 1,4 [5],12:i:-, Italy, June 2013 to September 2014.
Monophasic variant of Salmonella enterica subspecies enterica serovar Typhimurium (monophasic S. Typhimurium), with antigenic structure 1,4,[5],12:i:-, appears to be of increasing importance in Europe. In Italy, monophasic S. Typhimurium represented the third most frequent Salmonella serovar isolated from human cases between 2004 and 2008. From June 2013 to October 2014, a total of 206 human cases of salmonellosis were identified in Abruzzo region (Central Italy). Obtained clinical isolates characterised showed S. Typhimurium 1,4,[5],12:i:- with sole resistance to nalidixic acid, which had never been observed in Italy in monophasic S. Typhimurium, neither in humans nor in animals or foods. Epidemiological, microbiological and environmental investigations were conducted to try to identify the outbreak source. Cases were interviewed using a standardised questionnaire and microbiological tests were performed on human as well as environmental samples, including samples from fruit and vegetables, pigs, and surface water. Investigation results did not identify the final vehicle of human infection, although a link between the human cases and the contamination of irrigation water channels was suggested.


[Organogenesis of developing metanephroi allografted into nonimmunosuppressed adult rats].
To explore novel methods of possible donor organ supply and immunologic tolerance induction of organ transplantation. Whole metanephroi from d14-19 (E14-E19) embryos of pregnant rats were grouped and allografted into the omenta or near remnants of renal vessels of nonimmunosupressed adult rats. At the time of implantation, host rats underwent unilateral nephrectomy. Four weeks after implantation, allografted metanephroi in host rats were removed for gross, biochemical and histopathological examination. Four weeks post-implantation, (1) E19 and E18 metanephroi had enlarged,but were replaced by connective tissues. (2) E17 and E16 metanephroi showed the signs of acute rejection such as hypercellular glomeruli and lymphocyte infiltration in peritubular spaces. E16 grafted metanephroi underwent mild acute rejection of Banff schema, while E17 had moderate or severe acute rejection. When Cyclosporine A was administrated, E17 metanephroi formed mature nephrons and collecting ducts with few lymphocyte infiltration. (3) Metanephroi from E15 and E14 embryos allografted into the omentum or near remnants of renal vessels of uninephrectomized adult rats were enlarged and vascularized, and formed mature tubules and glomeruli. (4) The concentrations of urea nitrogen and creatinine in cyst fluid of E15 and E16 metanephroi were increased 40-fold and 50-fold, which were comparable to those in bladder urine. (5) In contrast, rat metanephroi did not grow or differentiate in rats without host kidney resection. E14 and E15 metanephroi allografted into nonimmunosuppressed adult rats or E17 into cyclosporine-treated hosts undergo growth and differentiation and become vascularized. A variety of factors affect the growth and development of allografted metanephroi, while rejection is the main one.


Elevated concentrations of endotoxin in indoor air due to cigarette smoking.
Exposure to environmental tobacco smoke (ETS) is an important worldwide public health issue. The present study demonstrates that cigarette smoke can be a major source of endotoxin (lipopolysaccharide, LPS) in indoor environments. Gas-chromatography/mass-spectrometry was used to determine 3-hydroxy fatty acids as markers of endotoxin in air-borne house dust in homes of smokers and non-smokers. Air concentrations of endotoxin were 4-63 times higher in rooms of smoking students than in identical rooms of non-smoking students. The fact that cigarette smoke contains large amounts of endotoxin may partly explain the high prevalence of respiratory disorders among smokers and may also draw attention to a hitherto neglected risk factor of ETS.


Epidermal growth factor receptor inhibition by tyrphostin 51 induces apoptosis in luteinized granulosa cells.
Growth factors may be involved in the control of ovarian cell fate and could contribute to regulation of ovarian cell apoptosis. Our objective is to test the hypothesis that, in human luteinized granulosa cells, epidermal growth factor (EGF) works through the MAPK signaling pathway and inhibition of EGF receptor by a specific tyrosine kinase inhibitor, tyrphostin 51, will inhibit the activation of MAPK and induce apoptosis. Luteinized granulosa cells from human in vitro fertilization aspirates were treated as follows: 1) vehicle (dimethylsulfoxide:ethanol), 2) EGF, 3) tyrphostin 51, and 4) tyrphostin 51 plus EGF. Blockage of EGF receptor by tyrphostin 51 reduced the MAPK activity and inhibited phosphorylation and nuclear translocation of activated MAPK. Blockage of EGF receptor also induced apoptosis as demonstrated by the activation of caspase-3, an executioner protease of the apoptotic pathway, and by an increased percentage of subdiploid apoptotic nuclei. These results support the hypothesis that in human luteinized granulosa cells, EGF works through the MAPK signaling pathway and that its inhibition by tyrphostin 51 inhibits MAPK phosphorylation and induces apoptotic nuclear changes. Our data thus provide additional information regarding regulation of apoptosis in luteinized granulosa cells.


[Effect of endoscopic vidian neurectomy in patients with coexisting allergic rhinitis and bronchial asthma].
Objective: To evaluate the clinical significance of endoscopic vidian neurectomy (EVN) on outcomes in patients with coexisting refractory allergic rhinitis (AR) and bronchial asthma, and to analyze its influence factor. Methods: Clinical data of 109 patients with moderate to severe persistent intractable AR and bronchial asthma who were allocated to the bilateral EVN group (surgery group, 70 cases) or conservative medication group (drug group, 39 cases) from 1 May 2008 to 30 April 2013 in Department of Otorhinolaryngology Head and Neck Surgery, Third Xiangya Hospital, Central South University were retrospectively analyzed, including 47 cases of male and 62 cases of female aged (32.7±6.8) years.Ninety-five patients were followed up for at least 3 years. The Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), Visual Analog Scale (VAS), Asthma Quality of Life Questionnaire (AQLQ), Total Asthma Symptom Score (TASS), forced expiratory volume in 1 second of predicted (FEV1) and medication scores were evaluated at 6 months, 1 year and 3 years after undergoing the initial treatments in the two groups. Multiple factor analysis was used to determine the factors influencing the improvement after EVN. Results: Postoperative scores of RQLQ were significantly lower than preoperative scores during follow-up in surgery group (the preoperative score and postoperative score at 6 months, 1 year, 3 years after operation was 2.39±0.61 (x±s), 0.81±0.43, 0.89±0.32, 1.06±0.24, respectively, all P<0.001). Postoperative scores of VAS were significantly lower than preoperative scores during follow-up in surgery group (the preoperative score and postoperative score at 6 months, 1 year,3 years after operation was 7.13±1.04, 2.52±1.47, 2.70±1.42, 2.85±1.64, respectively, all P<0.05). Scores of RQLQ and VAS in surgery group were significantly lower than those of drug group. Postoperative scores of AQLQ were significantly higher than preoperative scores during follow-up in surgery group (the preoperative score and postoperative score at 6 months, 1 year, 3 years after operation was 3.78±0.81, 4.99±0.45, 4.75±0.71, 4.62±0.64, respectively, all P<0.05), and were significantly higher than those of drug group. The TASS and FEV1 were not significantly changed in surgery group. The postoperative medication scores for AR were gradually reduced after surgery (the preoperative score and postoperative score at 6 months, 1 year, 3 years after operation was 0.99±0.21, 0.37±0.12, 0.39±0.26, 0.45±0.11, respectively, all P<0.05), and the postoperative medication scores for Asthma were gradually reduced after surgery too (the preoperative score and postoperative score at 6 months, 1 year, 3 years after operation was 1.27±0.31, 0.82±0.29, 0.85±0.23, 0.96±0.19, respectively, all P<0.05), and all the postoperative medication scores were significantly lower than those of drug group. At the end of the follow-up, the improvement rates for AR and asthma were 90.6% (58/64) and 45.3% (29/64), respectively. Asthma outcomes were significantly improved by controlling rhinitis symptoms in patients whose asthma attacks were induced by "rhinitis onset" or "climate change" . Conclusion: For patients with AR and bronchial asthma, EVN can significantly control AR symptoms, and improve asthma outcomes in patients whose asthma attacks are induced by rhinitis onset and/or climate change.


Experimental and theoretical studies of the products of laser-ablated thorium atom reactions with H2O in excess argon.
Reactions of laser-ablated Th atoms with H2O during condensation in excess argon have formed a variety of intriguing new Th, H, O species. Infrared absorptions at 1406.0 and 842.6 cm-1 are assigned to the H-Th and Th=O stretching vibrations of HThO. Absorptions at 1397.2, 1352.4, and 822.8 cm-1 are assigned to symmetric H-Th-H, antisymmetric H-Th-H, and Th=O stretching vibrations of the major primary reaction product H2ThO. Thorium monoxide (ThO) produced in the reaction inserts into H2O to form HThO(OH), which absorbs at 1341.0, 804.0, and 542.6 cm-1. Both HThO(OH) and ThO2 add another H2O molecule to give HTh(OH)3 and OTh(OH)2, respectively. Weaker thorium hydride (ThH1(-4)) absorptions were also observed. Relativistic DFT and ab initio calculations were performed on all proposed molecules and other possible isomers. The good agreement between experimental and calculated vibrational frequencies, relative absorption intensities, and isotopic shifts provides support for these first identifications of Th, H, O molecular species.


Wernicke's encephalopathy in a malnourished surgical patient: a difficult diagnosis.
Wernicke's encephalopathy is an acute neurological disorder resulting from thiamine deficiency mainly related to alcohol abuse. Severe thiamine deficiency is an emerging problem in non-alcoholic patients and it may develop in postoperative surgical patients with risk factors. We reported a case of a 46 years old woman who underwent, one year before, to cephalic duodenopancreatectomy complicated with prolonged recurrent vomiting. She underwent to a second surgical operation for intestinal sub-occlusion and postoperatively she developed septic shock and hemorrhagic Wernicke's disease. After ICU admission, because of neurological deterioration, she underwent CT scan and MRI that highlighted a strong suspicion for Wernicke's disease. We treated her with an initially wrong low dose of thiamine, then after MRI we increased the dosage with a neurological status improvement. Despite therapeutic efforts used to control septic shock and thrombocytopenia, she died on the 21st day after surgery because of massive cerebral bleeding and unresponsive cerebral edema. Early detection of subclinical thiamine deficiency is a difficult task, as symptoms may be nonspecific. Wernicke's disease remains a clinical diagnosis because there are no specific diagnostic abnormalities revealed in cerebrospinal fluid, electroencephalogram or evoked potentials. About this, the best aid for a correct diagnosis is the clinical suspicion and clinicians should consider the disorder in any patients with unbalanced nutrition, increased metabolism or impaired food absorption. A hallmark of our case was the brain hemorrhage in the typical areas of the Wernicke's disease, maybe triggered by the thrombocytopenia secondary to sepsis. It might be a good clinical practice administer thiamine to all patients presenting with coma or stupor and risk factors related with thiamine deficiency. Any therapeutic delay may result in permanent neurological damage or death.


Epidemiology of Breast Implant-Associated Anaplastic Large Cell Lymphoma in the United States: A Systematic Review.
Although textured implants represent fewer than 10% of implants used in the United States, the country reports the highest incidence of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). The aim of this study was to perform a systematic literature review on US-based epidemiology to update knowledge on BIA-ALCL in the United States. Publications on US BIA-ALCL epidemiology were searched between September 2022 and March 2023 on MEDLINE (National Institutes of Health; Bethesda, MD), Embase (Elsevier, Amsterdam, the Netherlands), Web of Science (Clarivate, London, UK), and SCOPUS (Elsevier, Amsterdam, the Netherlands). The US numerator was obtained by averaging the FDA MAUDE database and the PSF PROFILE registry, while the denominator was estimated from chest X-rays, and included female transgender individuals. Prevalence and risk were assessed accordingly, but the incidence rate (IR) could not be updated due to the lack of available follow-up data. Out of 987 identified manuscripts, 10 were included. The US prevalence of BIA-ALCL in the literature ranged from 1:300 to 1:500,000 and the IR from 4.5 per 10,000 to 31.1 per 100 million persons per year. A mean value of 453.5 BIA-ALCL cases was calculated. From a denominator of 4,264,618 individuals, which includes all breast implant surfaces, we calculated 414,521 individuals with textured implants, indicating a textured prevalence of 109.4 cases per 100,000 individuals and a risk of 1:913. BIA-ALCL IR, prevalence, and risk has increased when calculated exclusively for patients with textured devices. Although US macrotextured implants were recalled by the FDA, these findings may influence the surveillance of existing patients and the use of macrotextured implants in other parts of the world where they remain widespread.


Development, reproduction, and within-plant infestation patterns of Aphis craccivora (Homoptera: Aphididae) on alfalfa.
The goal of this research was to describe developmental rates, reproductive rates, and infestation patterns of Aphis craccivora Koch on alfalfa (Medicago sativa L.). All studies were conducted on the susceptible cultivar OK08 using aphids reared from collections made in Oklahoma. To determine thermal requirements for growth of A. craccivora, development from birth to adult was recorded at 7.2, 12.8, 18.3, 23.9, and 29.4 degrees C. The same constant temperature treatments (except for 7.2 degrees C being raised to 8.3 degrees C) were used to assess the influence of temperature on reproductive rates. Within-plant distribution patterns were determined by infesting three stems on each of 24 plants and recording numbers of A. craccivora on leaf blades, petioles, and internodal stems sections at 2-d intervals through 10 d after infestation. Aphid counts were analyzed to determine significant differences among node parts (leaf blades, petioles, and stem sections). The developmental threshold temperature for A. craccivora was calculated to be 7.1 degrees C, and the thermal constant for development from the first instar to reproducing adult was 100 DD ( degrees C). The optimal temperature range for reproduction on alfalfa was 18-24 degrees C, with a mean of 82 nymphs produced per female. From the initial infestation of three apterae per stem, numbers increased to a mean of 510 per stem after 10 d. Plant profiles showed that the greatest numbers of aphids were located in middle and lower portions of the plant canopy. On all sampling dates, the proportion of aphids on internodal stem sections was significantly greater (P < 0.05) than on petioles and leaf blades.


Surface Patterning of Closed Nanochannel Using VUV Light and Surface Evaluation by Streaming Current.
In nanofluidics, surface control is a critical technology because nanospaces are surface-governed spaces as a consequence of their extremely high surface-to-volume ratio. Various surface patterning methods have been developed, including patterning on an open substrate and patterning using a liquid modifier in microchannels. However, the surface patterning of a closed nanochannel is difficult. In addition, the surface evaluation of closed nanochannels is difficult because of a lack of appropriate experimental tools. In this study, we verified the surface patterning of a closed nanochannel by vacuum ultraviolet (VUV) light and evaluated the surface using streaming-current measurements. First, the C18 modification of closed nanochannels was confirmed by Laplace pressure measurements. In addition, no streaming-current signal was detected for the C18-modified surface, confirming the successful modification of the nanochannel surface with C18 groups. The C18 groups were subsequently decomposed by VUV light, and the nanochannel surface became hydrophilic because of the presence of silanol groups. In streaming-current measurements, the current signals increased in amplitude with increasing VUV light irradiation time, indicating the decomposition of the C18 groups on the closed nanochannel surfaces. Finally, hydrophilic/hydrophobic patterning by VUV light was performed in a nanochannel. Capillary filling experiments confirmed the presence of a hydrophilic/hydrophobic interface. Therefore, VUV patterning in a closed nanochannel was demonstrated, and the surface of a closed nanochannel was successfully evaluated using streaming-current measurements.


How Do We Assess Energy Availability and RED-S Risk Factors in Para Athletes?
Low energy availability (LEA) is considered to be the underlying cause of a number of maladaptations in athletes, including impaired physiological function, low bone mineral density (BMD), and hormonal dysfunction. This is collectively referred to as 'Relative Energy Deficiency in Sport' (RED-S). LEA is calculated through assessment of dietary energy intake (EI), exercise energy expenditure (EEE) and fat-free mass (FFM). The incidence of LEA in Paralympic athletes is relatively unknown; however, there are legitimate concerns that Para athletes may be at even higher risk of LEA than able-bodied athletes. Unfortunately, there are numerous issues with the application of LEA assessment tools and the criterion for diagnosis within the context of a Para population. The calculation of EEE, in particular, is limited by a distinct lack of published data that cover a range of impairments and activities. In addition, for several RED-S-related factors, it is difficult to distinguish whether they are truly related to LEA or a consequence of the athlete's impairment and medical history. This narrative review outlines deficits and complexities when assessing RED-S and LEA in Para athletes, presents the information that we do have, and provides suggestions for future progress in this important area of sports nutrition.


Micronucleus determination as a means to assess radiation exposure.
Radiation accidents require an easy to perform and rapid determination of the radiation response of the victim(s) affected by the exposure. Micronuclei in cytochalasin B blocked lymphocytes are able to serve this purpose. Micronuclei are particularly useful when it comes to screening many exposed people after a more or less homogeneous whole body exposure with a high dose rate. There are problems, as is the case for most biological indicators, with partial body (especially when it is due to internal emitters), chronic and fractionated exposure.


High ten-year implant survivorship and low patellofemoral complication rate for S-ROM rotating-hinge implants in revision total knee arthroplasty : a single-centre study.
The aim of this study was to evaluate medium-term outcomes and complications of the S-ROM NOILES Rotating Hinge Knee System (DePuy, USA) in revision total knee arthroplasty (rTKA) at a tertiary unit. A retrospective consecutive study of all patients who underwent a rTKA using this implant from January 2005 to December 2018. Outcome measures included reoperations, revision for any cause, complications, and survivorship. Patients and implant survivorship data were identified through both local hospital electronic databases and linked data from the National Joint Registry/NHS Personal Demographic Service. Kaplan-Meier survival analysis was used at ten years. A total of 89 consecutive patients (89 knees) were included with 47 females (52.8%) and a median age of 74 years (interquartile range 66 to 79). The main indications were aseptic loosening with instability (39.4%; n = 35) and infection (37.1%; n = 33) with the majority of patients managed through two-stage approach. The mean follow-up was 7.4 years (2 to 16). The overall rate of reoperation, for any cause, was 10.1% (n = 9) with a rate of implant revision of 6.7% (n = 6). Only two cases required surgery for patellofemoral complications. Kaplan-Meier implant-survivorship analysis was 93.3% at ten years, using revision for any cause as an endpoint. This implant achieved high ten-year survivorship with a low complication rate, particularly patellofemoral complications. These can be avoided by ensuring central patella tracking and appropriate tension of the patellofemoral joint in this posterior hinge design. Cite this article: Bone Jt Open 2022;3(3):205-210.


68Ga-PSMA 11 ligand PET imaging in patients with biochemical recurrence after radical prostatectomy - diagnostic performance and impact on therapeutic decision-making.
To evaluate the diagnostic performance of [68Ga]Ga-PSMAHBED-CC conjugate 11 positron emission tomography (PSMA-PET) in the early detection of metastases in patients with biochemical recurrence (BCR) after radical prostatectomy (RP) for clinically non-metastatic prostate cancer, to compare it to CT/MRI alone and to assess its impact on further therapeutic decisions. We retrospectively assessed 117 consecutive hormone-naïve BCR patients who had 68Ga-PSMA 11 PET/CT (n = 46) or PET/MRI (n = 71) between May 2014 and January 2017. BCR was defined as two PSA rises above 0.2 ng/ml. Two dedicated uro-oncological imaging experts (radiology/nuclear medicine) reviewed separately all images. All results were presented in a blinded sequential fashion to a multidisciplinary tumorboard in order to assess the influence of PSMA-PET imaging on decision-making. The median time from RP to BCR was 36 months (IQR 16-72). Overall, 69 (59%) patients received postoperative radiotherapy. Median PSA level at the time of imaging was 1.04 ng/ml (IQR 0.58-1.87). PSMA-positive lesions were detected in 100 (85.5%) patients. Detection rates were 65% for a PSA value of 0.2 to <0.5 ng/ml, 85.7% for 0.5 to <1, 85.7% for 1 to <2 and 100% for ≥2. PSMA-positive lesions could be confirmed by either histology (16%), PSA decrease in metastasis-directed radiotherapy (45%) or additional information in diffusion-weighted imaging when PET/MRI was performed (18%) in 79% of patients. PSMA-PET detected lesions in 67 patients (57.3%) who had no suspicious correlates according to the RECIST 1.1 criteria on MRI or CT. PSMA-PET changed therapeutic decisions in 74.6% of these 67 patients (p < 0.001), with 86% of them being considered for metastases-directed therapies. We confirm the high performance of PSMA-PET imaging for the detection of disease recurrence sites in patients with BCR after RP, even at relatively low PSA levels. Moreover, it adds significant information to standard CT/MRI, changing treatment strategies in a significant number of patients.


An immunohistochemical study of sarcomatoid liver carcinomas.
Six cases of primary hepatic carcinomas with a significant amount of sarcomatoid elements were examined by using immunohistochemical stainings. Four of the six cases were associated with ordinary hepatocellular carcinoma (HCC), one with cholangiocellular carcinoma (CCC), and one with mixed HCC and CCC. Alpha-fetoprotein and alpha-1-antitrypsin were negative in sarcomatoid cells of all cases; vimentin stained positively in sarcomatoid tumor cells in two of the six cases; and cytokeratin (CK8) was detected in five cases. The CK8 was not detected in tumor cells of two cases of hepatic angiosarcoma, two of metastatic leiomyosarcomas, and one of metastatic fibrosarcoma, although vimentin stained positively in all these true sarcomas. It was concluded that sarcomatoid dedifferentiation of liver carcinomas might derive from both HCC and CCC. In addition CK8 might be an excellent marker to make a differential diagnosis of sarcomatoid cancers from true metastatic or primary sarcomas of the liver.


Overexpression of manganese superoxide dismutase promotes the survival of prostate cancer cells exposed to hyperthermia.
It has been hypothesized that exposure of cells to hyperthermia results in an increased flux of reactive oxygen species (ROS), primarily superoxide anion radicals, and that increasing antioxidant enzyme levels will result in protection of cells from the toxicity of these ROS. In this study, the prostate cancer cell line, PC-3, and its manganese superoxide dismutase (MnSOD)-overexpressing clones were subjected to hyperthermia (43 degrees C, 1 h). Increased expression of MnSOD increased the mitochondrial membrane potential (MMP). Hyperthermic exposure of PC-3 cells resulted in increased ROS production, as determined by aconitase inactivation, lipid peroxidation, and H2O2 formation with a reduction in cell survival. In contrast, PC-3 cells overexpressing MnSOD had less ROS production, less lipid peroxidation, and greater cell survival compared to PC-3 Wt cells. Since MnSOD removes superoxide, these results suggest that superoxide free radical or its reaction products are responsible for part of the cytotoxicity associated with hyperthermia and that MnSOD can reduce cellular injury and thereby enhance heat tolerance.


Are of Osteomeatal Complex Variations Related to Nasolacrimal Canal Morphometry.
Due to the close anatomic relationship between paranasal structures and NLC, the morphometric measure of the nasolacrimal canal (NLC) could be affected by the osteomeatal complex (OMC) anatomical variations. The present study aimed to assess the effect of OMC variations on the NLC morphometric features using cone-beam computed tomography (CBCT). This cross-sectional study consisted of CBCT images of 150 subjects in the case group with at least one OMC variation and 40 cases in the control group without any OMC variation within the age range of 18-50 years. The presence of the OMC variations, including agger nasi, nasal septum deviation, concha bullosa, Haller cells, paradoxical middle turbinate, and pneumatization of the uncinate process, was evaluated in each patient. The NLC morphometric measurements were performed and compared between the case and control groups. The middle anteroposterior diameter and middle sectional area of NCL were significantly higher in patients with OMC variations, as compared to that in the control group. The NLC volume was significantly higher in patients with agger nasi, nasal septum deviation, concha bullosa, and pneumatization of the uncinate process, as compared to that in the control group. Nonetheless, no significant difference in NLC angulation with the nasal floor or Frankfurt horizontal plane was observed in the presence of each OMC variation. As evidenced by the obtained results, a higher volume of the canal was revealed in the presence of some of the OMC variations. Therefore, it can be suggested that OMC variations cannot be a predisposing factor in cases with primary acquired nasolacrimal duct obstruction.


Perceptions and knowledge of antipsychotics among mental health professionals and patients.
Aims and method To assess the patients' most influential concerns regarding long-acting injectable antipsychotics (LAIs) and mental health professionals' preconceptions about these concerns. For both groups, to assess the level of knowledge about LAIs. This cross-sectional study used semi-structured interviews of patients with schizophrenia or schizoaffective disorder (n = 164), nurses (n = 43) and physicians (n = 20). Results The mental health professionals overestimated many of the patients' fears of LAIs, and the expressed fears exceeded the actual experiences of patients already on LAIs. Acceptance to switch to LAIs was associated with shorter time from diagnosis. Nurses and patients disclosed limited knowledge of antipsychotics. Clinical implications Physicians and nurses should aim to identify the individual patient's concerns about LAIs in the discussion about choice of antipsychotic treatment early in the course of illness.


Group B streptococci and other gram-positive cocci bind to cytokeratin 8.
Group B streptococci (GBS) adhere to surface receptors present on epithelial cells; these receptors include fibronectin and laminin. To identify other possible receptors, plasma membranes from A549 cells, a respiratory tract epithelial cell line, were prepared. These plasma membranes were tested in a protein blot analysis using radiolabeled GBS as a probe. GBS adhered to two species, with molecular masses of 50 kDa (p50) and 57 kDa (p57). We concluded that p50 and p57 correspond to two forms of cytokeratin 8 (CK8) on the basis of the following results: (i) protein blot results demonstrated that p50 and p57 exactly comigrated with two forms of CK8 after separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (PAGE); (ii) p50 and p57 exactly comigrated with CK8 after separation by two-dimensional PAGE; (iii) CK8 in solution bound to GBS, as demonstrated by immunoblot analysis of proteins from A549 lysates that bound to GBS in a liquid-phase assay; and (iv) radiolabeled GBS bound to A549 lysate-derived CK8 that had been captured in anti-CK8-coated microtiter wells. CK8 bound to COH1-13, an acapsular mutant of COH1, demonstrating that adherence is not mediated by capsular polysaccharide. Trypsin-treated GBS did not bind to CK8, indicating that adherence is mediated via a protein on the surface of GBS. Soluble CK8 bound to six of six GBS strains tested. Soluble CK8 also bound to Staphylococcus aureus, Lactococcus lactis, Enterococcus faecalis, and Streptococcus pyogenes. We hypothesize that adherence of GBS to cytokeratin may be important for maintenance of colonization at sites of keratinized epithelium, such as the vagina, or for adherence of these bacteria to damaged epithelial cells at other sites.


Agro-Fruit-Forest Systems Based on Argan Tree in Morocco: A Review of Recent Results.
The argan tree, Argania spinosa (L.) Skeels, is a horticultural forestry species characterized by its endemicity and adaptation to arid and semi-arid zones in the southwest of Morocco. Despite its limited geographical distribution, argan tree presents large genetic diversity, suggesting that improvement of argan is possible. This species plays important ecological, and socioeconomic roles in the sustainable development of the country. The integration of arganiculture into Moroccan agricultural policy has been implemented through a sector strategy, which is fully aligned with the conservation and regeneration of argan forest. A. spinosa is suitable for incorporation into different agroforestry productive systems under agro-fruit-forest model and its domestication will provide a powerful means of socio-economic and environmental management. Here, we provide an overview of the argan tree literature and highlight the specific aspects of argan stands, as agro-forest systems, with the aim of developing an adequate strategy of conservation and domestication of this species. We introduce promising programs and projects for argan plantations and arganiculture, which have been adopted to relieve anthropogenic pressure on the natural argan forest.


Understanding macrophage diversity at the ontogenic and transcriptomic levels.
Macrophages are phagocytes characterized by high lysosomal activity and are involved in a wide range of biological processes. Consequently, macrophages have long been recognized for their critical roles in development as well as in healthy and pathological states. Our knowledge about macrophage biology has evolved greatly over the past several years. Significantly, it has now been demonstrated that monocytes are not direct precursors for most tissue-resident macrophages at the steady state. Only few tissue macrophage populations derive from monocytes during homeostasis; rather, monocytes give rise to inflammatory macrophages that infiltrate tissues during inflammation. Tissue-resident macrophages have recently been characterized at the transcriptional level, which provided the basis to uncover the molecular pathways controlling their functional diversity as well as to identify a core signature. Transcription factors controlling specific tissue-resident macrophage populations have been described, suggesting that diversity is under the control of specific regulatory programs. In this review, we discuss and summarize several of the new paradigms emerging in the field of macrophage biology. In particular, we emphasize new findings relevant to macrophage ontogeny, similarities and differences observed across macrophage populations, and gene regulatory programs controlling specialized aspects of tissue macrophage functions.


Combining Urease and Nitrification Inhibitors with Incorporation Reduces Ammonia and Nitrous Oxide Emissions and Increases Corn Yields.
Less than 50% of applied nitrogen (N) fertilizer is typically recovered by corn ( L.) due to climatic constraints, soil degradation, overapplication, and losses to air and water. Two application methods, two N sources, and two inhibitors were evaluated to reduce N losses and enhance crop uptake. The treatments included broadcast urea (BrUrea), BrUrea with a urease inhibitor (BrUrea+UI), BrUrea with a urease and a nitrification inhibitor (BrUrea+UI+NI), injection of urea ammonium nitrate (InjUAN), and injected with one or both inhibitors (InjUAN+UI, InjUAN+UI+NI), and a control. The BrUrea treatment lost 50% (64.4 kg N ha) of the applied N due to ammonia volatilization, but losses were reduced by 64% with BrUrea+UI+NI (23.0 kg N ha) and by 60% with InjUAN (26.1 kg N ha). Ammonia losses were lower and crop yields were greater in 2014 than 2013 as a result of the more favorable weather when N was applied in 2014. When ammonia volatilization was reduced by adding a urease inhibitor, NO emissions were increased by 30 to 31% with BrUrea+UI and InjUAN+UI compared with BrUrea and InjUAN, respectively. Pollution swapping was avoided when both inhibitors were used (BrUrea+UI+NI, InjUAN+UI+NI) as both ammonia volatilization and NO emissions were reduced, and corn grain yields increased by 5% with BrUrea+UI+NI and by 7% with InjUAN+UI+NI compared with BrUrea and InjUAN, respectively. The combination of two N management strategies (InjUAN+UI+NI) increased yields by 19% (12.9 t ha) compared with BrUrea (10.8 t ha).


Manual handling risk management: critical care beds and support systems.
This article examines the reduction of manual handling risk to nurses through discussion of the technical and ergonomic features of critical care beds and support systems. It describes the features of different types of manual handling equipment, in particular trolleys, beds and patient platform support surfaces.


Transcriptome Analysis of Peripheral Blood Mononuclear Cells in Pulmonary Sarcoidosis.
Sarcoidosis is a granulomatous systemic disease of unknown etiology. Mononuclear cells such as macrophages or lymphocytes in lung tissue and hilar or mediastinal lymph nodes have been recognized to play an essential role in granuloma formation in pulmonary sarcoidosis. Peripheral blood mononuclear cells (PBMCs) consist of several immunocompetent cells and have been shown to play a mechanistic role in the pathogenesis of sarcoidosis. However, the genetic modifications that occur in bulk PBMCs of sarcoidosis remain to be elucidated. This study aimed to explore the pathobiological markers of sarcoidosis in PBMCs by comparing the transcriptional signature of PBMCs from patients with pulmonary sarcoidosis with those of healthy controls by RNA sequencing. PBMC samples were collected from subjects with pulmonary sarcoidosis with no steroid/immunosuppressant drugs (n = 8) and healthy controls (n = 11) from August 2020 to April 2021, and RNA sequencing was performed with the PBMC samples. Principal component analysis using RNA sequencing datasets comparing pulmonary sarcoidosis with healthy controls revealed that the two groups appeared to be differentiated, in which 270 differentially expressed genes were found in PBMCs between sarcoidosis and healthy controls. Enrichment analysis for gene ontology suggested that some biological processes related to the pathobiology of sarcoidosis, such as cellular response to interleukin (IL)-1 and IFN-γ, regulation of IL-6 production, IL-8 secretion, regulation of mononuclear cell migration, and response to lipopolysaccharide, were involved. Enrichment analysis of the KEGG pathway indicated the involvement of tumor necrosis factor (TNF), toll-like receptor signaling, IL-17 signaling pathways, phagosomes, and ribosomes. Most of the genes involved in TNF and IL-17 signaling pathways and phagosomes were upregulated, while most of the ribosome-related genes were downregulated. The present study demonstrated that bulk gene expression patterns in PBMCs were different between patients with pulmonary sarcoidosis and healthy controls. The changes in the gene expression pattern of PBMCs could reflect the existence of sarcoidosis lesions and influence granuloma formation in sarcoidosis. These new findings are important to strengthen our understanding of the etiology and pathobiology of sarcoidosis and indicate a potential therapeutic target for sarcoidosis.


Combination therapy with AG-490 and interleukin 12 achieves greater antitumor effects than either agent alone.
Constitutive activation of Janus kinases (JAKs) and signal transducers and activators of transcription (STAT) occurs at very high frequency in various hematopoietic malignancies and solid tumors. It has been demonstrated that the tyrosine kinase inhibitor, AG-490, selectively blocks JAK activity and completely eliminates leukemia cells in a severe combined immunodeficient (SCID) mouse model. Because many cytokines, including interleukin (IL)-12, have been shown to signal through JAK/STAT pathways, AG-490 may inhibit cytokine-based cancer therapy. In this study, we evaluated the effects of AG-490 on IL-12 functional signaling and IL-12-mediated antitumor response in vivo. Previous studies have established the critical roles of macrophages and IFN-gamma in mediating IL-12-induced antitumor effects. Our results show that in vivo administration of AG-490 causes tumor cell apoptosis but does not inhibit IL-12-mediated macrophage activation and IFN-gamma production by lymphocytes. Furthermore, our data indicate that combined therapy with AG-490 and IL-12-induces greater antitumor effects than either agent alone in a murine myeloma tumor model. These results suggest that JAK/STAT inhibitors deserve further investigation for use with IL-12 therapy in treating human cancers with elevated JAK/STAT activity.


Novel Synthesis of Cu-Schiff Base Complex@Metal-Organic Framework MIL-101 via a Mild Method: A Comparative Study for Rapid Catalytic Effects.
The use of metal complex immobilized/decorated porous materials as catalysts has found various applications. As such, finding a new and mild method for synthesis of metal complex immobilized over porous material is of great interest. Immobilized porous materials for styrene oxidation were reported in this work. Immobilized porous material of Cu-Schiff base complex @MIL-101 were described, in which immobilized Cu-Schiff base complex within super cage of a metal-organic framework (MOF)-based porous material, chromium (III) terephthalate MIL-101. They were systematically characterized by using elemental analysis, powder X-ray diffraction, fourier transform infrared spectroscopy, N2 absorption-desorption, and so on, also used as catalyst for the selective oxidation of styrene to benzaldehyde. Comparatively, the immobilized heterogeneous catalyst of Cu-Schiff base complex@MIL-101 acted as an efficient heterostructure catalyst in the oxidation of styrene to benzaldehyde up to six cycles, and showed superior activity for styrene oxidation over MIL-101.


MUTYH exon 7 and 13 mutations associated with colorectal cancer (MAP syndrome) are not commonly associated with sporadic pancreatic cancer.
Biallelic MUTYH exon 7 and 13 mutations are associated with a high frequency of somatic K-ras gene guanine to thymine transversion mutations at codon 12 position 1 in MUTYH-associated polyposis patients who have increased risk of colon cancer. The purpose of this study was to determine if a similar association exists between exon 7 and 13 MUTYH mutations and pancreatic cancer. Genomic DNA samples from 140 patients with pancreatic cancer and 107 controls were sequenced and analyzed for mutations in each of MUTYH exons 7 and 13. Two patients with pancreatic cancer were identified as heterozygous for a MUTYH Y165C germline mutation. One pancreatic cancer patient was heterozygous for a G382D mutation and an additional patient was heterozygous for a novel missense mutation, L406M. No biallelic mutations were identified in pancreatic cancer or control subjects. Despite their association with somatic K-ras mutations and an increased risk of colorectal cancer in MUTYH-associated polyposis patients, MUTYH exon 7 and 13 mutations were not associated with pancreatic cancer in our cohort.


Deficiency in L-serine deaminase interferes with one-carbon metabolism and cell wall synthesis in Escherichia coli K-12.
Escherichia coli K-12 provided with glucose and a mixture of amino acids depletes L-serine more quickly than any other amino acid even in the presence of ammonium sulfate. A mutant without three 4Fe4S L-serine deaminases (SdaA, SdaB, and TdcG) of E. coli K-12 is unable to do this. The high level of L-serine that accumulates when such a mutant is exposed to amino acid mixtures starves the cells for C(1) units and interferes with cell wall synthesis. We suggest that at high concentrations, L-serine decreases synthesis of UDP-N-acetylmuramate-L-alanine by the murC-encoded ligase, weakening the cell wall and producing misshapen cells and lysis. The inhibition by high L-serine is overcome in several ways: by a large concentration of L-alanine, by overproducing MurC together with a low concentration of L-alanine, and by overproducing FtsW, thus promoting septal assembly and also by overexpression of the glycine cleavage operon. S-Adenosylmethionine reduces lysis and allows an extensive increase in biomass without improving cell division. This suggests that E. coli has a metabolic trigger for cell division. Without that reaction, if no other inhibition occurs, other metabolic functions can continue and cells can elongate and replicate their DNA, reaching at least 180 times their usual length, but cannot divide.


[Bidirectional relationship between atrial fibrillation and stroke.]
The temporal relationship between atrial fibrillation (AF) and stroke has always been considered one-way: the presence of arrhythmia favors the occurrence of stroke. Recent studies have questioned this association and raised the possibility that it may be bidirectional. Some ischemic events are actually due to stasis following AF episodes. Others are caused by the same substrate, atrial cardiomyopathy, which can cause both AF and stroke. Arrhythmia would in turn be both a possible causal factor and a marker of thrombo-embolic risk. It is therefore essential, in addition to always looking for a possible AF after a stroke, using the new technologies of prolonged cardiac monitoring, to highlight, regardless of the history, the common risk factors, whose treatment can improve the prognosis, not only with respect to prevention of thrombo-embolisms but also of heart failure and mortality.


Oxygen depletion in FLASH ultra-high-dose-rate radiotherapy: A molecular dynamics simulation.
We present a first-principles molecular dynamics (MD) simulation and expound upon a mechanism of oxygen depletion hypothesis to explain the mitigation of normal tissue injury observed in ultra-high-dose-rate (UHDR) FLASH radiotherapy. We simulated damage to a segment of DNA (also representing other biomolecules such as RNA and proteins) in a simulation box filled with H 2 O and O 2 molecules. Attoseconds physical interactions (ionizations, electronic, and vibrational excitations) were simulated by using the Monte Carlo track structure code Geant4-DNA. Immediately after ionization, ab initio Car-Parrinello molecular dynamics (CPMD) simulation was used to identify which H 2 O and O 2 molecules surrounding the DNA molecule were converted into reactive oxygen species (ROS). Subsequently, the femto- to nanosecond reactions of ROS were simulated by using MD with reactive force field (ReaxFF), to illustrate ROS merging into new types of non-reactive oxygen species (NROS) due to strong coupling among ROS. A coarse-grained model was constructed to describe the relevant collective phenomenon at the macroscopic level on ROS aggregation and formation of NROS agglomerates consistent with the underlying microscopic pathways obtained from MD simulations. Time-dependent molecular simulations revealed the formation of metastable and transient spaghetti-like complexes among ROS generated at UHDR. At the higher ROS densities produced under UHDR, stranded chains (i.e., NROS) are produced, mediated through attractive electric polarity forces, hydrogen bonds, and magnetic dipole-dipole interactions among hydroxyl ( . OH ) radicals. NROS tend to be less mobile than cellular biomolecules as opposed to the isolated and sparsely dense ROS generated at conventional dose rates (CDR). We attribute this effect to the suppression of biomolecular damage induced per particle track. At a given oxygen level, as the dose rate increases, the size and number of NROS chains increase, and correspondingly the population of toxic ROS components decreases. Similarly, at a given high dose rate, as the oxygen level increases, so do the size and number of NROS chains until an optimum level of oxygen is reached. Beyond that level, the amount of oxygen present may be sufficient to saturate the production of NROS chains, thereby reversing the sparing effects of UHDRs. We showed that oxygen depletion, hypothesized to lead to lower normal-tissue toxicity at FLASH dose rates, takes place within femto- to nanoseconds after irradiation. The mechanism is governed by the slow dynamics of chains of ROS complexes (NROS). Under physoxic (≈ 4-5% oxygen) conditions (i.e., in normal tissues), NROS are more abundant than in hypoxic conditions (e.g., <0.3% in parts of tumors), suggesting that biomolecular damage would be reduced in an environment with physoxic oxygen levels. Hence irradiation at UHDRs would be more effective for sparing physoxic normal tissues but not tumors containing regions of hypoxia. At much higher levels of oxygen (e.g., >10-15%), oxygen depletion by UHDRs may not be sufficient for tissue sparing.


Effect of protein binding on the in vitro activity and pharmacodynamics of faropenem.
The influence of protein binding upon different aspects of the in vitro activity of faropenem on recently isolated Staphylococcus aureus and respiratory pathogens was determined. The protein binding of faropenem was investigated in inactivated human serum and albumin by ultrafiltration. The effect of the presence of inactivated human serum and albumin on the in vitro activity of faropenem and amoxicillin was established and the influence of protein binding on the pharmacodynamic properties of faropenem and amoxicillin was compared. The protein binding of faropenem was 96% and 95% in pooled inactivated human serum and 99% and 98% in 45 mg/L human albumin, at 8 and 25 mg/L, respectively. The presence of inactivated human serum (20% and 70%) increased the mean faropenem MICs by two dilution steps and albumin increased the mean faropenem MICs by three dilution steps. The mean amoxicillin MICs were less affected than faropenem by the presence of either inactivated human serum or albumin. Faropenem and amoxicillin exhibited similar time-dependent kinetics. Faropenem was bacteriostatic on Moraxella catarrhalis, Haemophilus influenzae and group A streptococci, and bactericidal for Streptococcus pneumoniae (after 4 h with concentrations equivalent to 5 x and 10 x MIC) in Iso-Sensitest broth. In 70% inactivated human serum faropenem was slowly bactericidal against M. catarrhalis, H. influenzae (one strain) and S. pneumoniae (one strain) but not group A streptococci and the other S. pneumoniae strain. A significant inoculum effect was observed with all strains except S. pneumoniae. Both faropenem and amoxicillin appeared more active in 70% inactivated human serum than in Iso-Sensitest broth.


Effect of postural angle on back muscle activities in aging female workers performing computer tasks.
[Purpose] This study investigated the effects of postural angle on back muscle activity during a computer task in aging women. [Subjects] Seventeen women ≥50 years old participated. [Methods] The participants were instructed to perform computer-related tasks for 20 minutes on a workstation that simulated typical office working conditions. Back posture was measured from the measured trunk and pelvic angles. Electromyography activities were recorded simultaneously from the cervical erector spinae, longissimus, and multifidus muscles. [Results] The lowest mean percentages of maximum voluntary contraction for the cervical erector spinae and longissimus muscles were obtained when the upper trunk and pelvic angles were between 0° to -5° from the sagittal plane. The back muscle activities increased as the upper trunk and pelvic angles exceeded 0°. Statistical analysis showed significant correlations between upper trunk angle and cervical erector spinae and longissimus muscle activities. Similarly, pelvic angle was significantly correlated with cervical erector spinae and multifidus muscle activities. [Conclusion] A neutral back posture minimizes muscle activities in aging women performing computer tasks.


Drugs Causing Skin Eruptions.
Twenty one patients having drug eruptions are reported. The causative drugs were confirmed by provocation Tests. Eleven patients had exanthematous eruptions. The causative drugs were thiacetazone (3), para aminosalicylic acid (3), i-sonicotine acid hydrazide (1), Stereptomycin (1), ethambutol (1 , carbamazepine (1 and phenytoin sodium (1). In 4 patients having toxic epidermal necrolysis, the causative drugs were para aminosalicylic acid (2) isonicotinic acid hydrazide (1), streptomycin (1), tetracycline (1) and phenobarbitone (1). Two of these patients reacted to two drugs each, namely, streptomycin and para aminosalicysclic acid; and tetracycline and phenobarbitone respectively. In 3 patients with ex o ative dermatitis , the causative drugs were isonicotinic acid hydrazide (1), streptomycin (1), thiacetazone (1), and chloroquine (1).One patient reacted to both thiacetazone and chloroquine. In 3 patients who presented as urticaria, the causative drugs were analgin (1), phenylbutazone (1), and dilantin sodium (1).


Post-genome research on the biosynthesis of ergot alkaloids.
Genome sequencing provides new opportunities and challenges for identifying genes for the biosynthesis of secondary metabolites. A putative biosynthetic gene cluster of fumigaclavine C, an ergot alkaloid of the clavine type, was identified in the genome sequence of ASPERGILLUS FUMIGATUS by a bioinformatic approach. This cluster spans 22 kb of genomic DNA and comprises at least 11 open reading frames (ORFs). Seven of them are orthologous to genes from the biosynthetic gene cluster of ergot alkaloids in CLAVICEPS PURPUREA. Experimental evidence of the identified cluster was provided by heterologous expression and biochemical characterization of two ORFs, FgaPT1 and FgaPT2, in the cluster of A. FUMIGATUS, which show remarkable similarities to dimethylallyltryptophan synthase from C. PURPUREA and function as prenyltransferases. FgaPT2 converts L-tryptophan to dimethylallyltryptophan and thereby catalyzes the first step of ergot alkaloid biosynthesis, whilst FgaPT1 catalyzes the last step of the fumigaclavine C biosynthesis, i. e., the prenylation of fumigaclavine A at C-2 position of the indole nucleus. In addition to information obtained from the gene cluster of ergot alkaloids from C. PURPUREA, the identification of the biosynthetic gene cluster of fumigaclavine C in A. FUMIGATUS opens an alternative way to study the biosynthesis of ergot alkaloids in fungi.


Virtual screening of selective multitarget kinase inhibitors by combinatorial support vector machines.
Multitarget agents have been increasingly explored for enhancing efficacy and reducing countertarget activities and toxicities. Efficient virtual screening (VS) tools for searching selective multitarget agents are desired. Combinatorial support vector machines (C-SVM) were tested as VS tools for searching dual-inhibitors of 11 combinations of 9 anticancer kinase targets (EGFR, VEGFR, PDGFR, Src, FGFR, Lck, CDK1, CDK2, GSK3). C-SVM trained on 233-1,316 non-dual-inhibitors correctly identified 26.8%-57.3% (majority >36%) of the 56-230 intra-kinase-group dual-inhibitors (equivalent to the 50-70% yields of two independent individual target VS tools), and 12.2% of the 41 inter-kinase-group dual-inhibitors. C-SVM were fairly selective in misidentifying as dual-inhibitors 3.7%-48.1% (majority <20%) of the 233-1,316 non-dual-inhibitors of the same kinase pairs and 0.98%-4.77% of the 3,971-5,180 inhibitors of other kinases. C-SVM produced low false-hit rates in misidentifying as dual-inhibitors 1,746-4,817 (0.013%-0.036%) of the 13.56 M PubChem compounds, 12-175 (0.007%-0.104%) of the 168 K MDDR compounds, and 0-84 (0.0%-2.9%) of the 19,495-38,483 MDDR compounds similar to the known dual-inhibitors. C-SVM was compared to other VS methods Surflex-Dock, DOCK Blaster, kNN and PNN against the same sets of kinase inhibitors and the full set or subset of the 1.02 M Zinc clean-leads data set. C-SVM produced comparable dual-inhibitor yields, slightly better false-hit rates for kinase inhibitors, and significantly lower false-hit rates for the Zinc clean-leads data set. Combinatorial SVM showed promising potential for searching selective multitarget agents against intra-kinase-group kinases without explicit knowledge of multitarget agents.


Reduced Washing Cycle for Sustainable Mackerel (Rastrelliger kanagurta) Surimi Production: Evaluation of Bio-Physico-Chemical, Rheological, and Gel-Forming Properties.
Although dark muscle is currently the most important obstacle in marketing high-quality Indian mackerel (Rastrelliger kanagurta) surimi, reducing washing remains a challenge for long-term surimi production from this species. Herein, the impact of washing cycles (one (W1), two (W2), and three (W3) cycles) with a 1:3 mince to water ratio on the bio-physico-chemical properties, rheology, and gelling ability of mackerel surimi was evaluated. The yield, Ca2+-ATPase activity, TCA-soluble peptide, and myoglobin contents of surimi decreased as the number of washing cycles increased, while lipid removal, reactive SH content, and surface hydrophobicity of surimi increased. Surimi generated by W2 and W3 provided the same rheological patterns and Fourier-transform infrared spectroscopy (FTIR) spectra as unwashed mince, with the highest gel strength and whiteness, as well as the lowest expressible drip, thiobarbituric acid reactive substances (TBARS), and fishy odor. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) demonstrated the presence of polymerized proteins stabilized by disulfide and other interactions. Using a scanning electron microscope, several concentrated dense areas and distributed pores generated by myofibrillar proteins gel networks were found. Surimi from W2 and W3 appeared to be of similar overall quality, however W2 had a larger yield. As a result of the evaluation of bio-physico-chemical, rheological, and gel-forming capabilities, as well as product yield, W2 may be the best option for producing high-quality surimi from Indian mackerel in a sustainable manner.


[Effects of norcantharidin on angiogenesis of human gallbladder carcinoma and its anti-angiogenic mechanisms].
To investigate the effects of norcantharidin (NCTD) on angiogenesis of human gallbladder carcinoma and its anti-angiogenic mechanisms. Human gallbladder carcinoma cells of the line GBC-SD were cultured. BALB/c nude mice were inoculated subcutaneously with the GBC-SD cells and then randomly divided into 6 groups: NCTD group, injected intraperitoneally with 1/5 of the LD(50) of NCTD twice a week for 6 weeks; 5-fluorouracil (5-FU) group, injected intraperitoneally with 1/5 of the LD(50) of 5-FU twice a week for 6 weeks; endostatin (ES) group, intraperitoneally with ES; NCTD + 5-FU group, injected intraperitoneally with 1/5 of the LD(50) of NCTD and 1/5 of the LD(50) of 5-FU twice a week for 6 weeks; NCTD + ES group, injected intraperitoneally with 1/5 of the LD(50) of NCTD and ES twice a week for 6 weeks; and normal saline (NS) group (control group), injected with NS. The mice were killed in the 7th week. The tumors were taken out to measure their volumes and undergo microscopy. SABC method of immunohistochemistry was used to measure the microvessel density (MVD) and the protein expression of the angiogenesis-related factors: proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), angiopoietin (Ang)-2, thrombospondin (TSP), and tissue inhibitor of metalloprotease (TIMP)(2). Suspension of single tumor cell was prepared to examine the cell apoptosis by flow cytometry. RT-PCR was used to examine the mRNA expression of PCNA, VEGF, Ang-2, TSP, and TIMP2. (1) The MVD of the NCTD group was 4.12 +/- 1.4, significantly lower than those of the 5-FU group (15.8 +/- 5.9) and control group (17.6 +/- 3.2) (both P < 0.01), but not significantly different from those of the NCTD + 5-FU group (3.8 +/- 1.7), ES group (4.5 +/- 2.1), and NCTD + ES group (2.9 +/- 1.5) (all P > 0.05). The mice treated with NCTD showed significantly smaller tumor volume, lower PCNA protein expression, higher apoptotic rate, and higher PCNA/apoptosis ratio (P < 0.05 or P < 0.01), and significant correlation between MVD and tumor volume and between MVD and PCNA/apoptosis ratio (both P < 0.05). (2) The protein expression of VEGF and of Ang-2 of the NCTD group were both significantly lower than those of the control and 5-FU groups (all P < 0.01), however, not significantly different from those of the ES, NCTD + 5-FU, and NCTD + ES groups; and the protein expression of TSP and of TIMP2 of the NCTD group were both significantly higher than those of the control and 5-FU groups (all P < 0.01), however, not significantly different from those of the ES, NCTD + 5-FU, and NCTD + ES groups. MVD was positively correlated with VEGF and Ang-2 expression and negatively correlated with the expression of TSP and TIMP2 (all P < 0.05). (3) In comparison with the control group, the mRNA expression of VEGF and of Ang-2 of the tumor cells of the NCTD group were both significantly lower and the mRNA expression of TIMP2 was significantly higher. NCTD down-regulates the expression of the angiogenic factors, such as VEF|GF and Ang-2, and up-regulates the expression of the anti-angiogenic factors, such as TDP and TIMP2, thus inhibiting the angiogenesis in tumor, such as human gallbladder carcinoma, and further inhibiting the growth of tumor.


What is potent acid inhibition, and how can it be achieved?
The clinical response to antisecretory treatment correlates directly with the degree of inhibition of acid secretion achieved. Acid inhibition able to maintain the intragastric pH at a value greater than 4 for at least 16 h/day seems to heal even the most refractory acid-related diseases. It has also been shown that the degree of inhibition of acid secretion in response to antisecretory treatment depends on the genetic characteristics of the patient and on the presence of Helicobacter pylori infection. A possible definition of potent (or profound) acid inhibition is, therefore, the achievement of the aforementioned level of control of acid secretion regardless of patient characteristics or of the presence of H. pylori infection. Antisecretory drugs differ in their ability to reach potent acid inhibition. As far as the comparative efficacy of different drugs for inhibiting acid secretion is concerned, proton pump inhibitors are more efficient in inhibiting gastric acid secretion than histamine (H2) receptor antagonists. Among the different proton pump inhibitors, esomeprazole 40 mg/day exhibits greater antisecretory potency than the others at standard doses. Rabeprazole 20 mg/day and lansoprazole 30 mg/day exhibit a more rapid onset of action than omeprazole 20 mg/day or pantoprazole 40 mg/day.


Effect of High Cation Concentrations on Photosystem II Activities.
The effects of wide concentration ranges of NaCl, KCl, and MgCl(2) on ferricyanide reduction and the fluorescence induction curve of isolated spinach (Spinacia oleracea) chloroplasts were investigated. Concentrations of the monovalent salts above 100 mm and MgCl(2) above 25 mm produced a decrease in the rate of ferricyanide reduction by thylakoids uncoupled with 2.5 mm NH(4)Cl which cannot be attributed to changes in the primary photochemical capacity of photosystem II. Salt-induced decreases in the effective concentration of the secondary electron acceptor of photosystem II, plastoquinone, reduce the capacity for secondary photochemistry of photosystem II and this could contribute to the reduction in ferricyanide reduction by uncoupled thylakoids at high salinities. The rate of ferricyanide reduction by coupled thylakoids is little affected by salinity changes, indicating that the rate-limiting phosphorylation mechanism in electron flow from water to ferricyanide in coupled thylakoids is salt-tolerant, whereas the rate-limiting reaction in uncoupled ferricyanide reduction is considerably affected by salinity changes. Salt-induced changes in the fluorescence induction curve are interpreted in terms of changes in the rate constants for excitation decay by radiationless transitions, exciton transfer from photosystem II chlorophylls to other associated chlorophyll species, and photochemistry.


IL-4/CXCL12 loop is a key regulator of lymphoid stroma function in follicular lymphoma.
Follicular lymphoma (FL) is the most frequent indolent lymphoma and is characterized by the accumulation of germinal center-derived malignant B cells engaged in a bidirectional crosstalk with their supportive microenvironment in invaded lymph nodes (LNs) and bone marrow (BM). T follicular helper (TFH) cells and infiltrating stromal cells have been shown to favor FL B-cell growth, but the mechanisms of their protumoral effect and how the LN/BM microenvironment is converted into a lymphoma-permissive cell niche remain poorly understood. We demonstrated here that FL-infiltrating LN and BM stromal cells overexpressed CXCL12 in situ. Interleukin-4 high (IL-4hi) FL-TFH cells, unlike FL B cells themselves, triggered CXCL12 upregulation in human stromal cell precursors. In agreement, expression of CXCL12 was associated with IL-4 expression and signaling within the FL BM and LN niches. This IL-4/CXCL12 axis was amplified in activated lymphoid stromal cells as shown in our in vitro model of human lymphoid stroma differentiation and in an inducible mouse model of ectopic lymphoid organ formation. Finally, CXCL12 triggered primary FL B-cell activation, migration, and adhesion, a process antagonized by BTK and PI3K inhibitors. These data identified the IL-4/CXCL12 loop as a previously unrecognized pathway involved in lymphoid stroma polarization and as a potential therapeutic target in FL patients.


Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates.
The effects on thrombosis and hemostasis of thrombin-induced activation of endogenous protein C (PC) were evaluated in baboons. Thrombosis was induced by placing into arteriovenous shunts a segment of Dacron vascular graft, which generated arterial platelet-rich thrombus, followed by an expansion region of low-shear blood flow, which in turn accumulated fibrin-rich venous-type thrombus. Thrombosis was quantified by 111In-platelet imaging and 125I-fibrinogen accumulation. Intravenous infusion of alpha-thrombin, 1-2 U/kg-min for 1 h, increased baseline activated PC levels (approximately 5 ng/ml) to 250-500 ng/ml (P < 0.01). The lower thrombin dose, which did not deplete circulating platelets, fibrinogen, or PC, reduced arterial graft platelet deposition by 48% (P < 0.05), and platelet and fibrin incorporation into venous-type thrombus by > 85% (P < 0.01). Thrombin infusion prolonged the activated partial thromboplastin clotting time, elevated fibrinopeptide A (FPA), thrombin-antithrombin III complex (T:AT III), and fibrin D-dimer plasma levels (P < 0.01), but did not affect bleeding times. Thrombin's antithrombotic effects were blocked by infusing a monoclonal antibody (HPC-4) which prevented PC activation in vivo, caused shunt occlusion, increased the consumption of platelets and fibrinogen, elevated plasma FPA and T:AT III levels, and reduced factor VIII (but not factor V) procoagulant activity (P < 0.05). We conclude that activated PC is a physiologic inhibitor of thrombosis, and that activation of endogenous PC may represent a novel and effective antithrombotic strategy.


Antigenic and immunogenic investigation of the virulence motif of the Newcastle disease virus fusion protein.
Newcastle disease (ND) caused by virulent Newcastle disease virus (NDV) is a highly contagious viral disease of poultry. Virulent NDVs characteristically have a multibasic amino acid sequence (virulence motif) such as (112)RRQKRF(117) at the cleavage site of the precusor fusion (F0) protein. The antigenic and immunogenic characteristics of the virulence motif (112)RRQKRF(117) in the F0 protein of virulent NDVs were investigated. Epitope mapping analysis revealed that a RRQKRF-specific monoclonal antibody 4G2 recognized the KRF section of the motif. A synthetic peptide bearing the RRQKRF motif reacted strongly with sera from virulent NDV (with RRQKRF motif)-infected chickens. These sera also showed reactivity to peptides bearing other virulence motifs ((112)KRQKRF(117), (112)RRQRRF(117) and (112)RRRKRF(117)) but not an avirulence motif ((112)GRQGRL(117)) by ELISA. The synthetic bearing RRQKRF motif reacted with 60% to 91% of sera taken from surviving chickens on ND outbreak farms but not with sera from vaccinated birds, even though most of the sera had antibody to NDV due to vaccination. This indicates that the virulence motif has the potential to differentiate virulent NDV infected birds from vaccinated birds.


Fluorescence background quenching as a means to increase Signal to Background ratio - a proof of concept during Nerve Imaging.
Introduction: Adequate signal to background ratios are critical for the implementation of fluorescence-guided surgery technologies. While local tracer administrations help to reduce the chance of systemic side effects, reduced spatial migration and non-specific tracer diffusion can impair the discrimination between the tissue of interest and the background. To combat background signals associated with local tracer administration, we explored a pretargeting concept aimed at quenching non-specific fluorescence signals. The efficacy of this concept was evaluated in an in vivo neuronal tracing set-up. Methods: Neuronal tracing was achieved using a wheat germ agglutinin (WGA) lectin. functionalized with an azide-containing Cy5 dye (N3-Cy5-WGA). A Cy7 quencher dye (Cy7-DBCO) was subsequently used to yield Cy7-Cy5-WGA, a compound wherein the Cy5 emission is quenched by Förster resonance energy transfer to Cy7. The photophysical properties of N3-Cy5-WGA and Cy7-Cy5-WGA were evaluated together with deactivation kinetics in situ, in vitro (Schwannoma cell culture), ex vivo (muscle tissue from mice; used for dose optimization), and in vivo (nervus ischiadicus in THY-1 YFP mice).Results:In situ, conjugation of Cy7-DBCO to N3-Cy5-WGA resulted in >90% reduction of the Cy5 fluorescence signal intensity at 30 minutes after addition of the quencher. In cells, pretargeting with the N3-Cy5-WGA lectin yielded membranous staining, which could efficiently be deactivated by Cy7-DBCO over the course of 30 minutes (91% Cy5 signal decrease). In ex vivo muscle tissue, administration of Cy7-DBCO at the site where N3-Cy5-WGA was injected induced 80-90% quenching of the Cy5-related signal after 10-20 minutes, while the Cy7-related signal remained stable over time. In vivo,Cy7-DBCO effectively quenched the non-specific background signal up to 73% within 5 minutes, resulting in a 50% increase in the signal-to-background ratio between the nerve and injection site. Conclusion: The presented pretargeted fluorescence-quenching technology allowed fast and effective reduction of the background signal at the injection site, while preserving in vivo nerve visualization. While this proof-of-principle study was focused on imaging of nerves using a fluorescent WGA-lectin, the same concept could in the future also apply to applications such as sentinel node imaging.


Postmortem blood and vitreous humor ethanol concentrations in a victim of a fatal motor vehicle crash.
A 20-year-old male was found on the passenger side of a small car after a collision with a semi-trailer truck. Postmortem blood, collected from the chest cavity, and vitreous humor samples were collected following harvesting of the heart and bones. Gas chromatographic analysis revealed a blood ethanol concentration of 0.32 g/dL and a vitreous humor ethanol concentration of 0.09 g/dL. The stomach was intact and full of fluid and food, but its contents were not collected. Possible explanations for the large difference between the two results include diffusion of ethanol from the stomach into the chest cavity, contamination of the blood sample prior to collection, and ingestion of a large quantity of ethanol shortly before death. This case demonstrates the importance of proper quality assurance procedures in collecting postmortem specimens and of collecting a vitreous humor sample for ethanol analysis in postmortem toxicology cases.


Investigation of Preservice Science Teachers' Nature of Science Understanding and Decision Making on Socioscientific Issue through the Fractal Model.
The paper reports a qualitative study to reveal how preservice science teachers' decision making (DM) processes on socioscientific issue (SSI) in a referendum case compare between unsophisticated (Group U) and sophisticated (Group S) views in terms of nature of science (NOS) understandings. Firstly, pre-study was conducted with focus group interviews with pre-service science teachers. With the findings, one-on-one semi-structured in-depth interviews of the main study for DM on SSI, the artificial meat was developed. In the main study, 12 participants' responses were analyzed, and a new DM model named the Fractal Model of DM which reflects real-life situation DM process, especially referendum case, was constructed. In DM, NOS lens usages of five NOS aspects about creativity and imagination, observation and inference, empirical-basis, subjectivity, and social and cultural embeddedness and 23 other lens usages such as animal rights (morality), economic, and risk factor were detected and explained through the fractal model. Findings showed that there is a hidden and complex effect of NOS understandings about tentativeness of scientific knowledge on DM. With multiple lens usage, each participant had multi-perspective considerations in DM. While Group S used NOS lenses mainly parallel with their NOS understandings, Group U used them in a more complicated way.


Human Cytosolic Sulphotransferase SULT1C3: genomic analysis and functional characterization of splice variant SULT1C3a and SULT1C3d.
The cytosolic sulphotransferase SULT1C3 remained the most poorly understood human SULT. The SULT1C3 gene has been shown to contain alternative exons 7 and 8, raising the question concerning their evolutionary origin and implying the generation of multiple SULT1C3 variants. Two SULT1C3 splice variants, SULT1C3a and SULT1C3d, were investigated to verify the impact of alternative C-terminal sequences on their sulphating activity. Sequence homology and gene location analyses were performed to verify the orthology of the SULT1C3 gene. The SULT1C3 gene appears to be present only in humans and other primates, but alternative exons 7b and 8b share high degrees of homology with corresponding regions of rodent SULT1C1 genes, implying their evolutionary origin being from a defunct human SULT1C1 gene. Purified recombinant SULT1C3a and SULT1C3d were analyzed for sulphating activities toward a variety of endogenous and xenobiotic compounds. While SULT1C3a displayed weaker activities and strict substrate specificity toward hydroxyl-chlorinated biphenyls, SULT1C3d exhibited broader substrate specificity toward bile acids and thyroid hormones as well as hydroxyl-chlorinated biphenyls. Molecular docking simulation suggested that Tyr249 and Met257 may play an important role in substrate recognition by SULT1C3d. Alternative splicing of exons 7 and 8 sequences resulted in differential catalytic properties of SULT1C3 variants.


Cloning, genomic organization, expression, and effect on beta-casein promoter activity of a novel isoform of the mouse Oct-1 transcription factor.
The ubiquitously expressed transcription factor Oct-1, a member of the POU domain factors, is involved in the regulation of expression of many tissue-specific and house-keeping genes. Multiple alternatively spliced isoforms of Oct-1 have been identified in human and mouse cells. The expression patterns of these isoforms and the analysis of their genomic organization and structure have suggested that the structural variation of Oct-1 isoforms may be important in conferring target and tissue specificity to its transcriptional activity. In this study, we have cloned and sequenced a new mouse Oct-1 isoform, named mOct-1Z. This novel isoform differs markedly at the C-terminus from the previously identified Oct-1 isoforms A, B, and C. It is generated by alternative splicing from the Oct-1 gene and its transcript exhibits a frameshift followed by an early stop codon, thus, its predicted protein has a distinct, much shorter C-terminal tail. However, this truncated isoform could still effectively bind to a consensus Oct-1 motif oligonucleotide and, like Oct-1B, activated the basal promoter activity of the mouse beta-casein gene. Oct-1Z is another ubiquitously expressed Oct-1 isoform, its transcript being detected in all mouse tissues examined, including the mammary gland, liver, lung, kidney, spleen, small intestine mucosa, uterus, and ovary.


Cerebrovascular risk factors and cerebral hyperintensities among middle-aged and older adults with major depression.
To examine the association between cerebral hyperintensities and cerebrovascular risk factors (CVRF) among middle-aged and older adults with major depressive disorder (MDD). Thirty patients (aged 55-77 years) with MDD and no history of stroke participated in a magnetic resonance imaging assessment to assess for the presence of cerebral hyperintensities and underwent a physical examination to assess stroke risk as indexed by the Framingham Stroke Risk Profile (FSRP). In addition, intima medial thickness (IMT) was measured in the left and right carotid arteries. Higher FSRP levels were associated with total greater cerebral hyperintensities (r = 0.64), as well as greater subependymal hyperintensities (r = 0.47), confluent periventricular changes (r = 0.46), and tended to be associated with subcortical gray matter hyperintensities (r = 0.34). A quadratic relationship was observed between IMT and total cerebral hyperintensities (b = 4.84), and higher IMT levels were associated with greater subependymal hyperintensities (r = 0.40). Higher levels of CVRF are associated with graded increases in cerebral hyperintensities among middle-aged and older adults with MDD.


Intrinsically Motivated Exploration of Learned Goal Spaces.
Finding algorithms that allow agents to discover a wide variety of skills efficiently and autonomously, remains a challenge of Artificial Intelligence. Intrinsically Motivated Goal Exploration Processes (IMGEPs) have been shown to enable real world robots to learn repertoires of policies producing a wide range of diverse effects. They work by enabling agents to autonomously sample goals that they then try to achieve. In practice, this strategy leads to an efficient exploration of complex environments with high-dimensional continuous actions. Until recently, it was necessary to provide the agents with an engineered goal space containing relevant features of the environment. In this article we show that the goal space can be learned using deep representation learning algorithms, effectively reducing the burden of designing goal spaces. Our results pave the way to autonomous learning agents that are able to autonomously build a representation of the world and use this representation to explore the world efficiently. We present experiments in two environments using population-based IMGEPs. The first experiments are performed on a simple, yet challenging, simulated environment. Then, another set of experiments tests the applicability of those principles on a real-world robotic setup, where a 6-joint robotic arm learns to manipulate a ball inside an arena, by choosing goals in a space learned from its past experience.


[Work regulation in the context of new public versus private relations in health].
This work discusses the management of the work relations in the context of the new systems of public vs. private relation in health, having as reference the experience of the habilitation of Social Organizations (SO), responsible for the administration of a group of hospitals in the state of São Paulo. The urgency in this kind of management supported on the legal figure of the SO has implications in the management of Human Resources in Health (HRH) through the adoption of flexibilization mechanisms which include ways of selection, hiring and dismissal, payment rules and functional progression similar to the actions adopted by the market. The establishment of this sort of administration refers to the new paradigm proposed by the managerial administrative reform which suggests the exhaustion of the bureaucratic model to promote adjustment of the public administration to the transformations originated in the new stage of internationalization of the economy and its unfolding in the work world, as well as to the new standards of requirements of performance of the public field. Aspects related to the management of HHR are approached in the two ruling modalities in the Secretaria de Estado da Saúde de São Paulo: Direct Administration Hospitals (DAH) and units organized under the SO model (SOH).


Understanding of Phase Noise Squeezing Under Fractional Synchronization of a Nonlinear Spin Transfer Vortex Oscillator.
We investigate experimentally the synchronization of vortex based spin transfer nano-oscillators to an external rf current whose frequency is at multiple integers, as well as at an integer fraction, of the oscillator frequency. Through a theoretical study of the locking mechanism, we highlight the crucial role of both the symmetries of the spin torques and the nonlinear properties of the oscillator in understanding the phase locking mechanism. In the locking regime, we report a phase noise reduction down to -90 dBc/Hz at 1 kHz offset frequency. Our demonstration that the phase noise of these nanoscale nonlinear oscillators can be tuned and eventually lessened, represents a key achievement for targeted radio frequency applications using spin torque devices.


Few layer graphene-polypropylene nanocomposites: the role of flake diameter.
Graphene shows excellent potential as a structural reinforcement in polymer nanocomposites due to its exceptional mechanical properties. We have shown previously that graphene composites can be analysed using conventional composite theory with the graphene flakes acting as short fillers which have a critical length of ∼3 μm which is required for good reinforcement. Herein, polypropylene (PP) nanocomposites were prepared using electrochemically-exfoliated few layer graphene (FLG) with two different flake diameters (5 μm and 20 μm). The crystallization temperature and degree of crystallinity of the PP were found to increase with the loading of FLG, which suggests that the flakes acted as crystallisation nucleation sites. Mechanical testing showed that the 5 μm flakes behaved as short fillers and reinforced the PP matrix poorly. The modulus of the 20 μm flake composites, however, increased linearly with loading up to 20 wt%, without any of the detrimental aggregation effects seen in other graphene systems. The mechanical data were compared with our previous work on other graphene composite systems and the apparent need to balance the degree of functionalization to improve matrix compatibility whilst not encouraging aggregation is discussed.