Varieties of the extended self.
This article provides an overview and analysis of recent work on the extended self, demonstrating that the boundaries of selves are fluid, shifting across biological, artifactual, and sociocultural structures. First, it distinguishes the notions of minimal self, person, and narrative self. Second, it surveys how philosophers, psychologists, and cognitive scientists argue that embodiment, cognition, emotion, consciousness, and moral character traits can be extended and what that implies for the boundaries of selves. It also reviews and responds to various criticisms and counterarguments against the extended self. The main focus is on the link between the extended mind and extended self, which has received the most attention in recent literature. But accounts of the extended self developed independently of the extended mind are also briefly discussed. This article ends by drawing out some of the conceptual, methodological, and normative implications of the extended self and suggesting some directions for future research.


Modulation of substrate transport to the brain.
Variations of substrate transport across the cerebral capillary endothelium were examined in response to variations of the substrate demand of the brain tissue, and to variations of substrate concentration in the blood. The substrates examined included glucose and ketone bodies. The transport changes were measured in rats, using an indicator fractionation method modified by the reviewer. Four mechanisms appeared to contribute to the adjustment of substrate transport to variations in substrate demand. The first and least important mechanism was the change of concentration gradient across the endothelium that occurred when the substrate consumption rate changed. The second mechanism was the flow-dependency of the average capillary substrate concentration: the higher the perfusion rate, the higher the average capillary concentration. This mechanism failed to account for the changes of substrate transport observed during marked increases of the metabolic rate. The third and most important mechanism was a change of the capillary diffusion capacity, probably associated with a change of the number of perfused capillaries. The fourth mechanism, not previously described, was an adaptation of transport to permanent changes of substrate concentration in the blood. This mechanism appeared to reflect changes of the concentration (and affinity?) of transport proteins in the plasma membranes of endothelial cells, possibly in association with changes of cellular protein synthesis and gene expression.


A Magnetic Dynamic Microbiointerface with Biofeedback Mechanism for Cancer Cell Capture and Release.
Dynamic biointerfaces with reversible surface bioactivities enable dynamic modulation of cell-material interactions, thus attracting great attention in biomedical science. Herein, we demonstrated a paradigm shift of dynamic biointerfaces from macroscopical substrates to micron-sized particles by reversible engineering of a phenylboronic acid (PBA)-functionalized magnetic microbead with mussel-inspired cancer cell-targeting peptide. Due to reversible catechol-boronate interactions between the peptides and microbeads, the micron-sized dynamic biointerface exhibited sugar-responsive cancer-targeting activity, showing the potential as a microplatform for magnetic and noninvasive isolation of cancer cells through natural biofeedback mechanism (e.g., human glycemic volatility). Our results demonstrated that the dynamic magnetic platform was capable of selective cancer cell capture (∼85%) and sugar-triggered release of them (>93%) in cell culture medium with high efficiency. More importantly, by using this platform, a decent number of target cells (∼23 on average) could be magnetically isolated and identified from artificial CTC blood samples (1 mL) spiked with 100 cancer cells. In view of the biomimetic nature, high capture efficiency, excellent selectivity, and superiority in cell separation and purification processes, the dynamic magnetic microplatform reported here would be a promising and general tool for rare cell detection and separation and cell-based disease diagnosis.


Outcome in children with purpura fulminans: report on 16 patients.
Purpura fulminans (PF) is a severe disorder of acute onset with high morbidity and mortality. In children, this rapidly progressive illness is usually associated with severe bacterial or viral infections. However, some other conditions may participate in the development of PF. Our objective was to investigate the underlying and associated disorders and the outcomes of the disease in 16 children, 7 males and 9 females ranging in age from 3.5 months to 12 years (median age, 2 years). Thirteen of the 16 children (81%) were 4 years of age or younger. The remaining 3 patients were 9, 10, and 12 years of age. Among these 13 infants and small children, 7 (43%) had infection, 2 infants had congenital cardiac disorders necessitating minor or major surgical intervention, and 1 infant and 3 children had different miscellaneous disorders. The factor V G1691A mutation was present in six of the 13 small children (46%). None of the 3 older children carried the mutation. Six (37.5%) of the 16 patients had protein C deficiencies, and 9 (56%) had protein S deficiencies. These deficiencies, except one for protein S, were acquired. Ten patients except two who were diagnosed at this center were treated with fresh frozen plasma. They were also given heparin. Nine (69%) of the 13 children 4 years of age or younger and one of the older children (33%) required amputation. Five of the six patients (83%) who had factor V G1691A mutation, and who also exhibited severe infection, required amputation. This study suggests that an age of 4 years or less is a risk factor for the development of PF during severe infections, especially in the presence of factor V G1691A mutation and congenital heart disease, necessitating major or minor surgical interventions. This study also shows that the amputation rate in 10 patients, after excluding the patients who had been referred to our center after development of sequelae, was 60%. The survival rate among these 10 patients may indicate that, with the treatment protocol, PF need not be regarded as a lethal disease any more. It is also suggested that effective immunization programs and better health care have probably resulted in some changes in the etiological profile of PF.


Outcomes of morbidly obese patients receiving invasive mechanical ventilation: a nationwide analysis.
Critically ill, morbidly obese patients (BMI≥40 kg/m2) are at high risk of respiratory failure requiring invasive mechanical ventilation (IMV). It is not clear if outcomes of critically ill, obese patients are affected by obesity. Due to limited cardiopulmonary reserve, they may have poor outcomes. However, literature to this effect is limited and conflicted. We used the Nationwide Inpatient Sample from 2004 to 2008 to examine the outcomes of morbidly obese people receiving IMV and compared them to nonobese people. We identified hospitalizations requiring IMV and morbid obesity using International Classification of Diseases, 9th Revision, Clinical Modification codes. Primary outcomes studied were inhospital mortality, rates of prolonged mechanical ventilation (≥96 h), and tracheostomy. Multivariable logistic regression was used to adjust for potential confounding variables. We also examined outcomes stratified by number of organs failing. Of all hospitalized, morbidly obese people, 2.9% underwent IMV. Mean age, comorbidity score, and severity of illness were lower in morbidly obese people. The adjusted mortality was not significantly different in morbidly obese people (OR 0.89; 95% CI, 0.74-1.06). When stratified by severity of disease, there was a stepwise increase in risk for mortality among morbidly obese people relative to nonobese people (range: OR, 0.77; 95% CI, 0.58-1.01 for only respiratory failure, to OR, 4.14; 95% CI, 1.11-15.3 for four or more organs failing). Rates of prolonged mechanical ventilation were similar, but rate of tracheostomy (OR 2.19; 95% CI, 1.77-2.69) was significantly higher in patients who were morbidly obese. Morbidly obese people undergoing IMV have a similar risk for death as nonobese people if only respiratory failure is present. When more organs fail, morbidly obese people have increased risk for mortality compared with nonobese people.


Phrenic Nerve Blockade to Diagnose and Treat Diaphragmatic Pain After Surgical Repair of Congenital Diaphragmatic Eventration.
A 46-year-old woman presented with pain in the lateral side of the left chest wall and a sensation of fullness and pulling in the epigastric region, which started 4 weeks following diaphragmatic plication for left diaphragmatic eventration. The patient was diagnosed as suffering from post-thoracotomy pain syndrome (PTPS). A diagnostic intercostal nerve block relieved the chest wall pain, but not the epigastric pain. After a detailed evaluation, the epigastric pain was postulated to be of diaphragmatic origin and hence a diagnostic phrenic nerve block was performed which relieved the epigastric pain. Combined intercostal nerve neurolysis and phrenic nerve block relieved her pain completely. The phrenic nerve may play a role in pain transmission and the genesis of chronic pain following diaphragmatic surgery. Diaphragmatic pain following surgery may contribute to the development of chronic pain. Phrenic nerve blockade provides diagnostic information regarding the etiology of pain as well as being effective in providing analgesia. The technique of phrenic nerve block is presented and its role in the diagnosis and treatment of pain following thoracic surgery is reviewed.


Postprandial metabolite profiles reveal differential nutrient handling after bariatric surgery compared with matched caloric restriction.
Roux-en-Y gastric bypass (RYGB) surgery results in exaggerated postprandial insulin and incretin responses and increased susceptibility to hypoglycemia. We examined whether these features are due to caloric restriction (CR) or altered nutrient handling. We performed comprehensive analysis of postprandial metabolite responses during a 2-hour mixed-meal tolerance (MMT) test in 20 morbidly obese subjects with type 2 diabetes who underwent RYGB surgery or matched CR. Acylcarnitines and amino acids (AAs) were measured using targeted mass spectrometry. A linear mixed model was used to determine the main effect of interventions and interaction term to assess the effect of interventions on postprandial kinetics. Two weeks after these interventions, several gut hormones (insulin, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide 1), glucose, and multiple AAs, including branched-chain and aromatic species, exhibited a more rapid rate of appearance and clearance in RYGB surgery subjects than in CR subjects during the MMT test. In the RYGB surgery group, changes in leucine/isoleucine, methionine, phenylalanine, and glucagon-like peptide 1 response were associated with changes in insulin response. Levels of alanine, pyruvate, and lactate decreased significantly at the later stages of meal challenge in RYGB surgery subjects but increased with CR. RYGB surgery results in improved metabolic flexibility (ie, greater disposal of glucose and AAs and more complete β-oxidation of fatty acids) compared with CR. The changes in the AA kinetics may augment the hormonal responses seen after RYGB surgery. The reduction in key gluconeogenic substrates in the postprandial state may contribute to increased susceptibility to hypoglycemic symptoms in RYGB surgery subjects.


Systemic vascular resistance is increased and associated with accelerated arterial stiffening change in patients with chronic cervical spinal cord injury.
Despite of stiffening change of conduit arteries, how total peripheral resistance (TPR) is adapted to chronic spinal cord injury (SCI) remains unclear. To investigate how chronic cervical SCI influences hemodynamic characteristics Cross-sectional, case-control study. Rehabilitation department in the tertiary medical center. Twenty-one male patients with traumatic SCI resulting from cervical spine fracture were recruited. The injury occurred three to 289 months (46 months in average) previously. Twenty-one healthy male participants with matched age and body mass index were enrolled as control group. The subjects were asked to maintain supine rest (SR) and then head-up tilt (HUT) at 60 degree for five minutes, respectively. A novel noninvasive bio-reactance device was employed to measure cardiac hemodynamics, whereas heart rate variability was used to determine cardiac autonomic activity. Additionally, the digital volume pulse analysis was applied to calculate arterial stiffness index (SI) and arteriolar reflection index (RI). SCI patients revealed less stroke volume and cardiac output (CO), as well as, greater total peripheral resistance (TPR) and SI during SR than normal subjects did. Moreover, the positive correlation between TPR and SI was observed in SCI patients rather than normal subjects. In SCI patients, HUT (1) markedly decreased TPR while CO and cardio-acceleration responses remained intact and (2) decreased HF power value but failed to change LF/HF ratio. Furthermore, the degree of orthostatic hypotension was correlated with the TPRHUT/TPRSR ratio but not the COHUT/COSR ratio. Chronic cervical SCI leads to a progressively accelerated increase in vascular stiffness, which is associated with increase in systemic vascular resistance. Furthermore, the cervical SCI-related orthostatic hypotension lies in the impairment of vasoconstriction without cardiac dysfunction. Clinical Rehabilitation Impact. SI, rather than blood pressure, reflects not only cardiovascular risk but also TPR in chronic cervical SCI.


Dynorphin A (1-17) induces apoptosis in striatal neurons in vitro through alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor-mediated cytochrome c release and caspase-3 activation.
Dynorphin A (1-17), an endogenous opioid neuropeptide, can have pathophysiological consequences at high concentrations through actions involving glutamate receptors. Despite evidence of excitotoxicity, the basic mechanisms underlying dynorphin-induced cell death have not been explored. To address this question, we examined the role of caspase-dependent apoptotic events in mediating dynorphin A (1-17) toxicity in embryonic mouse striatal neuron cultures. In addition, the role of opioid and/or glutamate receptors were assessed pharmacologically using dizocilpine maleate (MK(+)801), a non-equilibrium N-methyl-D-aspartate (NMDA) antagonist; 6-cyano-7-nitroquinoxaline-2,3-dione, a competitive alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/kainate antagonist; or (-)-naloxone, a general opioid antagonist. The results show that dynorphin A (1-17) (>or=10 nM) caused concentration-dependent increases in caspase-3 activity that were accompanied by mitochondrial release of cytochrome c and the subsequent death of cultured mouse striatal neurons. Moreover, dynorphin A-induced neurotoxicity and caspase-3 activation were significantly attenuated by the cell permeable caspase inhibitor, caspase-3 inhibitor-II (z-DEVD-FMK), further suggesting an apoptotic cascade involving caspase-3. AMPA/kainate receptor blockade significantly attenuated dynorphin A-induced cytochrome c release and/or caspase-3 activity, while NMDA or opioid receptor blockade typically failed to prevent the apoptotic response. Last, dynorphin-induced caspase-3 activation was mimicked by the ampakine CX546 [1-(1,4-benzodioxan-6-ylcarbonyl)piperidine], which suggests that the activation of AMPA receptor subunits may be sufficient to mediate toxicity in striatal neurons. These findings provide novel evidence that dynorphin-induced striatal neurotoxicity is mediated by a caspase-dependent apoptotic mechanism that largely involves AMPA/kainate receptors.


Natural history of restricted synthesis and expression of measles virus genes in subacute sclerosing panencephalitis.
Subacute sclerosing panencephalitis (SSPE) is a slow infection caused by measles virus in which several years separate recovery from typical acute measles and the development of a slowly progressive neurological disease. We have investigated replication of measles virus in brain tissue obtained after the onset of neurological disease and in the terminal phase. With a hybridization tomographic technique that combines in situ hybridization with macroradioautographic screening of large areas of tissue, we analyzed the spatial and temporal distribution of virus genes in vivo, using region- and strand-specific probes for the nucleocapsid and matrix genes. We show that early in the course of SSPE there is a global repression in the synthesis and expression of the genome. In the final stage of SSPE most infected cells still have depressed levels of plus- and minus-strand viral RNA and contain nucleocapsid protein but lack matrix protein. These findings provide further evidence for a unified view of slow infections of the nervous system, where the general constraints on virus gene expression provide an explanation for persistence of virus in the face of the host's immune response, and the slow evolution of pathological change. In the final phases of SSPE the more specific block in virus replication accounts for the cell-associated state of the virus and the difficulty in virus isolation.


Two algorithms for neural-network design and training with application to channel equalization.
We describe two algorithms for designing and training neural-network classifiers. The first, the linear programming slab algorithm (LPSA), is motivated by the problem of reconstructing digital signals corrupted by passage through a dispersive channel and by additive noise. It constructs a multilayer perceptron (MLP) to separate two disjoint sets by using linear programming methods to identify network parameters. The second, the perceptron learning slab algorithm (PLSA), avoids the computational costs of linear programming by using an error-correction approach to identify parameters. Both algorithms operate in highly constrained parameter spaces and are able to exploit symmetry in the classification problem. Using these algorithms, we develop a number of procedures for the adaptive equalization of a complex linear 4-quadrature amplitude modulation (QAM) channel, and compare their performance in a simulation study. Results are given for both stationary and time-varying channels, the latter based on the COST 207 GSM propagation model.


Over-supplementation of vitamin D in two patients with primary hyperparathyroidism.
To describe the biochemical effects of an over-supplementation of vitamin D3 in two patients with primary hyperparathyroidism (PHPT). Two patients (A and B) with PHPT took erroneously 2,400,000 U (300,000 U/day for 8 days) and 4,500,000 U (300,000 U/day for 15 days) of cholecalciferol, respectively. They were followed for 4 months and ionized calcium, creatinine, PTH, 25 hydroxy-vitamin D, 1,25(OH)₂D and urinary calcium/creatinine levels were measured. Finally, the patients were operated on and a parathyroid adenoma was removed in both. One week after the last dose of vitamin D, serum ionized calcium (iCa) rose from 1.35 to 1.41 mMol/L (n.r. 1.14-1.31) for patient A, and from 1.43 to 1.62 for patient B, while fasting urinary Calcium/Creatinine (uCa/Cr) augmented from 0.31 to 0.50 mg/mg, and from 0.32 to 0.55, respectively. During the follow-up, the average levels of iCa were 1.37 ± 0.03 and 1.48 ± 0.07 mMol/L, while those of uCa/Cr were 0.29 ± 0.13 and 0.32 ± 0.13, both iCa and uCa/Cr levels returning to baseline values within 4 months. The unintentional over-supplementation of vitamin D in the two PHPT patients caused a moderate and temporary increase of hypercalcemia and hypercalciuria and was not associated with clinical signs of toxicity.


Integral fixation titanium/polyetheretherketone cages for cervical arthrodesis: Two-year clinical outcomes and fusion rates using β-tricalcium phosphate or supercritical carbon dioxide treated allograft.
Despite increasing promising reports regarding composite titanium (Ti)/PolyEtherEtherKetone (PEEK) cages, further longer-term, quality research is required. Synthetic bone graft substitutes are another rapidly developing area of spinal surgical research. The purpose of this study is to evaluate the outcomes of an integral fixation composite Ti/PEEK cage for anterior cervical discectomy and fusion (ACDF) and compare a synthetic bone graft substitute (β-tricalcium phosphate; [βTCP]) with allograft processed using supercritical fluid technology. Data from 195 consecutive patients were prospectively collected from a single centre. Indications were largely degenerative. Allograft and βTCP were used in a 3:1 randomization protocol. Patients were followed up for a minimum of 6 months and up to 48 months. Clinical outcomes included visual analogue scale and neck oswestry disability index. Radiographic outcomes included fusion rates, subsidence rates and implant complications. Graft sub-cohorts were largely comparable and included 133 and 52 patients in the allograft and βTCP sub-cohorts, respectively. Clinical outcomes overall significantly improved (P < 0.001), with no significant inter-cohort differences. There were no implant-related complications. Overall fusion rate was 94.1% (175/186). The allograft cohort produced a significantly greater fusion rate of 97.7% (126/129) compared to 77.6% (38/49) for the βTCP cohort (P = 0.001). This study demonstrates the viability of an integral fixation composite Ti/PEEK ACDF device in effectively and safely improving patient outcomes and achieving fusion. Allograft is more effective in achieving fusion compared to βTCP, though both were similarly efficacious in improving clinical outcomes.


Effect of low-osmolality intravenous contrast on serum osmolal gap in adults.
Contrast media used today is considered "low-osmolality." No study has evaluated the effect of intravenous contrast media on the measurement of the osmolal gap in adult patients. To determine if "low-osmolality" intravenous contrast media administered to adult patients undergoing computed tomography (CT) of the abdomen and pelvis affects the osmolal gap. We performed a prospective pilot study in the Emergency Department of a university-affiliated tertiary care center. Patients were enrolled if they were age ≥18 years and <60 years and the treatment team had ordered an abdomen and pelvis CT with intravenous (i.v.) contrast procedure and a serum basic metabolic panel (BMP) that included serum glucose, blood urea nitrogen, and sodium. Once enrolled, a serum osmolality and serum ethanol level was ordered and obtained on the same blood draw as the BMP before the CT. Patients were excluded if they had detectable ethanol on laboratory screen, if they were suspected to have ingested methanol, ethylene glycol, isopropanol, mannitol, or underwent CT with i.v. contrast within the prior 24 h. Paired samples were compared using the Wilcoxon signed-rank test. Of the 100 patients screened, 18 patients were lost due to withdrawal of consent or missing data. The median of the osmolal gap pre-CT was 8.18 with an interquartile range of 4.76-11.15. The median of the osmolal gap post-CT was 11.23 with an interquartile range of 7.29-14.83. The difference in the osmolal gap was a median of 2.34 (p = 0.0003) with an interquartile range of -1.32-5.97. Although the effect in our study was small, clinicians should be aware of the ability of contrast media to increase the osmolal gap.


Generation and Characterization of Monoclonal Antibodies against Swine Acute Diarrhea Syndrome Coronavirus Spike Protein.
Swine acute diarrhea syndrome coronavirus (SADS-CoV), a member of the family Coronaviridae and the genus Alphacoronavirus, primarily affects piglets under 7 days old, causing symptoms such as diarrhea, vomiting, and dehydration. It has the potential to infect human primary and passaged cells in vitro, indicating a potential risk of zoonotic transmission. In this study, we successfully generated and purified six monoclonal antibodies (mAbs) specifically targeting the spike protein of SADS-CoV, whose epitope were demonstrated specificity to the S1A or S1B region by immunofluorescence assay and enzyme-linked immunosorbent assay. Three of these mAbs were capable of neutralizing SADS-CoV infection on HeLa-R19 and A549. Furthermore, we observed that SADS-CoV induced the agglutination of erythrocytes from both humans and rats, and the hemagglutination inhibition capacity and antigen-antibody binding capacity of the antibodies were assessed. Our study reveals that mAbs specifically targeting the S1A domain demonstrated notable efficacy in suppressing the hemagglutination phenomenon induced by SADS-CoV. This finding represents the first instance of narrowing down the protein region responsible for SADS-CoV-mediated hemagglutination to the S1A domain, and reveals that the cell attachment domains S1A and S1B are the main targets of neutralizing antibodies.


Genetic Analysis of Flooding Tolerance in an Andean Diversity Panel of Dry Bean (Phaseolus vulgaris L.).
Climate change models predict temporal and spatial shifts in precipitation resulting in more frequent incidents of flooding, particularly in regions with poor soil drainage. In these flooding conditions, crop losses are inevitable due to exposure of plants to hypoxia and the spread of root rot diseases. Improving the tolerance of bean cultivars to flooding is crucial to minimize crop losses. In this experiment, we evaluated the phenotypic responses of 277 genotypes from the Andean Diversity Panel to flooding at germination and seedling stages. A randomized complete block design, with a split plot arrangement, was employed for phenotyping germination rate, total weight, shoot weight, root weight, hypocotyl length, SPAD index, adventitious root rate, and survival score. A subset of genotypes (n = 20) were further evaluated under field conditions to assess correlations between field and greenhouse data and to identify the most tolerant genotypes. A genome-wide association study (GWAS) was performed using ~203 K SNP markers to understand the genetic architecture of flooding tolerance in this panel. Survival scores between field and greenhouse data were significantly correlated (r = 0.55, P = 0.01). Subsequently, a subset of the most tolerant and susceptible genotypes were evaluated under pathogenic Pythium spp. pressure. This experiment revealed a potential link between flooding tolerance and Pythium spp. resistance. Several tolerant genotypes were identified that could be used as donor parents in breeding pipelines, especially ADP-429 and ADP-604. Based on the population structure analysis, a subpopulation consisting of 20 genotypes from the Middle American gene pool was detected that also possessed the highest root weight, hypocotyl length, and adventitious root development under flooding conditions. Genomic regions associated with flooding tolerance were identified including a region on Pv08/3.2 Mb, which is associated with germination rate and resides in vicinity of SnRK1.1, a central gene involved in response of plants to hypoxia. Furthermore, a QTL at Pv07/4.7 Mb was detected that controls survival score of seedlings under flooding conditions. The association of these QTL with the survivability traits including germination rate and survival score, indicates that these loci can be used in marker-assisted selection breeding to improve flooding tolerance in the Andean germplasm.


MicroRNA-29b-1 impairs in vitro cell proliferation, self‑renewal and chemoresistance of human osteosarcoma 3AB-OS cancer stem cells.
Osteosarcoma (OS) is the most common type of bone cancer, with a peak incidence in the early childhood. Emerging evidence suggests that treatments targeting cancer stem cells (CSCs) within a tumor can halt cancer and improve patient survival. MicroRNAs (miRNAs) have been implicated in the maintenance of the CSC phenotype, thus, identification of CSC-related miRNAs would provide information for a better understanding of CSCs. Downregulation of miRNA-29 family members (miR-29a/b/c; miR‑29s) was observed in human OS, however, little is known about the functions of miR-29s in human OS CSCs. Previously, during the characterization of 3AB-OS cells, a CSC line selected from human OS MG63 cells, we showed a potent downregulation of miR-29b. In this study, after stable transfection of 3AB-OS cells with miR-29b-1, we investigated the role of miR-29b-1 in regulating cell proliferation, sarcosphere-forming ability, clonogenic growth, chemosensitivity, migration and invasive ability of 3AB-OS cells, in vitro. We found that, miR-29b-1 overexpression consistently reduced both, 3AB-OS CSCs growth in two- and three-dimensional culture systems and their sarcosphere- and colony-forming ability. In addition, while miR-29b-1 overexpression sensitized 3AB-OS cells to chemotherapeutic drug-induced apoptosis, it did not influence their migratory and invasive capacities, thus suggesting a context-depending role of miR-29b-1. Using publicly available databases, we proceeded to identify potential miR-29b target genes, known to play a role in the above reported functions. Among these targets we analyzed CD133, N-Myc, CCND2, E2F1 and E2F2, Bcl-2 and IAP-2. We also analyzed the most important stemness markers as Oct3/4, Sox2 and Nanog. Real-time RT-PCR and western-blot analyses showed that miR-29b-1 negatively regulated the expression of these markers. Overall, the results show that miR-29b-1 suppresses stemness properties of 3AB-OS CSCs and suggest that developing miR-29b-1 as a novel therapeutic agent might offer benefits for OS treatment.


Dietary modification, body mass index (BMI), blood pressure (BP) and cardiovascular risk in medical students of a government medical college of Karachi.
To determine the prevalence of major risk factors including dietary modification, Body Mass Index (BMI), Blood Pressure (BP) and physical activity in medical students of government teaching hospitals of Karachi. A cross sectional study was conducted on students of Dow Medical College, Karachi, Pakistan through a structured pre-tested questionnaire. Non-probability purposive sampling was used. Smoking, hypertension, family history of cardiovascular disease (CVD), overweight and low physical activity levels are risk factors the presence of which can lead to development of CVD. Prevalence of these risk factors was determined by asking appropriate questions and through measurement of BMI and blood pressure for overweight and hypertension respectively. Awareness of risk factors was determined through knowledge of the effect of various food substances on development of CVD and of adoption of dietary changes keeping in mind the risk of developing CVD. SPSS 16.0 was used for statistical analysis. A total of 132 medical students were included in the study of which 57 (43.2%) and 75 (56.8%) were male and female respectively with mean age of 20.85 +/- 1.21 years. About 15.9% of students had elevated blood pressure i.e. > or = 140/90 mmHg. Twenty eight percent of the total students were found to be underweight and 17.4% were overweight, 5% had some history of CVD, 56.8% had family history of CVD, 9.4% were smokers and 29.5% had high physical activity level. About 87.1% had modified their diet for preventing CVD. Most of the students had adequate knowledge about the cardiovascular risk factors Majority of students were not overweight. A high prevalence of cardiovascular risk factors; family history and elevated blood pressure was present. Awareness in terms of knowledge was satisfactory but implementation in terms of diet modification and adequate physical activity was lacking.


Primary colorectal lymphoma.
To analyze our experience in the treatment of primary colorectal lymphomas. During the recent period from 1989 to 1995, a total number of 406 cases of malignant neoplasms of large intestine were treated at Department of Surgery, Hospital del S.A.S de Jerez de la Frontera. There were 5 cases of primary colorectal Non-Hodgkin's lymphomas, constituting 1.2% of all colorectal malignancies. Medical records of all five patients were carefully reviewed. Surgical pathology specimens were retrospectively reexamined to confirm the diagnosis, and immunohistochemistry staining methods were performed. Dawson, Cornes and Morson criteria were used to distinguish primary colonic lymphoma. For tumor staging, a modification of the Ann-Arbor system for gastrointestinal lymphoma proposed by Musshoff and Schmidt-Vollmer was used. All cases were Non-Hodgkin's lymphomas. There were no cases of lymphoma of the rectum. There were 2 males and 3 females. Their ages ranged from 12 to 73 years, with an average age of 31 years. The cecum was the site of the lesions in 4 patients and the other was located in the sigmoid colon. Acute abdomen in three cases, undiagnosed abdominal mass in one and intussusception in the other one were the clinical presentation. Inmunohistochemical studies showed B-cell phenotype in 4 and non-B non-T Ki-1-positive phenotype in 1 patient. Chemotherapy was administered following resection in 100% of patients. Intraoperative diagnosis of lymphoma was not suspected in all cases but the malignancy was always present. The cecum is the commonest site of involvement. Both of our two patients presented with perforated lymphoma were associated with a poor short term prognosis. It is necessary to unify the staging system and the histologic classifications enabling a comparison of several studies.


Review: The Perioperative Use of Thromboelastography for Liver Transplant Patients.
Thromboelastography (TEG) is a viscoelastic test that allows rapid evaluation of clot formation and fibrinolysis from a sample of whole blood. TEG is increasingly utilized to guide blood product resuscitation in surgical patients and transfusions for liver transplant patients. Patients with severe liver failure have significant derangement of their clotting function due to impaired production of procoagulant and anticoagulant factors. Traditional coagulation studies are limited by the short time needed for the result and provide little information about the dynamics and strength of clot formation. In addition, traditional coagulation studies do not correlate well with bleeding episodes and may lead to over-transfusion of various blood products. Evidence is less robust regarding the use of TEG for transfusion management decisions in severe liver failure patients awaiting, undergoing, or immediately after liver transplant surgery. However, the available evidence suggests that systematic implementation of TEG rather than traditional coagulation studies results in the administration of fewer blood products without increased mortality or complications. The purpose of this study is to review the literature regarding the use of TEG in liver failure patients prior to liver transplant, intraoperatively, and postoperatively. Additional high-quality randomized controlled studies should be performed to evaluate the use of TEG to guide transfusion decisions, particularly in the postoperative period following liver transplantation.


Increasing healthy lifespan by suppressing aging in our lifetime: preliminary proposal.
Although we do not know everything about aging, we now know enough to start its pharmacologic suppression using clinically approved drugs. Aging turns out to be driven by sensing-signaling pathways (such as the mTOR pathway). Given that some inhibitors of the mTOR pathway are already in clinical use, there is a unique opportunity to suppress aging, while treating and preventing diseases. By itself this will answer some burning questions in gerontology. Here I discuss a proposal, starting from retrospective clinical studies to animal and cellular models to drug screens in order to develop non-toxic and effective schedules and drug combinations for extending healthy life span in our lifetime.


Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer).
Lynch syndrome (hereditary non-polyposis colorectal cancer) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. The discovery of these genes, 15 years ago, has led to the identification of large numbers of affected families. In April 2006, a workshop was organised by a group of European experts in hereditary gastrointestinal cancer (the Mallorca-group), aiming to establish guidelines for the clinical management of Lynch syndrome. 21 experts from nine European countries participated in this workshop. Prior to the meeting, various participants prepared the key management issues of debate according to the latest publications. A systematic literature search using Pubmed and the Cochrane Database of Systematic Reviews reference lists of retrieved articles and manual searches of relevant articles was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described in this manuscript may be helpful for the appropriate management of families with Lynch syndrome. Prospective controlled studies should be undertaken to improve further the care of these families.


Ticagrelor-induced renal failure leading to statin-induced rhabdomyolysis.
Renal function deterioration is a rather frequent side effect of ticagrelor; this is especially so in patients over the age of 75, with pre-existent mild renal failure and/or taking an angiotensin receptor inhibitor. We describe a patient in whom deterioration of renal function due to ticagrelor led to a rise in serum concentration of rosuvastatin which resulted in rhabdomyolysis. The presented case emphasises the importance to check renal function routinely before and one month after starting ticagrelor and to screen carefully for possible interactions with other drugs.


Decoding Optical Responses of Contact-Printed Arrays of Thermotropic Liquid Crystals Using Machine Learning: Detection and Reporting of Aqueous Amphiphiles with Enhanced Sensitivity and Selectivity.
Surfactants and other amphiphilic molecules are used extensively in household products, industrial processes, and biological applications and are also common environmental contaminants; as such, methods that can detect, sense, or quantify them are of great practical relevance. Aqueous emulsions of thermotropic liquid crystals (LCs) can exhibit distinctive optical responses in the presence of surfactants and have thus emerged as sensitive, rapid, and inexpensive sensors or reporters of environmental amphiphiles. However, many existing LC-in-water emulsions require the use of complicated or expensive instrumentation for quantitative characterization owing to variations in optical responses among individual LC droplets. In many cases, the responses of LC droplets are also analyzed by human inspection, which can miss subtle color or topological changes encoded in LC birefringence patterns. Here, we report an LC-based surfactant sensing platform that takes a step toward addressing several of these issues and can reliably predict concentrations and types of surfactants in aqueous solutions. Our approach uses surface-immobilized, microcontact-printed arrays of micrometer-scale droplets of thermotropic LCs and hierarchical convolutional neural networks (CNNs) to automatically extract and decode rich information about topological defects and color patterns available in optical micrographs of LC droplets to classify and quantify adsorbed surfactants. In addition, we report computational capabilities to determine relevant optical features extracted by the CNN from LC micrographs, which can provide insights into surfactant adsorption phenomena at LC-water interfaces. Overall, the combination of microcontact-printed LC arrays and machine learning provides a convenient and robust platform that could prove useful for developing high-throughput sensors for on-site testing of environmentally or biologically relevant amphiphiles.


[Mohr's syndrome : type II orofaciodigital syndrome (author's transl)].
Mohr's syndrome consists of an association of three types of malformation : oral, facial, and digital. It is very similar, therefore, to the syndrome of Papillon-Léage and Psaume. Apart from this, precise, constant characteristics can be recognized which identify it as a separate entity. Firstly, the genetic mode of transmission differs. Secondly, clinical signs are dominated by the frequency and severity of the distal lesions, such that bilateral syndactyly of the big toe is a key element in the differential diagnosis.


Preoperative inner segment/outer segment junction in spectral-domain optical coherence tomography as a prognostic factor in epiretinal membrane surgery.
To evaluate the macular structure on spectral-domain optical coherence tomographic (SD-OCT) images to predict the outcome of surgery for idiopathic epiretinal membrane. Forty-five eyes of 45 consecutive patients with idiopathic epiretinal membrane who had a preoperative visual acuity of ≤ 20/32 and were scheduled to undergo a transconjunctival 25-gauge vitrectomy were involved in this prospective cohort study. The best-corrected visual acuity (BCVA) and SD-OCT images of the fovea were examined before the surgery and at 3, 6, and 12 months after the surgery. Associations between the visual acuity parameters and the preoperative SD-OCT features, including the morphology of the photoreceptor inner segment/outer segment junction, macular thickness, presence/absence of retinal cysts, and presence/absence of a macular pseudohole, were investigated as predictors of the outcome of the surgery. The main outcome measures were the association between the macular microstructure on preoperative SD-OCT images and the visual acuity parameters, such as the BCVA, at 12 months after the surgery (postoperative BCVA) and the difference between the preoperative visual acuity and the postoperative BCVA. A total of 45 patients were enrolled in this study. The postoperative visual acuity was significantly better for the eyes with an intact inner segment/outer segment junction on the preoperative SD-OCT images than for those with an irregular or a disrupted inner segment/outer segment junction on the images (P < 0.001). Better preoperative visual acuity was associated with better visual acuity at 12 months and a lesser degree of improvement in the visual acuity (P < 0.001, respectively). The presence of an intact inner segment/outer segment junction on the preoperative SD-OCT images was found to be an important predictor of better visual recovery and better postoperative BCVA after epiretinal membrane surgery.


A case-crossover study of acute alcohol use and suicide attempt.
Several studies have shown that acute alcohol use is associated with suicidal behavior, but the magnitude and nature of the relationship remain unclear. We report a study on the impact of acute alcohol use on suicide attempts treated in the emergency room (ER) using the case-crossover design. Seven ER studies carried out in the United States, Canada, Mexico and Australia from 1984 to 1996 with probability samples and similar methodology were merged yielding a total of 102 suicide attempters (overall 52% were male and 59% under 30 years of age). Thirty-six patients reported alcohol use within 6 hours prior to the suicide attempt. When usual alcohol consumption during the past 12 months served as the control value, the estimated relative risk (RR) for patients who reported alcohol use within 6 hours prior to the suicide attempt was 9.6 (95% confidence interval: 5.7-16.3). Although the prevalence of alcohol use differed by sex, there was no statistically significant difference in the estimated RRs (RR = 13.6 men and RR = 5.3 women, p = 0.11 for the heterogeneity test). A positive association was found between alcohol use 6 hours prior and suicide attempts in 102 ER cases in four countries. The case-crossover methodology is well suited to studies for which an external control group is not easily obtainable.


Early Experience in 100 Consecutive Patients With Injection Adipocytolysis for Neck Contouring With ATX-101 (Deoxycholic Acid).
Deoxycholic acid (DCA) is approved for improvement in the appearance of moderate to severe convexity or fullness associated with submental fat. To assess early treatment experience with DCA injection in a clinical practice setting. In this single-center, prospective, single-arm, observational study, 100 consecutive patients seeking to decrease submental fullness received subcutaneous DCA (2 mg/cm) injections in the submental area (maximum of 6 sessions at ≥1 month intervals). Treatment response was assessed 1 and 5 to 7 weeks posttreatment using the clinician-reported submental fat rating scale (CR-SMFRS) and retrospective independent photograph review by 2 physicians. Overall, 100 patients had 152 treatment sessions (58, 33, 8, and 1 patients had 1, 2, 3, and 4 sessions, respectively). CR-SMFRS score improved by ≥1 point from baseline in 88 (88%) patients; of these, 46, 33, 8, and 1 patients had 1, 2, 3, and 4 sessions, respectively. Local edema, numbness, and tenderness were reported for a mean (SD) of 7.7 (5.3), 28.5 (11.4), and 3.5 (3.5) days, respectively. Two patients experienced marginal mandibular nerve paresis. Deoxycholic acid injection, a minimally invasive procedure for neck contouring, was effective and generally well tolerated in the private practice setting.


Recurrent paraneoplastic wells syndrome in a patient with metastatic renal cell cancer.
A 58-year-old man with a history of hyperlipidemia and hypertension presented to the dermatology clinic with a 3-month history of a sudden onset, progressively worsening pruritic eruption involving the torso and extremities. Prior treatment included azithromycin and oral and intramuscular steroids, without improvement. Laboratory results demonstrated a serum eosinophil count of 7x10(3)/uL (normal 0-4). A 4-mm punch biopsy of the plaque on the patient's left thigh revealed a diffuse dermatitis with innumerable eosinophils with formation of "flame figures." Histologically, these findings are consistent with a diagnosis of Wells syndrome (WS). A work up for possible underlying malignancy found that the patient had underlying clear cell renal carcinoma. The eruption largely resolved following right laparoscopic nephrectomy with negative surgical margins, thus confirming the diagnosis of paraneoplastic WS. However, 2 years later the patient developed metastasis to his liver, lungs, and ribs. The patient's cancer has continued to progress despite treatment with high-dose interleukin-2, oral sunitinib, afinitor. avastin, azacytidine, and currently axitinib. Our case is the first to describe eosinophilic cellulitis arising in a patient with underlying renal cell carcinoma.


Rearrangement and expression of T-cell receptor genes in marmoset lymphoid cell lines with natural killer activity.
To study the role of the T-3/T-cell receptor complex in mediating natural killer activity, we have examined T-cell receptor gene configuration and expression in five transformed marmoset cell lines with natural killer activity. All lines showed rearrangement of the beta chain of the T-cell receptor and expressed full size beta chain transcripts as well as full size delta chain transcripts. Only three lines contained full size T-cell receptor alpha chain transcripts. Of the three lines which had potential for encoding functional T-3/T-cell receptor complex, those which possessed natural killer activity also expressed T-gamma transcripts. In addition, one clone with high natural killer activity which did express high levels of T-gamma mRNA was unable to produce functional T-3/T-cell receptor complex due to truncated T-cell receptor alpha chain message. The results in this paper provide strong evidence that natural killer activity is dependent upon expression of the T-cell receptor gamma chain.


[Application of Neoadjuvant Chemoimmunotherapy in Resectable NSCLC].
For resectable non-small cell lung cancer (NSCLC), the CheckMate-816 study demonstrated that neoadjuvant chemoimmunotherapy increased the rate of complete pathologic response (pCR) by 21.8% compared with chemotherapy alone and resulted in a significant benefit in event-free survival (EFS). This study aimed to investigate the safety and feasibility of this approach in the real world. Clinical data from patients with NSCLC who underwent surgery after neoadjuvant chemoimmunotherapy or chemotherapy alone in two centers were analyzed retrospectively, and subgroup analyses were performed for the chemoimmunotherapy group according to treatment cycle. The primary study endpoints were EFS and major pathologic response (MPR), and the secondary study endpoints were pCR, overall survival (OS), treatment-related adverse events (TRAEs), and surgery-related metrics. As of April 2023, 89 patients had been enrolled, including 54 in the chemoimmunotherapy group and 35 in the chemotherapy alone group. MPR was achieved in 31 (57.4%) and 5 (14.3%) patients in the chemoimmunotherapy group and chemotherapy alone group, respectively (OR=8.09, 95%CI: 2.72-24.04, P<0.001); pCR was achieved in 25 (46.3%) patients in the chemoimmunotherapy group and no patient in the chemotherapy alone group (P<0.001). The median follow-up time was 22.1 months. At 24 months, the EFS rates of the chemoimmunotherapy group and the chemotherapy alone group were 77.0% and 56.7%, respectively (P=0.026), and the OS rates were 87.1% and 67.7%, respectively (P=0.020). In the neoadjuvant chemoimmunotherapy group, there was no significant difference between the 1-2 cycles and 3-5 cycles groups in terms of operation time, intraoperative blood loss, and postoperative complications. Neoadjuvant chemoimmunotherapy was more effective than chemotherapy alone and did not increase the risk associated with surgery. An increase in the number of cycles of neoadjuvant chemoimmunotherapy had no significant effect on the difficulty of surgery.


[Living-related liver transplantation--first experiences at Rabin Medical Center].
Our experience with living-related liver transplantation is described. In 2 boys and 1 girl, aged 4-4.5 years with acute, fulminating hepatitis A, the presence of very severe jaundice (bilirubin levels > 18 mg%) associated with severe coagulopathy (INR > 10) and encephalopathy indicated the need for urgent liver transplantation. In all 3 cases the left lateral hepatic segment of a matched blood type parent was transplanted. None of the donors suffered a serious complication postoperatively and all returned to full activity in 6-16 weeks. The post-transplantation course was uneventful in 1 child, but in the other 2 there was hepatic arterial thrombosis in 1 at 1 day and in the other at 8 days post-transplantation. Early detection of arterial thrombosis by Doppler sonography permitted salvage of the 2 hepatic grafts after thrombectomy and re-anastomosis. In 1 of these 2 children an anastomotic biliary stricture was found 2 months after transplantation. It was corrected at surgery and a percutaneous stent was inserted. All 3 children are alive with normal graft function at 2, 7 and 8 months post-transplantation, respectively. This initial experience indicates that living-related liver transplantation is feasible in Israel. The technique might help to solve our severe organ shortage for children awaiting liver transplantation.


Adversarial Feature Alignment: Avoid Catastrophic Forgetting in Incremental Task Lifelong Learning.
Humans are able to master a variety of knowledge and skills with ongoing learning. By contrast, dramatic performance degradation is observed when new tasks are added to an existing neural network model. This phenomenon, termed catastrophic forgetting, is one of the major roadblocks that prevent deep neural networks from achieving human-level artificial intelligence. Several research efforts (e.g., lifelong or continual learning algorithms) have proposed to tackle this problem. However, they either suffer from an accumulating drop in performance as the task sequence grows longer, or require storing an excessive number of model parameters for historical memory, or cannot obtain competitive performance on the new tasks. In this letter, we focus on the incremental multitask image classification scenario. Inspired by the learning process of students, who usually decompose complex tasks into easier goals, we propose an adversarial feature alignment method to avoid catastrophic forgetting. In our design, both the low-level visual features and high-level semantic features serve as soft targets and guide the training process in multiple stages, which provide sufficient supervised information of the old tasks and help to reduce forgetting. Due to the knowledge distillation and regularization phenomena, the proposed method gains even better performance than fine-tuning on the new tasks, which makes it stand out from other methods. Extensive experiments in several typical lifelong learning scenarios demonstrate that our method outperforms the state-of-the-art methods in both accuracy on new tasks and performance preservation on old tasks.


Diagnosis of congenital heart disease in an era of universal prenatal ultrasound screening in southwest Ohio.
Diagnostic ultrasound is widespread in obstetric practice, yet many babies with major congenital heart disease remain undiagnosed. Factors affecting prenatal diagnosis of major congenital heart disease are not well understood. This study aims to document prenatal detection rates for major congenital heart disease in the Greater Cincinnati area, and identify factors associated with lack of prenatal diagnosis. All living infants diagnosed with major congenital heart disease by 4 months of age at our centre were prospectively identified. Prenatal care data were obtained by parent interview. Neonatal records were reviewed for postnatal data. Obstetricians were contacted for diagnostic ultrasound data. A total of 100 infants met the inclusion criteria. In all, 95 infants were analysed, of whom 94 were offered diagnostic ultrasound. In all, 41 had a prenatal diagnosis of major congenital heart disease. The rate of prenatal detection varied by cardiac lesion, with aortic arch abnormalities, semilunar valve abnormalities, and venous anomalies going undetected in this sample. Among subjects without prenatal detection, the highest proportion consisted of those having Level 1 diagnostic ultrasound only (66%). Prenatal detection was not significantly influenced by maternal race, education level, income, or insurance type. Despite nearly universal diagnostic ultrasound, detection rates of major congenital heart disease remain low in southwest Ohio. An educational outreach programme including outflow tract sweeps for community-level obstetrical personnel may improve detection rates.


Biological characteristics of fish germ cells and their application to developmental biotechnology.
We have revealed several unique characteristics of germ cell development using rainbow trout, including the fact that spermatogonia transplanted into the peritoneal cavity of newly hatched embryos migrate toward recipient gonads, that spermatogonia transplanted into female recipients start oogenesis and produce functional eggs and that diploid germ cells transplanted into triploid trout can complete gametogenesis. By combining these unique features of fish germ cells, we established allogeneic and xenogeneic transplantation systems for spermatogonia in several fish species. Spermatogonia isolated from the mature testes of vasa-green fluorescent protein (Gfp) transgenic rainbow trout were transplanted into the peritoneal cavity of triploid masu salmon newly hatched embryos. These spermatogonia migrated toward recipient salmon genital ridges with extending pseudopodia and were subsequently incorporated into them. We further confirmed that the donor-derived spermatogonia resumed gametogenesis and produced sperm and eggs in male and female salmon recipients, respectively. By inseminating the resulting eggs and sperm, we obtained only rainbow trout offspring in the F1 generation, suggesting that the triploid salmon recipients produced functional gametes derived only from donor trout. We further confirmed that this intra-peritoneal transplantation of germ cells is applicable to several marine fishes, which could be of benefit in the production of bluefin tuna that has a large broodstock (>100 kg) and is difficult to maintain in captivity. Gamete production of bluefin tuna could be more easily achieved by generating a surrogate species, such as mackerel, that can produce tuna gametes.


A case of tracheobronchomegaly.
Tracheobronchomegaly (Mounier-Kuhn syndrome) is a rare condition characterized by an abnormally enlarged trachea and main bronchi. Herein, we present a case of 79-year-old male with idiopathic pulmonary fibrosis and acute hypoxemic respiratory failure due to multilobar pneumonia. Computed tomography of the chest demonstrated a markedly dilated trachea, with the transverse diameter of 31mm and the sagittal diameter of 30mm. The clinical manifestations as well as its diagnosis, classification, and treatment are discussed.


Experimentally induced infections bovine keratoconjunctivitis: effectiveness of a pilus vaccine against exposure to homologous strains of Moraxella bovis.
A study was conducted to determine whether vaccination with sonicated pili of Moraxella bovis would protect cattle from subsequent infection and disease when experimentally challenged by exposure to homologous cultures of M bovis. Some calves were intramuscularly inoculated 2 times with pili of M bovis suspended in water, and others were subcutaneously inoculated 2 times with pili of M bovis suspended in oil; 21 days were allowed between inculations. Controls were nonvaccinated calves. Fourteen days after the last inculation, all calves were exposed to virulent homologous cultures of M bovis. The results indicated that vaccination with sonicated pili of M bovis may induce protective immunity against homologous strain challenge exposure. Vaccines in oil that were injected subcutaneously protected to a greater extent than did vaccines in water that were injected intramuscularly. The development of inflammatory nodules at the site of inoculation was associated with resistance to infection and disease. Only 1 of the vaccinated calves that resisted disease lacked precipitating antibodies against sonicated pili at the time of the challenge exposure. This calf had antibodies 2 weeks later.


Porphyrin boxes constructed by homochiral self-sorting assembly: optical separation, exciton coupling, and efficient excitation energy migration.
meso-Pyridine-appended zinc(II) porphyrins Mn and their meso-meso-linked dimers Dn assemble spontaneously, in noncoordinating solvents such as CHCl3, into tetrameric porphyrin squares Sn and porphyrin boxes Bn, respectively. Interestingly, formation of Bn from Dn proceeds via homochiral self-sorting assembly, which has been verified by optical separations of B1 and B2. Optically pure enantiomers of B1 and B2 display strong Cotton effects in the CD spectra, which reflect the length of the pyridyl arm, thus providing evidence for the exciton coupling between the noncovalent neighboring porphyrin rings. Excitation energy migration processes within Bn have been investigated by steady-state and time-resolved spectroscopic methods in conjunction with polarization anisotropy measurements. Both the pump-power dependence on the femtosecond transient absorption and the transient absorption anisotropy decay profiles are directly associated with the excitation energy migration process within the Bn boxes, where the exciton-exciton annihilation time and the polarization anisotropy rise time are well described in terms of the Förster-type incoherent energy hopping model by assuming a number of hopping sites of N = 4 and an exciton coherence length of L = 2. Consequently, the excitation energy hopping rates between the zinc(II) diporphyrin units have been estimated for B1 (48 ps)(-1), B2 (98 +/- 3 ps)(-1), and B3 (361 +/- 6 ps)(-1). Overall, the self-assembled porphyrin boxes Bn serve as a well-defined three-dimensional model for the light-harvesting complex.


Absence of Pathological Proof of Cancer Associated with Improved Outcomes in Early-Stage Lung Cancer.
The purpose of this study was to assess the trends in use of clinical diagnosis and its impact on treatment outcomes in patients receiving radiation therapy for early-stage lung cancer. The Surveillance, Epidemiology, and End Results registry was queried from 2004 to 2012 for patients at least 18 years old in whom stage I (clinical stage T1a-T2a) lung cancer had been diagnosed and who underwent radiation therapy alone. Trends in diagnostic confirmation patterns were characterized. A Cox proportional hazards model was used to assess overall survival, and competing risk regression analysis was used to assess cancer-specific survival (CSS). A total of 7050 patients were included; the disease of 6399 of them (90.8%) was pathologically diagnosed and that of 651 (9.2%) was clinically diagnosed. There was no significant change in the utilization of clinical versus pathologic diagnosis (p = 0.172) over time. Patients with T1 disease (p < 0.001), tumors 0 to 1.9 cm in size (p < 0.001), and upper lobe tumors (p = 0.004) were more likely to have been clinically diagnosed. On multivariable analysis, clinical diagnosis was associated with an improved CSS (hazard ratio [HR] = 0.82, 95% confidence interval [CI]: 0.71-0.96) but was not associated with an improved overall survival (HR = 1.01, 95% CI: 0.90-1.13). When stratified by T stage, patients whose disease had been clinically diagnosed as stage T1a had an improved CSS (HR = 0.75, 95% CI: 0.58-0.96, p = 0.022). There was a trend toward improved CSS in patients with clinical stage T1b tumors (HR = 0.74, 95% CI: 0.55-1.00, p = 0.052). The improved CSS in patients with a clinical diagnosis suggests treatment of benign disease, particularly in smaller tumors. Prudent patient selection is needed to reduce the potential for overtreatment.


Linking emergency medical department and road traffic police casualty data: a tool in assessing the burden of injuries in less resourced countries.
The study aimed to (1) assess the magnitude of road traffic injuries in a country missing a formal linkage system of police with hospital data, (2) quantify the underreporting, and (3) produce a convenient algorithm exploring its constituent components. Linkage of disaggregate (individual) data collected by the road traffic police (RTP) with those by the Emergency Department Injury Surveillance System (EDISS) on the Greek island of Corfu and coded with different classification systems was carried out. The applied four-step methodology, also comprising the calculation of underreporting coefficients of the variation by basic demographic variables, mode of transport, and injury outcome, led to the identification of the overall underreporting from either registry. RTP data captured 96.6% (coefficient: 1.035), whereas EDISS captured only 54.4% of total fatalities (overall concordance: 51.1%). On the contrary, EDISS captured 94.6% of nonfatal injuries, whereas RTP only captured 16% (coefficient: 6.238), resulting in a low overall concordance (10.6%). Considering severity of injury assessed by EDISS, by using the ISS as the gold standard, RTP data misclassified 20.3% of severe injuries as less severe, and a statistically significant difference in the underreporting by gender was also noted. Relatively simple methodologies can provide essential coefficients to assess the actual numbers, severity, and components of road casualties by complementing routinely collected RTP with sentinel emergency department reporting systems.


Rapid Resolution of Grief with IV Infusion of Ketamine: A Unique Phenomenological Experience.
Ketamine, a primarily FDA-approved anaesthetic agent is also used as recreational drug. Based on preclinical findings and later the clinical observations it is noted to have rapid antidepressant effect due to its mechanisms related to NMDA antagonism. In spite of established evidence of ketamine being effective in depression with significant role in treatment resistant cases as well, there was absolute dearth of literature regarding its utility in grief-related disorders. In this context we present a case of 28-year-old graduate male who presented to us in complicated grief following death of his wife due to obstetric complications. With the patient and immediate family members consenting for use of ketamine as off-label use, patient had single IV infusion of ketamine following which he had unique phenomenological experience ultimately resolving his grief in few minutes. Through this case we highlight the enormous therapeutic promise of ketamine in complicated grief.


Marketing strategies in a competitive managed care environment.
In the new health care marketplace dominated by managed care, patients expect more from their physicians and other providers. Because cost is not an issue for the managed care patient, physicians must find a way to distinguish their practices from others in the managed care plan directory. This article provides low-cost strategies that physicians may use to do so. These include: focusing on the customer; ensuring friendly, attentive, and trained staff using patient-friendly office policies; making the patient priority number one; listening to and communicating with patients; being a patient advocate; giving patients choices to increase their control over their care; respecting the time demands on the patient and his or her family, and others.


Depolarization of polarized light caused by high altitude clouds. 1: Depolarization of lidar induced by cirrus.
A scattering model is described for the investigation of depolarization of polarized light caused by ice clouds. The scattering by a single particle is described by refraction, reflection, and diffraction. The ice cloud is assumed to be a random mixture of hexagonal columns and plates of random orientation and size. Multiple scattering effects are included by means of a Monte Carlo method, where single photon histories are constructed from random samples of the distributions governing the basic scattering parameters. The dependence of depolarization on cloud extinction coefficient, receiver field of view, and mixing ratio of columns to plates are studied. Lidar measurements of depolarization by a high altitude cirrus cloud are presented and discussed within the frame of the present model. Good agreement can be obtained assuming a variation of crystal shape distribution with height.


Microtubule sliding in mutant Chlamydomonas axonemes devoid of outer or inner dynein arms.
To clarify the functional differentiation between the outer and inner dynein arms in eukaryotic flagella, their mechanochemical properties were assessed by measuring the sliding velocities of outer-doublet microtubules in disintegrating axonemes of Chlamydomonas, using wild-type and mutant strains that lack either of the arms. A special procedure was developed to induce sliding disintegration in Chlamydomonas axonemes which is difficult to achieve by ordinary methods. The flagella were first fragmented by sonication, demembranated by Nonidet P-40, and then perfused under a microscope with Mg-ATP and nagarse, a bacterial protease with broad substrate specificity. The sliding velocity varied with the Mg-ATP concentration in a Michaelis-Menten manner in the axonemes from the wild type and a motile mutant lacking the outer dynein arm (oda38). The maximal sliding velocity and apparent Michaelis constant for Mg-ATP were measured to be 13.2 +/- 1.0 micron/s and 158 +/- 36 microM for the wild type and 2.0 +/- 0.1 micron/s and 64 +/- 18 microM for oda38. These maximal sliding velocities were significantly smaller than those estimated in beating axonemes; the reason is not clear. The velocities in the presence or absence of 10(-5) M Ca2+ did not differ noticeably. The axonemes of nonmotile mutants lacking either outer arms (pf13A, pf22) or inner arms (pf23) were examined for their ability to undergo sliding disintegration in the presence of 0.1 mM Mg-ATP. Whereas pf13A axonemes underwent normal sliding disintegration, the other two species displayed it only very poorly. The poor ability of pf23 axonemes to undergo sliding disintegration raises the possibility that the outer dynein arm cannot function well in the absence of the inner arm.


A comparison of dexmedetomidine sedation with and without midazolam for dental implant surgery.
Dexmedetomidine (DEX) has a minimal respiratory depressive effect, which is beneficial for dentistry; however, it has the disadvantage of permitting an intraoperative arousal response such that the patient appears to be suddenly no longer sedated, and it has a variable amnestic effect. Since midazolam (MDZ) in an appropriate dose has a profound amnesic effect, we investigated whether additional MDZ compensates for the disadvantage of DEX and enables a better quality of sedation. Forty-three subjects were randomly divided into 4 groups. In group 1, MDZ (0.02 mg/kg) was administered intravenously, followed by a dose of 0.01 mg/kg every 45 minutes. After the first dose of MDZ, preloading with DEX (2 µg/kg/h for 10 minutes) was started and maintained with a dosage of 0.5 µg/kg/h. In group 2, MDZ was infused in the same manner as in group 1, followed by preloading with DEX (1 µg/kg/h for 10 minutes) and maintenance (0.3 µg/kg/h). In group 3, MDZ was infused 0.03 mg/kg, and a dose of 0.01 mg/kg was given every 30 minutes; DEX was administered at the same as in group 2. In group 4, DEX was infused using the same method as in group 1 without MDZ. The sedation levels, amnesia, and patient satisfaction were also investigated. Group 2 had a lower sedation level and a poor evaluation during the first half of the operation. Group 4 did not exhibit an amnesic effect at the beginning of the operation. An evaluation of the degree of patient satisfaction did not reveal any differences among the groups. Optimal sedation was achieved through the combined use of MDZ (0.02 mg/kg with the addition of 0.01 mg/kg every 45 minutes) and DEX (2 µg/kg/h for 10 minutes followed by 0.5 µg/kg/h).


Effect of aortic angulation on the outcomes of fenestrated-branched endovascular aortic repair.
To investigate the effect of aortic angulation on the early and midterm outcomes of fenestrated-branched endovascular aneurysm repair for thoracoabdominal aortic aneurysms (TAAA) or pararenal aortic aneurysms (PRAA). We retrospectively reviewed the data of consecutive patients enrolled in a prospective nonrandomized physician-sponsored investigational device exemption study (2013-2018). The infrarenal, suprarenal, and supraceliac aortic angles were measured on three-dimensional reconstructions of the preoperative computed tomography angiogram; a 45° cutoff was used for the analysis. End points were technical success, freedom from endograft-related complications (defined by type IA/IB/IIIA/IIIB/IIID endoleaks, and limb thrombosis); and freedom from target vessel instability (defined by branch-related death, occlusion, rupture or reintervention for stenosis, endoleak, or disconnection). Cox proportional hazard multivariable regression analyses were preformed to assess impact of covariates. There were 298 patients treated for 102 PRAAs (34%) and 196 TAAAs (66%) (78 extent IV, 118 extent I-III) with 1156 renal-mesenteric vessels incorporated. An angulation of >45° was present in the infrarenal aortic axis in 94 patients (32%), suprarenal axis in 39 (13%), and supraceliac axis in 93 (31%). A supraceliac angle of >45° was more common with extent I-III TAAAs (P = .01). Technical success was 97% and was not significantly related to aortic angulation; the total operating time and fluoroscopy time were significantly longer in patients with any aortic angulation of >45°. Freedom from endograft-related complications was 93% (95% confidence interval [CI], 90%-97%) at 42 months, and was not associated with infrarenal (HR, 1.0; 95% CI, 0.4-2.9; P = .976), suprarenal (HR, 1.7; 95% CI, 0.5-1.8; P = .428), or supraceliac (HR, 0.9; 95% CI, 0.3-2.6; P = .886) aortic angles of >45°. Overall freedom from target vessel instability was 92% (95% CI, 90%-94%) at 42 months. By multivariable analysis, target vessel instability was not affected by an infrarenal angle of >45° (HR, 1.5; 95% CI, 0.9-2.4; P = .135) and a supraceliac angle of >45° (HR, 0.9; 95% CI, 0.5-1.5; P = .627), but was associated with a suprarenal angle of >45° (HR, 5.6; 95% CI, 3.5-9.1; P < .001), even after adjustment for aneurysm extent and type of bridging stent. In this subgroup of patients, the use of directional branch vs fenestration (P = .10) and the type of bridging stent (P = .10) did not significantly impact target vessel instability. Fenestrated-branched endovascular aneurysm repair can achieve excellent early and midterm results among patients with an aortic angulation of >45°, with no increase in rates of graft-related complications. However, increased aortic angulation was associated with longer operative and fluoroscopy times. The suprarenal aortic angle was the most important determinant of more target vessel events, independent of stent design or which bridging stent was selected.


Working Memory and Hearing Aid Processing: Literature Findings, Future Directions, and Clinical Applications.
Working memory-the ability to process and store information-has been identified as an important aspect of speech perception in difficult listening environments. Working memory can be envisioned as a limited-capacity system which is engaged when an input signal cannot be readily matched to a stored representation or template. This "mismatch" is expected to occur more frequently when the signal is degraded. Because working memory capacity varies among individuals, those with smaller capacity are expected to demonstrate poorer speech understanding when speech is degraded, such as in background noise. However, it is less clear whether (and how) working memory should influence practical decisions, such as hearing treatment. Here, we consider the relationship between working memory capacity and response to specific hearing aid processing strategies. Three types of signal processing are considered, each of which will alter the acoustic signal: fast-acting wide-dynamic range compression, which smooths the amplitude envelope of the input signal; digital noise reduction, which may inadvertently remove speech signal components as it suppresses noise; and frequency compression, which alters the relationship between spectral peaks. For fast-acting wide-dynamic range compression, a growing body of data suggests that individuals with smaller working memory capacity may be more susceptible to such signal alterations, and may receive greater amplification benefit with "low alteration" processing. While the evidence for a relationship between wide-dynamic range compression and working memory appears robust, the effects of working memory on perceptual response to other forms of hearing aid signal processing are less clear cut. We conclude our review with a discussion of the opportunities (and challenges) in translating information on individual working memory into clinical treatment, including clinically feasible measures of working memory.


In-situ atomic force microscopy study of beta-amyloid fibrillization.
We report the use of atomic force microscopy to observe the initial stages of beta-amyloid fibrillization in situ. The growth of individual beta-amyloid protofibrils on a mica substrate was followed over several hours. The first in situ visualization of protofibril formation from single aggregate units of beta-amyloid is reported. The growth of these protofibrils through the subsequent addition of these aggregate units is also observed. Growth of the protofibrils is bi-directional and the outgrowth of protofibrils from a common amyloid/heterogeneous core is also observed. Elongation also occurred by the addition of protofibrils from solution. This data provides an exciting insight into the early stages of beta-amyloid fibrillization and can be used to enhance the understanding of the mechanism(s) by which beta-amyloid fibrillizes and may consequently enable inhibition of one or more stages of fibrillization as a potential therapeutic strategy.


Enterohepatic helicobacter in ulcerative colitis: potential pathogenic entities?
Changes in bacterial populations termed "dysbiosis" are thought central to ulcerative colitis (UC) pathogenesis. In particular, the possibility that novel Helicobacter organisms play a role in human UC has been debated but not comprehensively investigated. The aim of this study was to develop a molecular approach to investigate the presence of Helicobacter organisms in adults with and without UC. A dual molecular approach to detect Helicobacter was developed. Oligonucleotide probes against the genus Helicobacter were designed and optimised alongside a validation of published H. pylori probes. A comprehensive evaluation of Helicobacter genus and H. pylori PCR primers was also undertaken. The combined approach was then assessed in a range of gastrointestinal samples prior to assessment of a UC cohort. Archival colonic samples were available from 106 individuals for FISH analysis (57 with UC and 49 non-IBD controls). A further 118 individuals were collected prospectively for dual FISH and PCR analysis (86 UC and 32 non-IBD controls). An additional 27 non-IBD controls were available for PCR analysis. All Helicobacter PCR-positive samples were sequenced. The association between Helicobacter and each study group was statistically analysed using the Pearson Chi Squared 2 tailed test. Helicobacter genus PCR positivity was significantly higher in UC than controls (32 of 77 versus 11 of 59, p = 0.004). Sequence analysis indicated enterohepatic Helicobacter species prevalence was significantly higher in the UC group compared to the control group (30 of 77 versus 2 of 59, p<0.0001). PCR and FISH results were concordant in 74 (67.9%) of subjects. The majority of discordant results were attributable to a higher positivity rate with FISH than PCR. Helicobacter organisms warrant consideration as potential pathogenic entities in UC. Isolation of these organisms from colonic tissue is needed to enable interrogation of pathogenicity against established criteria.


Risk of cervical HPV infection and prevalence of vaccine-type and other high-risk HPV types among sexually active teens and young women (13-26 years) enrolled in the VALHIDATE study.
HPV vaccination is expected to reduce the incidence of cervical cancer. The greatest and the earliest health gains will be ensured by high vaccine coverage among all susceptible people. The high costs and the risk of a reduced cost/effectiveness ratio in sexually active girls still represent the main obstacles for a more widespread use of HPV vaccination in many countries. Data on the rate, risk factors, and HPV types in sexually active women could provide information for the evaluation of vaccination policies extended to broader age cohorts. Sexually active women aged 13-26 years enrolled in an Italian cohort study were screened for cervical HPV infections; HPV-DNA positive samples were genotyped by InnoLipa HPV Genotyping Extra or by RFLP genotype analysis.: Among the 796 women meeting the inclusion criteria, 10.80% (95% CI 8.65-12.96) were HPV-DNA infected. Age>18 years, lifetime sexual partners>1, and history of STIs were associated to higher risk of HPV infection in the multivariable models adjusted for age, lifetime sexual partners, and time of sexual exposure. The global prevalence of the four HPV vaccine-types was 3.02% (95% CI 1.83-4.20) and the cumulative probability of infection from at least one vaccine-type was 12.82% in 26-years-old women and 0.78% in 18-years-old women.: Our data confirm most of the previously reported findings on the risk factors for HPV infections. The low prevalence of the HPV vaccine-types found may be useful for the evaluation of the cost/efficacy and the cost/effectiveness of broader immunization programs beyond the 12-years-old cohort.


Effects of disease-modifying anti-rheumatic drugs (DMARDs) on the activities of rheumatoid arthritis-associated cathepsins K and S.
Rheumatoid arthritis is an inflammatory and disabling joint disease affecting 0.5-1.5% of the population. Although various anti-inflammatory (NSAIDs) and disease-modifying (DMARDs) drugs are in clinical use, their precise mechanisms of action are not always defined. In this report, we discuss the effects of widely used DMARDs such as gold derivatives and chloroquine on cathepsins K and S, which have been implicated as critical mediators of inflammation and joint erosion in rheumatoid arthritis. We demonstrate that clinically potent gold derivatives inhibit cathepsins K and S in in vitro and cell-based assays. An X-ray analysis of the gold thiomalate/cathepsin K complex reveals that the inhibitor is bound to the active-site cysteine residue of the protease. Chloroquine, a lysosomotropic agent of lower clinical potency than gold derivatives, inhibits neutral pH-labile cathepsins intracellularly, but does not affect the neutral pH-stable cathepsin S. The potent inhibition of cathepsins implicated in the pathogenesis of rheumatoid arthritis by gold derivatives may explain the therapeutic efficacy of these drugs.


Exercise training in kidney transplant recipients: a systematic review.
Evidences on the benefits of physical exercise in kidney transplant patients (KTx) are not conclusive and concerns on safety remain. We here gather and interpret current evidence on the benefits/harms of exercise training intervention in KTx. Systematic review of exercise training programs in KTx. A total of 24 studies including 654 KTx patients on intervention and 536 controls were evaluated. The median age was 46 years; the transplant vintage was 2 days to 10 years. The intervention was an aerobic or resistance exercise program or a combination of both; interventions consisted of 20-60 min' sessions, 2-3 times per week repetitions and 5.5 months' median duration. Most studies improved cardiorespiratory fitness (expressed as VO2peak) as well as maximum heart rate, which was associated with a significant increase in muscle performances and strength. No significant changes in body weight or composition were observed, but a trend towards weight reduction in overweight or obese patients on stable KTx was noted. The arterial blood pressure reduced a little after exercise when it was high at start. Exercise intervention had no clinically relevant impact on anaemia, glycaemia or lipidaemia. In contrast, exercise training improved several aspects of quality of life. No data on long-term hard outcomes or on high-risk subpopulations such comorbid or elderly patients were available. In adult kidney transplant patients, a structured physical exercise program improved the aerobic capacity and ameliorated muscle performance and quality of life. No harms were observed in the short-term, but long-term RCTs are required. Overall, in mid-age kidney transplant patients without major comorbidities, an aerobic or resistance supervised exercise lasting 3-6 months could be suggested within the comprehensive treatment of kidney transplant.


Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity: Evidence From Mouse and Human Studies.
The CXCL12/CXCR4 chemokine ligand/receptor axis controls (progenitor) cell homeostasis and trafficking. So far, an atheroprotective role of CXCL12/CXCR4 has only been implied through pharmacological intervention, in particular, because the somatic deletion of the CXCR4 gene in mice is embryonically lethal. Moreover, cell-specific effects of CXCR4 in the arterial wall and underlying mechanisms remain elusive, prompting us to investigate the relevance of CXCR4 in vascular cell types for atheroprotection. We examined the role of vascular CXCR4 in atherosclerosis and plaque composition by inducing an endothelial cell (BmxCreERT2-driven)-specific or smooth muscle cell (SMC, SmmhcCreERT2- or TaglnCre-driven)-specific deficiency of CXCR4 in an apolipoprotein E-deficient mouse model. To identify underlying mechanisms for effects of CXCR4, we studied endothelial permeability, intravital leukocyte adhesion, involvement of the Akt/WNT/β-catenin signaling pathway and relevant phosphatases in VE-cadherin expression and function, vascular tone in aortic rings, cholesterol efflux from macrophages, and expression of SMC phenotypic markers. Finally, we analyzed associations of common genetic variants at the CXCR4 locus with the risk for coronary heart disease, along with CXCR4 transcript expression in human atherosclerotic plaques. The cell-specific deletion of CXCR4 in arterial endothelial cells (n=12-15) or SMCs (n=13-24) markedly increased atherosclerotic lesion formation in hyperlipidemic mice. Endothelial barrier function was promoted by CXCL12/CXCR4, which triggered Akt/WNT/β-catenin signaling to drive VE-cadherin expression and stabilized junctional VE-cadherin complexes through associated phosphatases. Conversely, endothelial CXCR4 deficiency caused arterial leakage and inflammatory leukocyte recruitment during atherogenesis. In arterial SMCs, CXCR4 sustained normal vascular reactivity and contractile responses, whereas CXCR4 deficiency favored a synthetic phenotype, the occurrence of macrophage-like SMCs in the lesions, and impaired cholesterol efflux. Regression analyses in humans (n=259 796) identified the C-allele at rs2322864 within the CXCR4 locus to be associated with increased risk for coronary heart disease. In line, C/C risk genotype carriers showed reduced CXCR4 expression in carotid artery plaques (n=188), which was furthermore associated with symptomatic disease. Our data clearly establish that vascular CXCR4 limits atherosclerosis by maintaining arterial integrity, preserving endothelial barrier function, and a normal contractile SMC phenotype. Enhancing these beneficial functions of arterial CXCR4 by selective modulators might open novel therapeutic options in atherosclerosis.


Clinical development of retroviral replicating vector Toca 511 for gene therapy of cancer.
The use of tumor-selectively replicating viruses is a rapidly expanding field that is showing considerable promise for cancer treatment. Retroviral replicating vectors (RRV) are unique among the various replication-competent viruses currently being investigated for potential clinical utility, because they permanently integrate into the cancer cell genome and are capable of long-term persistence within tumors. RRV can mediate efficient tumor-specific delivery of prodrug activator genes, and subsequent prodrug treatment leads to synchronized cell killing of infected cancer cells, as well as activation of antitumor immune responses. Here we review preclinical studies supporting bench-to-bedside translation of Toca 511, an optimized RRV for prodrug activator gene therapy, the results from Phase I through III clinical trials to date, and potential future directions for this therapy as well as other clinical candidate RRV. Toca 511 has shown highly promising results in early-stage clinical trials. This vector progressed to a registrational Phase III trial, but the results announced in late 2019 appeared negative overall. However, the median prodrug dosing schedule was not optimal, and promising possible efficacy was observed in some prespecified subgroups. Further clinical investigation, as well as development of RRV with other transgene payloads, is merited.


Reversible synthesis and characterization of dynamic imino analogues of trimethine and pentamethine cyanine dyes.
A new family of unsymmetrical imine-based trimethine and pentamethine cyanine dye analogues is reported that can form under reversible and thermodynamically controlled conditions from non- or weakly emissive amine and aldehyde building blocks. These dynamic fluorophores show spectroscopic properties comparable to those of their parent cyanine dyes and are responsive to external effectors.


Understanding the concurrence of environmental characteristics in Latino youth: A person-centered approach.
The current study aimed to identify profiles of youth presenting with a unique combination of environmental characteristics and understand the differential relationship between profile membership, anxiety, and depression symptoms. Data were drawn from 158 Latino youth between the ages of 11 and 13. Youth provided information on community violence exposure, acculturative stress, familial and peer support, and parental supervision. Main analyses included Latent Profile Analysis and Multivariate Analysis of Variance. Support for a four-profile model was found. Profiles are distinguished by mean levels of community violence exposure, acculturative stress, familial and peer support, and parental supervision. Profile membership was significantly associated with anxiety and depression, separately. Those belonging to the profile with the highest levels of environmental risk reported the highest levels of anxiety and depression. Findings contribute to a personalized understanding of risk and protective experiences in the environment for Latino youth.


Octadecyltrichlorosilane (OTS)-coated ionic liquid drops: Micro-reactors for homogenous catalytic reactions at designated interfaces.
An ionic liquid (IL), 1-butyl-3-methylimidazolium chloride ([Bmim]Cl) can assemble on prefabricated carboxylic acid-terminated chemical patterns on octadecyltrichlorosilane (OTS) film. The chemical pattern controls the position, shape and size of the IL on the surface. After the IL assembly - by incubating IL drops assembled on sample surface in an OTS silane vapor - an OTS layer was coated on the IL drop surface which encapsulated the IL drop. The OTS-coated capsule can exist stably under aqueous solution. The OTS coating protected the IL drops from being instantaneously dissolved by other solutions. We found that a homogenous catalyst (FeCl(3)) dissolved in [Bmim]Cl can be assembled together on the chemical patterns and subsequently encapsulated together with [Bmim]Cl by OTS coating. The pinhole defects within the vapor-coated silane layer provide space for the catalyst inside the capsule and reactants outside the capsule to meet and react. When the OTS-coated capsule containing a FeCl(3)/IL mixture was soaked under H(2)O(2) solution, the Fe(3+) ions catalyzed the decomposition reaction of hydrogen peroxide at the vapor-coated OTS-water interface. Since the shape and position of the interface is defined by the underneath chemical pattern, our findings show that the OTS-coated IL drops assembled on chemical patterns can be used as novel micro-reactors. This allows homogenous catalytic reactions to occur at the designated interfaces.


Cytotoxic effects of gammadelta T cells expanded ex vivo by a third generation bisphosphonate for cancer immunotherapy.
Nitrogen containing-bisphosphonates (N-BPs), widely used to treat bone diseases, have direct antitumor effects via the inactivation of Ras proteins. In addition to the direct antitumor activities, N-BPs expand gammadeltaT cells, which exhibit major histocompatibility complex-unrestricted lytic activity. BPs accumulate intermediate metabolites which may be tumor antigens in target cells. The purpose of our study was to clarify the cytotoxicity of gammadelta T cells expanded ex vivo by the most potent N-BP, zoledronate (ZOL). Especially, we focused on the importance of pretreatment against target cells also with ZOL; 1 microM ZOL plus IL-2 increased the absolute number of gammadeltaT cells 298-768 fold for 14 days incubation. The small cell lung cancer and fibrosarcoma cell lines pretreated with 5 microM ZOL showed a marked increase in sensitivity to lysis by gammadeltaT cells. While, untreated cell lines were much less sensitive to lysis by gdT cells. Video microscopy clearly demonstrated that gammadeltaT cells killed target cells pre-treated with ZOL within 3 hr. Pretreatment with 80 microg/kg ZOL also significantly enhanced the antitumor activity of gammadeltaT cells in mice xenografted with SBC-5 cells. These findings show that ZOL significantly stimulated the proliferation of gammadeltaT cells and that gammadeltaT cells required pre-treatment with ZOL for cytotoxic activity against target cells.


High-risk Opioid Prescribing Associated with Postoperative New Persistent Opioid Use in Adolescents and Young Adults.
In this study, we explored which postoperative opioid prescribing practices were associated with persistent opioid use among adolescents and young adults. Approximately 5% of adolescents and young adults develop postoperative new persistent opioid use. The impact of physician prescribing practices on persistent use among young patients is unknown. We identified opioid-naïve patients aged 13 to 21 who underwent 1 of 13 procedures (2008-2016) and filled a perioperative opioid prescription using commercial insurance claims (Optum Deidentified Clinformatics Data Mart Database). Persistent use was defined as ≥ 1 opioid prescription fill 91 to 180 days after surgery. High-risk opioid prescribing included overlapping opioid prescriptions, co-prescribed benzodiazepines, high daily prescribed dosage, long-acting formulations, and multiple prescribers. Logistic regression modeled persistent use as a function of exposure to high-risk prescribing, adjusted for patient demographics, procedure, and comorbidities. High-risk opioid prescribing practices increased from 34.9% to 43.5% over the study period; the largest increase was in co-prescribed benzodiazepines (24.1%-33.4%). High-risk opioid prescribing was associated with persistent use (aOR 1.235 [1.12,1.36]). Receipt of prescriptions from multiple opioid prescribers was individually associated with persistent use (aOR 1.288 [1.16,1.44]). The majority of opioid prescriptions to patients with persistent use beyond the postoperative period were from nonsurgical prescribers (79.6%). High-risk opioid prescribing practices, particularly receiving prescriptions from multiple prescribers across specialties, were associated with a significant increase in adolescent and young adult patients' risk of persistent opioid use. Prescription drug monitoring programs may help identify young patients at risk of persistent opioid use.


Phase Diagram and Structure Map of Binary Nanoparticle Superlattices from a Lennard-Jones Model.
A first-principles prediction of the binary nanoparticle phase diagram assembled by solvent evaporation has eluded theoretical approaches. In this paper, we show that a binary system interacting through the Lennard-Jones (LJ) potential contains all experimental phases in which nanoparticles are effectively described as quasi hard spheres. We report a phase diagram consisting of 53 equilibrium phases, whose stability is quite insensitive to the microscopic details of the potentials, thus giving rise to some type of universality. Furthermore, we show that binary lattices may be understood as consisting of certain particle clusters, i.e., motifs, that provide a generalization of the four conventional Frank-Kasper polyhedral units. Our results show that metastable phases share the very same motifs as equilibrium phases. We discuss the connection with packing models, phase diagrams with repulsive potentials, and the prediction of likely experimental superlattices.


Identifying educational influentials for formal and informal continuing medical education in the province of British Columbia.
The objective of this study was to identify physicians in the province of British Columbia (BC) who are perceived by their colleagues to be the most educationally influential. A cross-sectional study using a previously validated survey tool was mailed to a randomly selected sample of 2300 BC registered primary care physicians. Follow-up mailings were sent to nonresponders. The survey response rate was 53%. A list of 375 educationally influential physicians (EIs) was proportionately determined and tabulated by region. The top 5% of provincial EIs were identified to serve as a resource for formal and informal continuing medical education (CME). Their names will be brought forward in response to selected requests for CME speakers.


Prevention of lethal murine pancreas ischemia reperfusion injury is specific for tetrahydrobiopterin.
Tetrahydrobiopterin has been shown to efficiently abrogate ischemia reperfusion injury (IRI). However, it is unclear, whether its beneficial action relies on cofactor activity of one of the five known tetrahydrobiopterin-dependent reactions or on its antioxidative capacity. We therefore compared tetrahydrobiopterin with the pterin derivate tetrahydroneopterin (similar biochemical properties, but no nitric oxide synthase cofactor activity) and the antioxidants vitamin C and 5-methyltetrahydrofolate. Donor mice were pretreated with tetrahydrobiopterin, tetrahydroneopterin, vitamin C, or 5-methyltetrahydrofolate. Pancreatic grafts were subjected to 16-h cold ischemia time and implanted in syngeneic recipients. Untreated and nontransplanted animals served as controls. Following 2-h reperfusion, microcirculation was analyzed by intravital fluorescence microscopy. Graft damage was assessed by histology and nitrotyrosine immunostaining, and tetrahydrobiopterin levels were determined by HPLC. Recipient survival served as ultimate readout. Prolonged cold ischemia time resulted in microcirculatory breakdown. Only tetrahydrobiopterin pretreatment succeeded to preserve the capillary net, whereas all other compounds showed no beneficial effects. Along with increased intragraft tetrahydrobiopterin levels during recovery and implantation, only tetrahydrobiopterin pretreatment led to significant reduction of IRI-related parenchymal damage enabling recipient survival. These results show a striking superiority of tetrahydrobiopterin in preventing lethal IRI compared with related compounds and suggest nitric oxide synthases as treatment target.