The approach to coronary bifurcation treatment and its outcomes in Poland: The single center experience.
Coronary bifurcation lesions pose therapeutic problems during percutaneous coronary interventions. The aim of this study was to analyze the strategy of coronary bifurcation treatment and associated angiographic as well as clinical outcomes in a large hospital in Northern Poland. Between January 2012 and January 2014 patients with stable coronary artery disease or non-ST-elevation acute coronary syndrome (NSTE-ACS) were treated with regular drug-eluting stents (rDES) or dedicated bifurcation stents (BiOSS Expert® or BiOSS LIM®). Clinical and angiographic controls were planned at 12 months. The primary endpoint was major adverse cardiovascular events (MACE) rate composed of cardiac death, myocardial infarction, and target lesion revascularization (TLR) at 12 months. In total, 152 patients were enrolled in whom 158 stents were deployed (99 BiOSS stents and 59 rDES). Left anterior descending artery (50%) was the dominant target vessel followed by left circum¬flex (25%). There was no stent implantation failure. In 10 (6.3%) patients rDES was required within the side branch. At 12 months MACE rate was 11.2%, whereas TLR rate was 7.9%. In the logistic regression analysis final kissing balloon technique was the prognostic factor for better clinical outcome, whereas NSTE-ACS and true bifurcations were risk factors of a poor outcome. Percutaneous coronary bifurcation treatment is a safe and effective procedure, and pro¬visional T-stenting is the preferred technique. Both rDES as well as dedicated bifurcation stents enabled a simple and fast bifurcation treatment option with comparable MACE and TLR rates. (Cardiol J 2017; 24, 6: 589-596).


[Study on nature, function and indication of Melastomataceae plants in China].
There are 63 species Melastomataceae plants in 17 genus, which widely distribute along Yangtze River and the south of China ranging from Tibet autonomous region to Taiwan province. They used as herb medicine in China. A large part of the Melastomataceae plants have bitter, pungent and sweet taste. The meridian distribution of them is liver, spleen and stomach, they have many functions such as "cure rheumatism", "clear heat" and "detoxication", "regulate the flow of qi and alleviate pain", "diuresis and detumescence", "activate the blood and eliminate stasis". Melastomataceae plants not only have exact medical value, but also have abundant resource. So it has very bright perspective of exploitation and utilization.


Solid-State 15N and 17O NMR Studies of S-Nitrosothiols.
We report a solid-state 15N and 17O NMR study of two representative S-nitrosothiols (RSNO): S-nitroso N-acetylpenicillamine (SNAP) and S-nitrosoglutathione (GSNO). The 15N and 17O NMR tensors are experimentally determined for the first time for this important class of nitric-oxide (NO)-related compounds. The observed NMR characteristics for RSNO include large 15N and 17O chemical shift anisotropies and large 17O quadrupole coupling constants. Quantum chemical calculations are also performed for the 15N and 17O NMR tensors in two simple RSNO models: t-BuSNO and MeSNO. On the basis of computational results, we have identified the molecular orbitals that are responsible for the observed large chemical shift anisotropies in RSNO compounds.


Spirometric reference values in greek children and adolescents.
This study was performed to describe the relationship among anthropometric parameters and lung function in Greek children, to produce reference values for spirometry and to compare these results with other data sets. Spirometric values were measured with electronic portable Spirometer Spirolab II (MIR) in 414 healthy, nonsmoking Greek children, aged 6-18 years. Multiple linear regression analysis was performed for each spirometric parameter against age, height, weight and body mass index (BMI). The highest correlation was found with height. Predictive equations for: forced expiratory volume in the first sec (FEV(1)), forced vital capacity (FVC), forced expiratory flow from 25%-75% of the vital capacity (FEF(25-75%)) and peak expiratory flow (PEF) with standing height as the dependent variable are presented for both sexes. Our reference values are close to those of other European children. The developed predictive equations can be used in clinical practice in Greece and in other neighboring Balkan countries.


A non-beta-lactam antibiotic inhibitor for enterohemorrhagic Escherichia coli O104:H4.
The overuse of antibiotics has caused an increased prevalence of drug-resistant bacteria. Bacterial resistance in E. coli is regulated via production of β-lactam-hydrolyzing β-lactamases enzymes. Escherichia coli O104: H4 is a multi-drug resistant strain known to resist β-lactam as well as several other antibiotics. Here, we report a molecular dynamic simulation-combined docking approach to identify, screen, and verify active pharmacophores against enterohemorrhagic Escherichia coli (EHEC). Experimental studies revealed a boronic acid cyclic monomer (BACM), a non-β-lactam compound, to inhibit the growth of E. coli O104: H4. In vitro Kirby Bauer disk diffusion susceptibility testing coupled interaction analysis suggests BACM inhibits E. coli O104:H4 growth by not only inhibiting the β-lactamase pathway but also via direct inhibition of the penicillin-binding protein. These results suggest that BACM could be used as a lead compound to develop potent drugs targeting beta-lactam resistant Gram-negative bacterial strains. KEY MESSAGES: • An in silico approach was reported to identify pharmacophores against E. coli O104: H4. • In vitro studies revealed a non-β-lactam compound to inhibit the growth of E. coli O104: H4. • This non-β-lactam compound could be used as a lead compound for targeting beta-lactam strains.


Child support orders: a perspective on reform.
This article presents a brief historical account of child support reform in the United States during this century. Reform in this area primarily reflects a shift from judicial discretion to administrative regularity. The two predominant types of child support guidelines in use today, income shares and percentage of income, are described and compared. The authors then present information on some of the current issues with regard to child support guideline reform. Finally, a Child Support Assurance system, which would provide a publicly guaranteed minimum benefit award to custodial parents under special circumstances, is proposed. Further discussion of child support reform is presented in the Overview and Analysis section of this journal issue.


Plant and pathogen nutrient acquisition strategies.
Nutrients are indispensable elements required for the growth of all living organisms including plants and pathogens. Phyllosphere, rhizosphere, apoplast, phloem, xylem, and cell organelles are the nutrient niches in plants that are the target of bacterial pathogens. Depending upon nutrients availability, the pathogen adapts various acquisition strategies and inhabits the specific niche. In this review, we discuss the nutrient composition of different niches in plants, the mechanisms involved in the recognition of nutrient niche and the sophisticated strategies used by the bacterial pathogens for acquiring nutrients. We provide insight into various nutrient acquisition strategies used by necrotrophic, biotrophic, and hemibiotrophic bacteria. Specifically we discuss both modulation of bacterial machinery and manipulation of host machinery. In addition, we highlight the current status of our understanding about the nutrient acquisition strategies used by bacterial pathogens, namely targeting the sugar transporters that are dedicated for the plant's growth and development. Bacterial strategies for altering the plant cell membrane permeability to enhance the release of nutrients are also enumerated along with in-depth analysis of molecular mechanisms behind these strategies. The information presented in this review will be useful to understand the plant-pathogen interaction in nutrient perspective.


The impact of the COVID-19 pandemic on presentation of surgical disease in paediatric patients at a tertiary centre in Cape Town, South Africa.
Children are less susceptible to infection with SARS-CoV-2 and subsequent severe disease, yet especially vulnerable to the indirect effects of the pandemic. A constrained healthcare service, combined with the societal and behavioural changes observed during the pandemic, is likely to have altered the presentation of paediatric surgical disease. The objective was to investigate the impact of the COVID-19 pandemic on the volume of paediatric surgical admissions, the severity of disease and the type of surgical pathology treated at our centre. A retrospective cohort study compared paediatric surgical admissions in an eleven-month period before COVID-19 to the same period during the pandemic. Comparisons in volume and diagnoses were based on the number of admissions. Predetermined criteria for severity of disease using triage scores, intraoperative findings and intensive care admissions were compared. A total of 1 810 admissions were recorded, 1061 in the pre-COVID group and 749 during COVID. Emergency admissions reduced by 9.2%, most notably due to a reduction in trauma, caustic ingestions and constipation. There was an increase in incarcerated inguinal hernias and helminth-related pathologies. Significantly more intussusceptions failed pneumatic reduction requiring surgical intervention with bowel resection. There was a two-fold increase in patients requiring emergency intensive care. Paediatric surgical volumes at our centre decreased during the COVID-19 pandemic. There was evidence of more advanced disease on presentation of inguinal hernias and intussusception and a generalised increased demand for emergency ICU admission.


Nurses' views of infection control: an interview study.
An interview study was conducted among 173 nurses in two hospitals to explore their views concerning infection risks to themselves and patients and to identify any problems they perceived in safely performing infection control precautions during routine activities. Subjects were interested in the topic of infection control and keen to perform optimally, but perceived difficulties related to lack of expert guidance whether or not they had access to an infection control nurse. In one hospital subjects identified shortages of vital equipment (gloves, appropriate handwashing agents), and this was corroborated on a checklist used independently to document the availability of resources. When the opinions of nurses working in intensive care, surgical and medical units were compared, few differences emerged other than those explained by variation in supplies of equipment, except that intensive care unit nurses were more likely to rate their patients and themselves as particularly at risk of infection, Nurses who had been qualified longer, with more than 3 years experience in their specialty, were more conscious of infection risks.


Tracing the biosynthetic origin of limonoids and their functional groups through stable isotope labeling and inhibition in neem tree (Azadirachta indica) cell suspension.
Neem tree serves as a cornucopia for triterpenoids called limonoids that are of profound interest to humans due to their diverse biological activities. However, the biosynthetic pathway that plant employs for the production of limonoids remains unexplored for this wonder tree. Herein, we report the tracing of limonoid biosynthetic pathway through feeding experiments using 13C isotopologues of glucose in neem cell suspension. Growth and development specific limonoid spectrum of neem seedling and time dependent limonoid biosynthetic characteristics of cell lines were established. Further to understand the role of mevalonic acid (MVA) and methylerythritol phosphate (MEP) pathways in limonoid biosynthesis, Ultra Performance Liquid Chromatography (UPLC)- tandem mass spectrometry based structure-fragment relationship developed for limonoids and their isotopologues have been utilized. Analyses of labeled limonoid extract lead to the identification of signature isoprenoid units involved in azadirachtin and other limonoid biosynthesis, which are found to be formed through mevalonate pathway. This was further confirmed by treatment of cell suspension with mevinolin, a specific inhibitor for MVA pathway, which resulted in drastic decrease in limonoid levels whereas their biosynthesis was unaffected with fosmidomycin mediated plastidial methylerythritol 4-phosphate (MEP) pathway inhibition. This was also conspicuous, as the expression level of genes encoding for the rate-limiting enzyme of MVA pathway, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGR) was comparatively higher to that of deoxyxylulose-phosphate synthase (DXS) of MEP pathway in different tissues and also in the in vitro grown cells. Thus, this study will give a comprehensive understanding of limonoid biosynthetic pathway with differential contribution of MVA and MEP pathways. Limonoid biosynthesis of neem tree and cell lines have been unraveled through comparative quantification of limonoids with that of neem tree and through 13C limonoid isotopologues analysis. The undifferentiated cell lines of neem suspension produced a spectrum of C-seco limonoids, similar to parental tissue, kernel. Azadirachtin, a C-seco limonoid is produced in young tender leaves of plant whereas in the hard mature leaves of tree, ring intact limonoid nimocinol accumulates in high level. Furthermore, mevalonate pathway exclusively contributes for isoprene units of limonoids as evidenced through stable isotope labeling and no complementation of MEP pathway was observed with mevalonate pathway dysfunction, using chemical inhibitors.


Oxidative nucleophilic cyclization of 2-alkynylanilines with thiophenols under metal-free conditions.
An oxidative nucleophilic cyclization of 2-alkynylanilines with thiophenols under metal-free conditions was developed. The one-pot two-step reaction involves a PhI(OAc)2-mediated oxidative dearomatization and a Brønsted acid promoted nucleophilic cyclization. DFT calculations were performed to understand the reaction pathway.


Erythromycin- and chloramphenicol-induced ribosomal assembly defects are secondary effects of protein synthesis inhibition.
Several protein synthesis inhibitors are known to inhibit ribosome assembly. This may be a consequence of direct binding of the antibiotic to ribosome precursor particles, or it could result indirectly from loss of coordination in the production of ribosomal components due to the inhibition of protein synthesis. Here we demonstrate that erythromycin and chloramphenicol, inhibitors of the large ribosomal subunit, affect the assembly of both the large and small subunits. Expression of a small erythromycin resistance peptide acting in cis on mature ribosomes relieves the erythromycin-mediated assembly defect for both subunits. Erythromycin treatment of bacteria expressing a mixture of erythromycin-sensitive and -resistant ribosomes produced comparable effects on subunit assembly. These results argue in favor of the view that erythromycin and chloramphenicol affect the assembly of the large ribosomal subunit indirectly.


Investigating the Correlation between Electrolyte Concentration and Electrochemical Properties of Ionogels.
Ionogels are hybrid materials comprising an ionic liquid confined within a polymer matrix. They have garnered significant interest due to their unique properties, such as high ionic conductivity, mechanical stability, and wide electrochemical stability. These properties make ionogels suitable for various applications, including energy storage devices, sensors, and solar cells. However, optimizing the electrochemical performance of ionogels remains a challenge, as the relationship between specific capacitance, ionic conductivity, and electrolyte solution concentration is yet to be fully understood. In this study, we investigate the impact of electrolyte solution concentration on the electrochemical properties of ionogels to identify the correlation for enhanced performance. Our findings demonstrate a clear relationship between the specific capacitance and ionic conductivity of ionogels, which depends on the availability of mobile ions. The reduced number of ions at low electrolyte solution concentrations leads to decreased ionic conductivity and specific capacitance due to the scarcity of a double layer, constraining charge storage capacity. However, at a 31 vol% electrolyte solution concentration, an ample quantity of ions becomes accessible, resulting in increased ionic conductivity and specific capacitance, reaching maximum values of 58 ± 1.48 μS/cm and 45.74 F/g, respectively. Furthermore, the synthesized ionogel demonstrates a wide electrochemical stability of 3.5 V, enabling diverse practical applications. This study provides valuable insights into determining the optimal electrolyte solution concentration for enhancing ionogel electrochemical performance for energy applications. It highlights the impact of ion pairs and aggregates on ion mobility within ionogels, subsequently affecting their resultant electrochemical properties.


Transitioning Out of the Coronavirus Lockdown: A Framework for Evaluating Zone-Based Social Distancing.
In the face of elevated pandemic risk, canonical epidemiological models imply the need for extreme social distancing over a prolonged period. Alternatively, people could be organized into zones, with more interactions inside their zone than across zones. Zones can deliver significantly lower infection rates, with less social distancing, particularly if combined with simple quarantine rules and contact tracing. This paper provides a framework for understanding and evaluating the implications of zones, quarantines, and other complementary policies.


Self-monitoring of blood glucose--psychological aspects relevant to changes in HbA1c in type 2 diabetic patients treated with diet or diet plus oral antidiabetic medication.
To investigate the influence of psychological aspects on glycemic control in type 2 diabetic patients treated with diet alone or diet plus oral antidiabetic medication using meal-related self-monitoring of blood glucose (SMBG). These psychological aspects refer to the process of self-management including the tendency to structure situations and activate resources (self-perception), to accept options for action (self-reflection) and to believe in self-efficacy (self-regulation). In a randomized controlled 6-month group comparison study, one group (n = 113; mean age 58.7 years) used a blood glucose monitoring device, kept a blood glucose/eating diary and received standardized counseling focusing on self-perception, self-reflection and self-regulation. A control group (n = 110; mean age 60.5 years) received non-standardized counseling on diet and lifestyle. Statistically significant endpoint differences between the SMBG and the control group were seen in glycemic control (p = 0.0086) and the well-being item 'depression' (p = 0.032). All aspects of counseling were influenced by SMBG with the extent of self-perception and self-reflection gradually increasing over time. Three HbA1c response types were identified among SMBG patients: continuous-achievers, late-achievers and non-achievers. This study identified processes (structuring the situation and activating resources, accepting options for action and believing in self-efficacy) which lead to a change in the metabolic profile. SMBG coupled with structured counseling provided patients with a tool for taking on more self-control and resulted in an improved outlook on life. This short-term intervention involved a structured counseling algorithm which requires 5-10 min of physician-patient contact and a structured documentation of metabolic control by the patient and can be taught by a diabetes training team within 4 h. The identification of the different response types might be of importance in clinical practice as it enables the physician to determine the right counseling option.


Selecting and tailoring implementation interventions: a concept mapping approach.
To improve the uptake of research into practice, knowledge translation frameworks recommend tailoring implementation strategies to address practice barriers. This study reports our experience pairing the Theoretical Domains Framework with information from multiple stakeholder groups to co-develop practice-informed strategies for improving the implementation of an evidence-based outcome measurement tool across a large community health system for preschoolers with communication impairments. Concept mapping was used to identify strategies for improving implementation of the Focus on the Outcomes of Communication Under Six (FOCUS) in Ontario Canada's Preschool Speech and Language Program. This work was done in five stages. First, we interviewed 37 speech-language pathologists (clinicians) who identified 90 unique strategies to resolve practice barriers to FOCUS implementation. Second, clinicians (n = 34), policy-makers (n = 3), and members of the FOCUS research team (n = 6) sorted and rated the strategies by importance and feasibility. Third, stakeholders' sorting data were analyzed to generate a two-dimensional concept map. Based on the rating data from stakeholders, we prioritized a list of strategies that were rated as highly important and highly feasible, and summarized the practice barriers addressed by each of the prioritized strategies. Fourth, we validated these findings with stakeholders via an online survey. Fifth, the mechanisms of action of the prioritized list of strategies were considered based on available evidence from the Theoretical Domains Framework and associated behavior change literature. Stakeholders categorized the 90 unique implementation strategies into a six-cluster concept map. Based on stakeholders' ratings, a list of 14 implementation strategies were prioritized. These implementation strategies were reported to resolve barriers within the environmental context and resources and beliefs about consequences domains of the Theoretical Domains Framework. All but one of the prioritized strategies have a demonstrated link in resolving existing barriers according to the behavioral change literature. Our study contributes to a growing literature that demonstrates the process of tailoring implementation strategies to specific barriers. Practical drawbacks and benefits of using concept mapping as a way to engage stakeholders in implementation research are discussed.


Short piston-cylinder pressure cells based on Ni-Cr-Al cylinders and their application to fragile materials.
In this decade, the performance of piston-cylinder pressure cells has been drastically improved by using robust materials such as nickel-chromium-aluminum and cobalt-nickel-chromium-molybdenum alloys to construct the inner cylinders. In this article, we present several experimental techniques for carrying out resistivity measurements under high pressure by applying the piston-cylinder devices based on the nickel-chromium-aluminum cylinders to fragile materials such as organics. These techniques are, in principle, applicable to measurements on any solid-state conductor. First, we introduce the construction of our piston-cylinder cells including two kinds of wired platforms for transport measurements. Second, we describe the construction of the platforms and the method of introducing the samples. After reporting test results for conventional materials such as ammonium fluoride, bismuth, and tellurium, lastly, we present examples of the successful application of our method to organic materials.


Self-assembly of metal-organic supramolecules: from a metallamacrocycle and a metal-organic coordination cage to 1D or 2D coordination polymers based on flexible dicarboxylate ligands.
To assemble metal-organic supramolecules such as a metallamacrocycle and metal-organic coordination cage (MOCC), a series of flexible dicarboxylate ligands with the appropriate angle, 2,2'-(2,3,5,6-tetramethyl-1,4-phenylene)bis(methylene)bis(sulfanediyl)dibenzoic acid (H(2)L(1)), 2,2'-(2,5-dimethyl-1,4-phenylene)bis(methylene)bis(sulfanediyl)dibenzoic acid (H(2)L(2)), 2,2'-(2,4,6-trimethyl-1,3-phenylene)bis(methylene)bis(sulfanediyl)dinicotinic acid (H(2)L(3)), and 2,2'-(2,4,6-trimethyl-1,3-phenylene)bis(methylene)bis(sulfanediyl)dibenzoic acid (H(2)L(4)), have been designed and synthesized. Using these flexible ligands to assemble with metal ions, six metal-organic supramolecules, Cd(2)(L(1))(2)(dmf)(4)(H(2)O)(2).H(2)O (1), Mn(3)((1)L(2))(2)((2)L(2))(dmf)(2)(H(2)O)(2).5dmf (2), Cu(4)(L(3))(4)(H(2)O)(4).3dmf (3), Cu(4)(L(4))(4)(dmf)(2)(EtOH)(2).8dmf.6H(2)O (4), Mn(4)(L(4))(4)(dmf)(4)(H(2)O)(4).6dmf.H(2)O (5), and Mn(3)(L(4))(3)(dmf)(4).2dmf.3H(2)O (6), possessing a rectangular macrocycle, MOCCs or their extensions, and 1D or 2D coordination polymers, have been isolated. All complexes have been characterized by single-crystal X-ray diffraction, elemental analysis, and thermogravimetric analysis. Complex 1 is a discrete rectangular macrocycle, while complex 2 is a 2D macrocycle-based coordination polymer in which the L(2) ligand adopts both syn and anti conformations. Complexes 3-5 are discrete MOCCs in which two binuclear metal clusters are engaged by four organic ligands. The different geometries of the secondary building units (SBUs) and the axial coordinated solvates on the SBUs result in their different symmetries. Complex 6 is a 1D coordination polymer, extended from a MOCC made up of two metal ions and three L(4) ligands. All of the flexible dicarboxylate ligands adopt a syn conformation except that in complex 2, indicating that the syn conformational ligand is helpful for the formation of a metallamacrocycle and a MOCC. The magnetic properties of complexes 5 and 6 have also been studied.


The Microbiome and the Gut-Liver-Brain Axis for Central Nervous System Clinical Pharmacology: Challenges in Specifying and Integrating In Vitro and In Silico Models.
The complexity of integrating microbiota into clinical pharmacology, environmental toxicology, and opioid studies arises from bidirectional and multiscale interactions between humans and their many microbiota, notably those of the gut. Hosts and each microbiota are governed by distinct central dogmas, with genetics influencing transcriptomics, proteomics, and metabolomics. Each microbiota's metabolome differentially modulates its own and the host's multi-omics. Exogenous compounds (e.g., drugs and toxins), often affect host multi-omics differently than microbiota multi-omics, shifting the balance between drug efficacy and toxicity. The complexity of the host-microbiota connection has been informed by current methods of in vitro bacterial cultures and in vivo mouse models, but they fail to elucidate mechanistic details. Together, in vitro organ-on-chip microphysiological models, multi-omics, and in silico computational models have the potential to supplement the established methods to help clinical pharmacologists and environmental toxicologists unravel the myriad of connections between the gut microbiota and host health and disease.


Basic Concepts on the Role of Nuclear Factor Erythroid-Derived 2-Like 2 (Nrf2) in Age-Related Diseases.
The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is one of the most important oxidative stress regulator in the human body. Once Nrf2 regulates the expression of a large number of cytoprotective genes, it plays a crucial role in the prevention of several diseases, including age-related disorders. However, the involvement of Nrf2 on these conditions is complex and needs to be clarified. Here, a brief compilation of the Nrf2 enrollment in the pathophysiology of the most common age-related diseases and bring insights for future research on the Nrf2 pathway is described. This review shows a controversial response of this transcriptional factor on the presented diseases. This reinforces the necessity of more studies to investigate modulation strategies for Nrf2, making it a possible therapeutic target in the treatment of age-related disorders.


[Diagnosis and treatment of benign duodenal tumor].
To investigate the diagnosis and treatment of benign duodenal tumor. Clinical data of 14 patients with benign duodenal tumor confirmed pathologically or by operation from Oct.1988 to Oct.2001 were analyzed retrospectively. Of 14 patients, 5 had Brunner's grand adenoma, 4 mesenchymoma, 2 leiomyoma, 2 hemangioma, 1 lipoma. Upper abdominal discomfort (64% ), gastrointestinal bleeding(50% ) and abdominal pain(20% ) were common manifestations. All cases received gastroscopy and only one case was diagnosed. Five cases received duodenoscope and the diagnosis was confirmed in 4 cases. Nine cases received hypotonic duodenography and lesions were found in 8 cases. Digital subtraction angiography was performed in 3 cases and detected all lesions. Computed tomographic scan and B-ultrasound were performed in 2 cases and only one case was diagnosed. Eleven cases (79% ) got definite diagnosis before operation. Tumor resection was performed in all patients. Perioperative death occurred in one patient. No recurrence occurred in 13 cases after following up from 2 to 11 years. Upper abdominal discomfort and gastrointestinal bleeding are common features in patients with benign duodenal tumor. Duodenoscopy and hypotonic duodenography are good diagnostic approaches. Surgical tumor resection is the first choice of treatment.


Iris reconstruction using artificial iris prosthesis for management of aniridia.
To discuss the limitations and benefits of the BrightOcular prosthetic artificial iris device in management of aniridia associated with aphakia or cataract. This is a retrospective study including 5 eyes of 4 patients who underwent implantation of the BrightOcular iris prosthesis (Stellar Devices) for total or partial aniridia. The cases included 2 eyes of 1 patient with congenital aniridia associated with congenital cataract and 3 eyes with traumatic aniridia: 1 with subluxated cataractous lens and 2 with aphakia. In all cases, the iris prosthesis was implanted after a 3-piece acrylic intraocular lens was implanted. We evaluated the clinical course with a minimum follow-up period of 6 months, the intraoperative and postoperative complications, and the cosmetic satisfaction of patients. All patients had improved uncorrected distance visual acuity and best-corrected distance visual acuity. All patients had a transient corneal edema that resolved within the first postoperative week. Only the patient with congenital aniridia had a permanent increase in intraocular pressure and developed a band keratopathy throughout a 2-year follow-up period. The prosthesis was well-centered in all eyes except for one case that required scleral suture fixation after 3 months. All patients had a satisfactory cosmetic appearance. BrightOcular iris prosthesis is a safe and useful tool to correct aniridia associated with pseudophakia or aphakia. Being foldable, it is easy to be implanted through a small incision and placed in the ciliary sulcus without sutures when properly sized. Cosmetic results are satisfactory. Sizing methods should be improved.


Hypoglycemia-induced inhibition of LH and stimulation of ACTH secretion in the rhesus monkey is blocked by alprazolam.
Insulin-induced hypoglycemia inhibits luteinizing hormone (LH) secretion and has been used as a model to study stress-induced inhibition of reproductive function. Endogenous opioid peptides have been implicated in mediating the inhibitory effect of hypoglycemia on LH secretion in sheep and rat. The objective of the present study was to determine if corticotropin-releasing hormone (CRH) and endogenous opiates are involved in the LH response to hypoglycemia in the nonhuman primate. Blood samples were collected at 15-min intervals for 6 h from ovariectomized rhesus monkeys (n = 6). Hypoglycemia was induced by injecting insulin 1 h after initiating blood collection. Animals were pretreated 15 min prior to insulin with either saline (n = 6), naloxone, a nonselective opiate receptor antagonist (n = 4), or alprazolam (n = 6), a potent benzodiazepine which has been shown to inhibit CRH. The LH, glucose, adrenocorticotropin (ACTH), and cortisol responses to insulin were determined. Insulin-induced hypoglycemia significantly inhibited LH secretion and increased ACTH and cortisol concentrations. Alprazolam prevented hypoglycemia-induced inhibition of LH independent of an effect on glucose concentrations. The mean (+/- SEM) LH pulse interval in response to hypoglycemia was decreased in the alprazolam pretreated group compared to the saline pretreated group (77.4 +/- 6.0 vs. 130.0 +/- 18.4 min), while LH pulse amplitude and mean LH levels were significantly increased (56.2 +/- 7.1 vs. 28.3 +/- 5.5 ng/ml, and 105.6 +/- 14.4 vs. 60.9 +/- 12.1 ng/ml respectively). In contrast, naloxone did not prevent hypoglycemia-induced LH inhibition. The mean LH pulse interval, LH pulse amplitude, and LH concentration in the naloxone pretreated monkeys were 152.1 +/- 33.4 min, 37.1 +/- 8.9 ng/ml, and 63.7 +/- 9.1 ng/ml respectively. Alprazolam pretreatment also markedly attenuated the ACTH response to hypoglycemia whereas the cortisol response was only moderately affected. We conclude that insulin-induced hypoglycemia in the monkey inhibits LH secretion through a mechanism involving CRH but not endogenous opiates.


Changes in Colorectal Cancer Screening Knowledge, Behavior, Beliefs, Self-Efficacy, and Barriers among Community Health Clinic Patients after a Health Literacy Intervention.
The objective in this pre- and post-survey assessment was to compare the effectiveness of a health literacy-directed intervention designed to increase knowledge, beliefs, barriers, self-efficacy and behavior associated with CRC screening with FOBT among patients cared for in predominantly rural community clinics and the change in these characteristics over the first 15 months after enrolling in a study designed to assess screening strategies. Between 2008 and 2011, a quasi-experimental intervention was conducted in 8 predominantly rural Federally Qualified Health Centers. Patients were orally administered a 15-minute survey at enrollment by a clinic research assistant (RA) and at 15 months by phone by a central RA. Participants included 428 community clinic patients aged 50-85 (mean 58.5); the majority (79%) were female, 69% were African American, and 54% had limited health literacy. There was significant improvement across all groups with the number of patients reporting they had been given information /education on CRC testing (p<.0001), been given an FOBT kit (p<.0001), and completed an FOBT (p<.0001) with significant improvement in having a doctor recommendation in all groups except usual care. Confidence in an FOBT's potential to decrease chances of dying from CRC improved across all groups as well (p<0.002). In addition, patients 'belief that they would get CRC in their lifetime' decreased across all groups post-intervention (p<0.03) as did their worry that they may find out they have CRC (p<0.04). Overall these low income FQHC patients who were not up-to-date with screening had heard of CRC screening, had positive attitudes toward screening and wanted to know if they had cancer. Results demonstrate the value of giving patients a recommendation and a kit; patients in all groups reported significant increases at 15 months in completing CRC screening (>83%) as confirmed by study records.


Functional group dependent site specific fragmentation of molecules by low energy electrons.
Functional group dependence is observed in the dissociative electron attachment (DEA) to various organic molecules in which the DEA features seen in the precursor molecules of the groups are retained in the bigger molecules. This functional group dependence is seen to lead to site-selective fragmentation of these molecules at the hydrogen sites. The results are explained in terms of the formation of core-excited Feshbach resonances. The results point to a simple way of controlling chemical reactions as well as interpreting the DEA data from bigger biological molecules.


Tetrasulfur, S4: rotational spectrum, interchange tunneling, and geometrical structure.
The rotational spectrum of S4 has been observed for the first time in an electrical discharge through sulfur vapor. Two techniques have been used: Fourier transform microwave spectroscopy and long-path millimeter-wave absorption spectroscopy. Small, but systematic shifts of the measured transition frequencies of the normal isotopic species indicate that S4 has C2v symmetry but with a low-lying transition state of D2h symmetry, yielding interchange tunneling at 14.1(2) kHz in its ground vibrational state. From the rotational constants of the normal and the single 34S isotopic species, an experimental (r0) structure has been derived: S4 is a singlet planar trapezoid with a terminal bond length of 1.899(7) A, a central bond of 2.173(32) A, and an S-S-S angle of 103.9(8) degrees. Like thiozone (S3), S4 is a candidate for detection in the atmosphere of the Jovian moon Io and in other astronomical sources.


Intracellular regulation of zinc by metal-organic framework-mediated genome editing for prostate cancer therapy.
Normal prostate tissues generally exhibit a higher level of zinc to maintain their special "citrate-producing" metabolism, while its level dramatically decreases during prostate tumorigenesis. Despite the significant antitumor effects, the intracellular accumulation of zinc in prostate cancer cells also promotes the expression of ZNT1, which in turn results in the efflux of zinc and attenuated cytotoxicity against cancer cells. To solve the dilemma, we developed a 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid (DUPA)-decorated zeolitic imidazolate framework-8 (ZIF8), which is able to load plasmid DNA encoding the Cas9 editor and single-guide RNA to form Cas9@ZIF8-DUPA nanocomplexes. The intracellular delivery of Cas9@ZIF8-DUPA simultaneously increases the level of zinc and inhibits the ZNT-1 function by disrupting the SLC30A1 gene to prevent the efflux of zinc in prostate cancer cells. Due to the high affinity between DUPA and the prostate-specific membrane antigen, Cas9@ZIF8-DUPA nanocomplexes exhibit excellent prostate tumor-targeting ability. The internalization and degradation of Cas9@ZIF8-DUPA not only release free zinc and Cas9 editors, but also reduce zinc efflux through Cas9-mediated genome editing that disables the function of ZNT1. As a result, Cas9@ZIF8-DUPA nanocomplexes exhibit significant antitumor activity and extended survival in the mouse model bearing prostate tumors. The current platform offers an alternative therapeutic strategy and holds tremendous translational potential as an anticancer nanomedicine for prostate cancer treatment.


Synthesis and Anticancer Activities of Pyrazole-Thiadiazole-Based EGFR Inhibitors.
Lung cancer is one of the most common cancer types of cancer with the highest mortality rates. However, while epidermal growth factor receptor (EGFR) is an important parameter for lung cancer, EGFR inhibitors also show great promise in the treatment of the disease. Therefore, a series of new EGFR inhibitor candidates containing thiadiazole and pyrazole rings have been developed. The activities of the synthesized compounds were elucidated by in vitro MTT, (which is chemically 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), cytotoxicity assay, analysis of mitochondrial membrane potential (MMP) by flow cytometry, and EGFR inhibition experiments. Molecular docking and molecular dynamics simulations were performed as in silico studies. Compounds 6d, 6g, and 6j showed inhibitor activity against the A549 cell line with IC50 = 5.176 ± 0.164; 1.537 ± 0.097; and 8.493 ± 0.667 μM values, respectively. As a result of MMP by flow cytometry, compound 6g showed 80.93% mitochondrial membrane potential. According to the results of the obtained EGFR inhibitory assay, compound 6g shows inhibitory activity on the EGFR enzyme with a value of IC50 = 0.024 ± 0.002 μM.


Peroxidatic metabolism of benzidine by intact tissue: a prostaglandin H synthase-mediated process.
Metabolism of benzidine was assessed with rabbit renal inner medullary slices. 3-(Glutathion-S-yl)-benzidine was identified as a product of metabolism. This thioether conjugate was shown to be identical to synthetic conjugate by chromatographically assisted hydrodynamic voltammetric and enzymatic techniques. A good correlation between PGE2 synthesis and conjugate formation was observed with a variety of incubation conditions including tissue weight, arachidonic acid concentration and incubation time. With 0-0.01 mM idomethacin, an inhibitor of the fatty acid cyclo-oxygenase component of prostaglandin H synthase (PHS), a linear relationship between conjugate formation and prostaglandin E2 synthesis was observed. In contrast, the peroxidase cosubstrates propylthiouracil, phenidone, ascorbate and methimazole inhibited arachidonic acid stimulation of conjugate formation but not prostaglandin E2 synthesis. These cosubstrates may be functioning as competitive inhibitors of benzidine co-oxidation. The results are consistent with peroxidatic metabolism of benzidine in intact tissue by a PHS-mediated process. 3-(Glutathion-S-yl)-benzidine may be a useful marker for studying peroxidatic metabolism in intact tissue and in investigating selective inhibition of this process.


[Comparison of the concept of "responsibility" in neuroscience and in French criminal law: A cross-literature review for the psychiatric forensic practice].
In forensic psychiatry, experts have to determine the level of responsibility of a subject with regard to their acts. Neuroscience and cognitive sciences have been increasingly studying the brain functions that are supposed to underlie individual responsibility. In neuroscience, impairment of responsibility is underlain by disruptions of different types of cognitive processes. This processes are executive functions, theory of mind, agency, volition and empathy. In the juridical conception, the term of responsibility refers to a broader perspective than in the neuroscientific approach.


Disposition of intravenous glycofurol: effect of hepatic cirrhosis.
The disposition of intravenous glycofurol, a solvent for some drugs, was followed in nine male patients with hepatic cirrhosis. In comparison with age-matched controls, glycofurol clearance in the patients with cirrhosis was reduced 43% and terminal t 1/2 was prolonged 103%. There was no significant difference between the cirrhotic and control groups in volume of distribution.


Investigations of retinoic acid receptor-related orphan receptor-gamma t (RORγt) agonists: a combination of 3D-QSAR, molecular docking and molecular dynamics.
Retinoic acid receptor-related orphan receptor-gamma t (RORγt) is an attractive target for Th17-driven autoimmune diseases. In the present work, a series of RORγt agonists were investigated by a molecular modeling study combining three-dimensional quantitative structure activity relationship (3D-QSAR), molecular docking, molecular dynamics (MD) simulations and binding free energies to get insight into the molecular features that would promote binding activity. The optimum comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models for 3D-QSAR studies possess satisfactory predictive ability, with R2cv=0.615, R2pred=0.8702 for CoMFA, and R2cv=0.670, R2pred=0.7683 for CoMSIA model, respectively. In addition, molecular docking studies, molecular dynamics simulations and binding free energies were used to find the actual conformations of compounds in the active site of RORγt, and key residues GLN-286, LEU-287, HIS-323 and ARG-367 for higher binding activity were pointed out. The predicted models will help us to understand the structural requirements of RORγt agonists for the designing of better active compounds. Communicated by Ramaswamy H. Sarma.


Eumelanin Precursor 2-Carboxy-5,6-Dihydroxyindole (DHICA) as Doping Factor in Ternary (PEDOT:PSS/Eumelanin) Thin Films for Conductivity Enhancement.
The integration of the pristine not-doped commercial poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) PH1000 with eumelanin, the brown to black kind of melanin pigment, was achieved by dissolving the melanogenic precursors 2-carboxy-5,6-dihydroxyindole (DHICA) in the PH1000 suspension. Solid state oxidative polymerization of the catecholic indole allowed obtaining the ternary blend PEDOT:PSS/eumelanin. The introduction of DHICA into PH1000 produced a noticeable increase in the conductivity of PEDOT thin films akin to that produced by dimethyl sulfoxide (DMSO) treatment, opening up novel strategies for the simultaneous integration of eumelanin polymer and conductivity enhancement of PEDOT containing coatings, as well as the long term goal of replacing PSS by DHICA eumelanin for PEDOT pairing.


Microdebriders used in functional endoscopic sinus surgery: secondary analysis and validation of a new tissue model.
To validate a previously reported in vitro tissue model for microdebrider comparison and determine which microdebrider, tissue type, blade type, and suction strength is most efficient. Specifically, the goal of the secondary analysis is to expand on the results of the preliminary analysis by increasing the sample size, and introduce an aspiration efficiency score (AES) to facilitate microdebrider comparison. Prospective randomized comparison. A prospective randomized comparison of the Diego Powered Dissector and XPS 3000 Powered ENT System was conducted using a soft tissue and a firm tissue model. In addition to evaluating tissue aspiration with straight and angled blades, clogging rates and clearance times were measured. Both standard wall suction and liposuction were used. Basic statistical analysis, a one-way analysis of variance, and a post hoc Student's t test were performed to compare outcomes. With standard wall suction, the microdebriders were equivalent for the overall microdebrider comparison. For the ''head to head'' comparison with standard wall suction, the devices were also equivalent when using the straight blades, but the XPS 3000 aspirated more tissue when using the angled blades. With liposuction, the XPS 3000 and liposuction independently aspirated more tissue but clogged more often compared with the Diego PD and regular suction. The aspiration efficiency of soft tissue (oysters) and straight blades was superior compared with firm tissue (scallops) and angled blades. For the ''head to head'' comparison with liposuction, the XPS 3000 aspirated more tissue regardless of tissue type, but the Diego PD clogged less with firm tissue (scallops). Overall, the AES favored the XPS 3000, soft tissue (oysters), straight blades, and liposuction. Our tissue model represents a reliable and reproducible means of microdebrider comparison. Statistically significant differences between the Diego PD and XPS 3000, as well as between tissue types, blade types, and suction strengths, are reported. Using these results, microdebrider manufacturers can adopt similar tissue models, expand on the current AES, and include other commercially available microdebrider devices to test and report product performance to the consumer. Perhaps an optimal open to closed ratio or liposuction pressure can be determined that yields the greatest tissue aspiration with the fewest number of clogs.


Reduction of the ocular complications of herpes zoster ophthalmicus by oral acyclovir.
Herpes zoster ophthalmicus (HZO) is a unique form of zoster dermatitis associated with a high rate of ocular complications that tend to be chronic and may cause vision loss. The ocular complications are highly varied, with keratitis and uveitis being more persistent sequellae of HZO. Oral acyclovir treatment of acute HZO reduces the incidence of the more common ocular complications, including keratitis and uveitis. Although patients treated early in the course of this disease experience a greater clinical response, treatment as late as seven days after onset of cutaneous lesions confers a beneficial prophylactic effect with respect to the ocular complications of HZO.


Stopping the clock: neobiosis as a predecessor of mammalian hibernation and possible key to the abolition of aging.
A number of mammals undergo hibernation during their lifespan. The euthermal condition that occurs prior to hibernation is characterized by inhibition of cellular proliferation, reduction of stress reactivity, a decrease in metabolism, and changes in the immune system (seasonal thymus involution). Analysis of data of young red voles (Clethrionomys glareolus), common shrews (Sorex araneus), and fat dormice (Glis glis) while entering into the euthermal condition shows characteristic biphasic growth with a delay that can vary in its periods. A biological mechanism for reversible growth arrest effectively "stops the clock" of these animals. It is suspected that this mechanism is triggered by an increase in somatostatin synthesis with inhibition of growth hormone, thyroid-stimulating hormone, and melatonin, and with a loss of circadian function in the suprachiasmatic nuclei of the hypothalamus.


Embryo transfers performed during daylight savings time led to reduced live birth rates in older patients.
To study the impact of undergoing an embryo transfer during the week of daylight savings time transition on live birth rates. We performed a retrospective observational cohort study of patients undergoing embryo transfer at an academic infertility practice during the week of spring or fall daylight savings time transition (cases), or the 2 weeks preceding and following the daylight savings transition (controls) between 2015 and 2021. The primary exposure was completion of an embryo transfer during the week of daylight savings time transition. The primary outcome was a comparison of live birth rate per embryo transfer among individuals undergoing an embryo transfer during the week of daylight savings time (DST) transition and those who did not. A total of 309 embryo transfers occurred during the week of daylight savings transition and 1242 embryo transfers occurred in the control group outside of the daylight savings transition week. The live birth rate after embryo transfer during DST transition weeks was 39.2% (121/309) compared to 40.8% (507/1242) (p = 0.59). When restricting the analysis to individuals (age > 37 years), the live birth rate after embryo transfer during DST transition week was 23.5% (24/102) compared to 34.8% (149/429) (p = 0.03). This difference persisted in the mixed-effects regression model demonstrating that after adjusting for relevant covariates, embryo transfer during DST transition weeks resulted in a 45% decrease in the odds of achieving a live birth. Daylight savings time transition may be associated with less favorable outcomes after embryo transfer among an older infertile patient population. Future work is needed to prospectively examine the influence of circadian rhythm disruption on reproductive outcomes.


Effect of increased vascular pressure on lung fluid balance in unanesthetized sheep.
In 20 unanesthetized sheep, we measured lung lymph flow and lymph and plasma protein concentrations during steady-state base-line conditions and during steady-state elevations of pulmonary microvascular hydrostatic pressure (range 3 to 23 cm H2O). In every sheep there was a base-line lung lymph flow (average 5.7 +/- 2.5 (SD) ml/hour), demonstrating that net fluid filtration occurred. The base-line lymph-plasma total protein ratio averaged 0.69 +/- 0.05, indicating a high protein osmotic pressure in the interstitial fluid at the filtration site. Lymph flow increased and lymph protein concentration decreased approximately linearly whenever hydrostatic pressure rose. A new steady-state condition was reached in 1-2 hours. The difference in plasma-to-lymph protein osmotic pressure increased by half the hydrostatic pressure increment (50% negative feedback regulation). Extravascular lung water content, measured post-mortem, did not change significantly until microvascular hydrostatic pressure more than doubled, indicating a large safety factor that protects the lungs against fluid accumulation normally. The major contributions to the safety factor appeared to be a sensitive and efficient lymph pump coupled to a washout of interstitial protein. The fluid filtration coefficient, whose calculation required many assumptions, averaged 1.64 +/- 2.65 ml/(cm H2O times hour) in the base-line condition and did not change significantly over the pressure range studied.


Nesting innovations in neotropical parrots associated to anthropogenic environmental changes.
Parrots are among the most diverse and widely distributed groups of birds and one of the most threatened bird orders mainly due to habitat loss and illegal poaching. Most parrots are obligate cavity nesters, so the logging of mature trees and the transformation of natural cliffs represent important threats to their conservation. Here, we report novel observations of Neotropical parrots nesting in previously unrecorded substrates. We show the first documented case of the cliff-nesting burrowing parrots trying to breed at ground level in an abandoned burrowing owl cavity. Additionally, we provide the first documented observations of this species attempting to nest in building cavities in three urbanized areas of Argentina. Moreover, we report data from four countries of 148 pairs of eight species typically breeding in tree cavity using palm tree bracts as nest sites. Behavioral plasticity in nest sites may allow parrots to maximize their nesting success by exploiting alternative breeding substrates. Moreover, these novelties could contribute to cope with habitat loss and further transformation. However, further research is needed to assess the consequences of these nesting innovations in terms of individual fitness and population dynamics as well as potential factors promoting their appearance.


Impact of COVID-19 on the treatment of depressive patients in Germany-a gap in care for the mentally ill?
The COVID-19 pandemic led to a higher incidence of depression and a worsening of psychiatric conditions, while pre-existing constraints of the healthcare system and safety regulations limited psychiatric care. We investigated the impact of the pandemic on the clinical care of patients with a single episode (SE-MDD) or major depressive disorder (MDD) in Germany. Nationwide inpatient data were extracted from the German Institute for Hospital Remuneration System for 2020 and 2021 (depression data) and the Robert Koch Institute (COVID-19 incidence). Changes in inpatients were tested with linear regression models. Local cases of depression in our department compared to 2019 were explored with one-way ANOVA and Dunnett's test. Across Germany, the inpatient numbers with both SE-MDD and MDD declined by more than 50% during three out of four COVID-19 waves. Higher COVID-19 incidence correlated with decreased inpatient numbers. In our department, fewer MDD inpatients were treated in 2020 (adj. p < 0.001) and 2021 (adj. p < 0.001) compared to 2019, while the number of SE-MDD inpatients remained stable. During this period fewer elective and more emergency inpatients were admitted. In parallel, MDD outpatient admissions increased in 2021 compared to 2019 (adj. p = 0.002) and 2020 (adj. p = 0.003). During high COVID-19 infection rates, MDD patients received less inpatient care, which might cause poor outcomes in the near future. These data highlight the necessity for improved infrastructure in the in- and outpatient domains to facilitate accessibility to adequate care.


Pharmacokinetics in clinical practice. 2. Applications.
The pharmacokinetic concepts introduced and defined in a preceding article are now applied to the management of drug therapy for the individual patient. The factors that affect the time course of drug concentrations in plasma produced by repetitive administration include the dosing rate, total clearance, biologic half-life, and systemic availability of the drug. A clinical pharmacokinetics service can monitor drug concentrations in biologic fluids, design individualized drug-dosing regimens, and carry out pharmacokinetic diagnostic work-ups to help determine the reasons for a patient's unusual response to drug therapy.


Reversible immobilization of soybean beta-amylase on phenylboronate-agarose.
Soybean beta-amylase (EC 220.127.116.11) wap immobilized on phenylboronate-agarose by strong interactive binding. The insoluble derivative was active and more stable to temperature changes than the free enzyme. The absence of enzyme leakage even in the presence of substrate was demonstrated. Changes in pH over a wide range (4.0-8.0) did not affect the stability of the complex. The support could be recovered by sorbitol elution, which demonstrated the reversibility of the binding. Since the enzyme was not retained on phenylagarose under similar conditions, we rejected hydrophobic interactions as a cause of the strong binding of the enzyme to phenylboronate-agarose. We suggest that the bonding of the enzyme to the phenylboronate ligand occurs by a charge transfer mechanism between the trigonal boronate and the side chain nitrogenated groups. It was concluded that phenylboronate-agarose has good properties as a support, which recommends its use for the preparation of immobilized enzymes.


Cadaveric position of unilateral vocal cord: a case of cricoid fracture with ipsilateral arytenoid dislocation.
We report a case of cricoid cartilage fracture with unilateral arytenoid dislocation following a motorcycle accident. This 25 year old male sustained blunt injury to the head, face and neck. He presented late to the hospital with one week history of dysphonia. Laryngoscopy revealed cadaveric position of the non-functioning left vocal cord. CT and MRI showed laterally displaced left vocal cord. Displaced fractures were noted in the cricoid at the junction of lamina with the anterior arch on the left side and at the right side of the anterior arch, along with dislocated left arytenoid resulting in ipsilateral vocal cord palsy. Medialization thyroplasty was performed to improve his phonation. Laryngeal trauma warrants close monitoring because of the risk of airway compromise. Radiologists play a crucial role in early diagnosis and should always have high index of suspicion. Recognition of laryngeal injury is important for initial resuscitation as well as for long term airway and vocal function.


[Nursing report on patients' release. Do observations coincide?].
The Nursing Report upon a patient's release guarantees treatment continuity. The nursing supervisor carries out an annual internal audit of all reports. A second investigator reviews this audit. The authors want to show how a degree of concordance between these two observations is achieved. The authors analyzed 31 items in all the reports, a total of 233, filled out by the gynecology service in 2004. The Kappa index was used to evaluate the degree of concordance. The second investigator analyzed 15% of these reports. The kappa index was calculated and the authors evaluated the discrepancies of those items with k less than or equal to 0.80; concepts were redefined. The second investigator revises 15% of the reports and carried out a new analysis of the discrepancies. Finally this second researcher supervised the remaining 70% of the reports and carried out a final analysis.


[5]Helicene-based chiral triarylboranes with large luminescence dissymmetry factors over a 10-2 level: synthesis and design strategy via isomeric tuning of steric substitutions.
Constructing chiral luminescent systems with both large luminescence dissymmetry factor (glum) and high luminous efficiency has been considered a great challenge. We herein describe a highly efficient approach to sterically stabilize the helical configurations of carbo[5]helicenes for improved CPL properties in a series of π-donor and π-acceptor substituted [5]helicenes (1, 2, 3, 4 and 5). Enabled by the ortho-installation of methyl groups as well as the steric effects of triarylamine (Ar3N) and triarylborane (Ar3B) handles in meta-substituted [5]helicenes, their optical resolution into enantiomers has been accomplished using preparative chiral HPLC. The molecular chirality of [5]helicenes can be transferred to Ar3B and Ar3N as light emitters, which allowed further investigations of their chiroptics, including optical rotation, circular dichroism (CD) and circularly polarized luminescence (CPL). Remarkably, 4 has been demonstrated to display dramatically enhanced CPL performance with a much larger glum (>1.2 × 10-2) and an increased emission quantum efficiency (ΦS = 0.75) compared with the other analogues, as a result of the isomeric tuning of substitutions with differential steric and electronic effects. These experimentally observed CPL activities were rationalized by TD-DFT computations for the angle (θμ,m) between electric and magnetic transition dipole moments in the excited states. In addition, the conspicuous intramolecular donor-acceptor charge transfer led to thermal responses in the emissions of 2 and 4 over a broad temperature range.


MicroRNA-582 promotes tumorigenesis by targeting phosphatase and tensin homologue in colorectal cancer.
A number of studies have implicated that a class of non‑coding RNAs named microRNAs (miRNAs or miRs) is associated with tumorigenesis and have identified miRNAs as promising targets for pharmaceutical intervention. Recently, the deregulated expression of miR‑582 in tumor cells has been reported. However, the exact function of miR‑582 in colorectal cancer (CRC) remains largely unknown. In thi study, we demonstrate that miR‑582 is extensively upregulated in CRC tissues and cell lines. The overexpression of miR‑582 significantly enhanced the proliferation and migration ability of the CRC cells. However, the use of a specific miR‑582 inhibitor counteracted these effects. miR‑582 may also play an oncogenic role by promoting tumor growth in vivo. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) was identified as a putative target of miR‑582; transfection of the cells with a lentivirus with miR‑582 mimics substantially decreased both the mRNA and protein levels of PTEN. The restoration of PTEN expression in the CRC cells reversed the adverse effects of miR‑582. Our findings therefore indicate that miR‑582 promotes CRC progression by decreasing PTEN expression. These findings may also imply that miR‑582 may be a target for therapeutic intervention in patients with CRC.


Effects of chronically skipping meals on atrial fibrillation risk.
Atrial fibrillation is the most common form of arrhythmia and can result in significant morbidity and mortality. While there are many potential causes of atrial fibrillation that have been well studied, this work considers the potential effect of chronically skipping meals on the development of atrial fibrillation. The authors discuss the various processes that skipping meals initiates in the body that may ultimately result in atrial fibrillation. Through a better understanding of the various disease pathophysiologies that can contribute to the development of atrial fibrillation, this narrative review may help lead to more advanced therapeutic and preventive approaches.


Determinants of geographic variation in Helicobacter pylori infection among children on the US-Mexico border.
Rates of Helicobacter pylori infection are traditionally higher in developing countries than in developed countries, but the specific reasons for these differences are not fully clear. While chronic diseases resulting from H. pylori are generally of adult onset, chronic infection usually begins in childhood. In this cross-sectional study (1998-2000), the authors compared prevalences of H. pylori infection among children under age 6 years on both sides of the Rio Grande. Participants included 264 children of women from low-income families who were receiving services at health clinics in Juarez, Mexico, or El Paso, Texas, from April 1998 through October 2000. Data were collected through personal interviews and serologic testing for H. pylori antibodies. The crude odds ratio for H. pylori prevalence among Mexican children as compared with US children was 3.94 (95% confidence interval: 1.72, 9.06). After adjustment for covariates, the odds ratio decreased to 1.70 (95% confidence interval: 0.64, 4.52). The adjustments that produced the greatest reduction in the odds ratio for location were those for household crowding and maternal education. This study identified specific factors that may explain geographic variation in H. pylori prevalence among children.


Phenylalanine side chain behavior of the intestinal fatty acid-binding protein: the effect of urea on backbone and side chain stability.
The equilibrium unfolding behavior of the intestinal fatty acid-binding protein has been investigated by (19)F-NMR after incorporation of 4-fluorophenylalanine and by pulsed field gradient diffusion (1)H-NMR. At low urea concentrations (0-3 m) but prior to the global unfolding that begins at 4 m urea, the protein exhibits dynamic motion in the backbone and an expanded hydrodynamic radius with no major change in the side chain orientation. As monitored by two-dimensional (19)F-(19)F nuclear Overhauser effect, the distance between two phenylalanine residues (Phe(68) and Phe(93)) located in the two different beta-sheets that enclose the internal cavity did not change up to 4 m urea. Additionally, the chemical shifts of these two residues changed almost identically as a function of denaturant. At all urea concentrations, as well as in the native protein, multiple conformations exist. These conformers interconvert at different rates under different conditions, ranging from slow exchange by showing separate peaks in the native state to intermediate exchange at intermediate urea concentrations. Residual structure persisted around Phe(62) even at very high concentrations of denaturant, suggesting that region as a nucleation site during folding. The results were compared with previous studies examining the backbone behavior (Hodsdon, M. E., and Frieden, C. (2001) Biochemistry 40, 732-742) and suggest that the side chains show more stability than the backbone prior to global unfolding of the protein.


E74-Like Factor (ELF3) and Leptin, a Novel Loop Between Obesity and Inflammation Perpetuating a Pro-Catabolic State in Cartilage.
The E74-like factor 3 (ELF3) is an inflammatory mediator that participates in cartilage destruction in osteoarthritis. Leptin and other adipokines negatively impact articular cartilage, triggering catabolic and inflammatory responses in chondrocytes. Here, we investigated whether leptin induces ELF3 expression in chondrocytes and the signaling pathway involved in this process. We determined mRNA and protein levels of ELF3 by RT-qPCR and Western blotting using cultured human primary chondrocytes and the human T/C-28a2 chondrocyte cell line. Further, we measured luciferase activities of different reporter constructs, and we assessed the contribution of leptin to the induction of ELF3 mRNA by knocking down hLEPR gene expression using siRNA technology. Leptin synergizes with IL-1β in inducing ELF3 expression in chondrocytes. We also found that PI3K, p38, and JAK2 signaling pathways are at play in the leptin-driven induction of ELF3. Moreover, we confirm the participation of NFΚB in the leptin/IL-1β synergistic induction of ELF3. Here we show, for the first time, the regulation of ELF3 expression by leptin, suggesting that this transcription factor likely mediates the inflammatory responses triggered by leptin in articular chondrocytes.


Specific interaction of mannosylated glycopolymers with macrophage cells mediated by mannose receptor.
Poly[N-p-vinylbenzyl-O-beta-mannopyranosyl-(1-4)-D-gluconamide] (PV-Man) is a polystyrene derivative that contains mannose moieties and interacts with the mannose-receptor-carrying macrophage cell line. To clarify the specific interaction between the PV-Man and the macrophage cell line J774A1, PV-Man polymer labeled with fluorescent fluorescein isothiocyanate (FITC) was used to amonitor the specific interaction, which was visualized by confocal laser microscopy. We found that PV-Man strongly binds to macrophage cells, probably due to a specific interaction mediated by the presence of mannose receptors on the cell membrane. The fluorescence intensity of PV-Man and macrophage cells was up to 7-fold that of any other glycopolymers bound to macrophage cells. Moreover, cellular fluorescence intensity increased significantly with increasing incubation time and polymer concentration. Many macrophage cells strongly express mannose and mannose receptor-related receptors, and receptor-mediated gene transfer via the mannose receptor using a PV-Man glycopolymer is a versatile means of targeted gene delivery into these cells.


Elucidation of characteristic structural features of ligand binding sites of protein kinases: a neural network approach.
Protein kinases play important roles in regulating cellular signal transduction and other biochemical processes, and they are attractive targets for drug discovery programs in many disease areas. Most kinase inhibitors under development as drugs act by directly competing with ATP at the ATP-binding site of the kinase. There are more than 500 protein kinases, and the ATP-binding site is highly conserved among them. Therefore selectivity is an essential requirement for clinically effective drugs, and understanding the structural characteristics of ATP-binding sites is of crucial importance. The objective of the present study was to elucidate the structural characteristics of the adenosine-binding site of four major kinase groups, AGC (PKA, PKG, and PKC families), CaMK (calcium/calmodulin-dependent protein kinases), CMGC (CDK, MAPK, GSK3, and CLK families), and TK (tyrosine kinases). To do this, we classified the kinases into groups by using feed-forward multilayer perceptron (MLP) neural networks and structural, electronic, and hydrophobic descriptors of the amino acids at the adenosine-binding site. A total of 275 kinases were classified in two ways: (1) kinases belonging to a certain group were distinguished from those not belonging to that group, and (2) all of the kinases were classified into four groups. More than 85% of the kinases were correctly classified by both methods. Trained neural networks clarified which amino acids and which properties characterize the adenosine-binding site of each group, and the results were visualized by molecular graphics. Comparison of the modeled neural networks and the distributions of amino acids provided more detailed information on the structural characteristics of each group. Application of the present results to drug development is also discussed.


The adaptive value of habitat preferences from a multi-scale spatial perspective: insights from marsh-nesting avian species.
Habitat selection and its adaptive outcomes are crucial features for animal life-history strategies. Nevertheless, congruence between habitat preferences and breeding success has been rarely demonstrated, which may result from the single-scale evaluation of animal choices. As habitat selection is a complex multi-scale process in many groups of animal species, investigating adaptiveness of habitat selection in a multi-scale framework is crucial. In this study, we explore whether habitat preferences acting at different spatial scales enhance the fitness of bird species, and check the appropriateness of single vs. multi-scale models. We expected that variables found to be more important for habitat selection at individual scale(s), would coherently play a major role in affecting nest survival at the same scale(s). We considered habitat preferences of two Rallidae species, little crake (Zapornia parva) and water rail (Rallus aquaticus), at three spatial scales (landscape, territory, and nest-site) and related them to nest survival. Single-scale versus multi-scale models (GLS and glmmPQL) were compared to check which model better described adaptiveness of habitat preferences. Consistency between the effect of variables on habitat selection and on nest survival was checked to investigate their adaptive value. In both species, multi-scale models for nest survival were more supported than single-scale ones. In little crake, the multi-scale model indicated vegetation density and water depth at the territory scale, as well as vegetation height at nest-site scale, as the most important variables. The first two variables were among the most important for nest survival and habitat selection, and the coherent effects suggested the adaptive value of habitat preferences. In water rail, the multi-scale model of nest survival showed vegetation density at territory scale and extent of emergent vegetation within landscape scale as the most important ones, although we found a consistent effect with the habitat selection model (and hence evidence for adaptiveness) only for the former. Our work suggests caution when interpreting adaptiveness of habitat preferences at a single spatial scale because such an approach may under- or over-estimate the importance of habitat factors. As an example, we found evidence only for a weak effect of water depth at territory scale on little crake nest survival; however, according to the multi-scale analysis, such effect turned out to be important and appeared highly adaptive. Therefore, multi-scale approaches to the study of adaptive explanations for habitat selection mechanisms should be promoted.


Implementing spatial segregation measures in R.
Reliable and accurate estimation of residential segregation between population groups is important for understanding the extent of social cohesion and integration in our society. Although there have been considerable methodological advances in the measurement of segregation over the last several decades, the recently developed measures have not been widely used in the literature, in part due to their complex calculation. To address this problem, we have implemented several newly proposed segregation indices in R, an open source software environment for statistical computing and graphics, as a package called seg. Although there are already a few standalone applications and add-on packages that provide access to similar methods, our implementation has a number of advantages over the existing tools. First, our implementation is flexible in the sense that it provides detailed control over the calculation process with a wide range of input parameters. Most of the parameters have carefully chosen defaults, which perform acceptably in many situations, so less experienced users can also use the implemented functions without too much difficulty. Second, there is no need to export results to other software programs for further analysis. We provide coercion methods that enable the transformation of our output classes into general R classes, so the user can use thousands of standard and modern statistical techniques, which are already available in R, for the post-processing of the results. Third, our implementation does not require commercial software to operate, so it is accessible to a wider group of people.


Field evaluation of SD BIOLINE HIV/Syphilis Duo assay among pregnant women attending routine antenatal care in Juba, South Sudan.
The SD BIOLINE HIV/Syphilis Duo assay is the first World Health Organization prequalified dual rapid diagnostic test for simultaneous detection of HIV and Treponema pallidum antibodies in human blood. Prior to introducing the test into antenatal clinics across South Sudan, a field evaluation of its clinical performance in diagnosing both HIV and syphilis in pregnant women was conducted. SD Bioline test performance on venous blood samples was compared with (i) Vironostika HIV1/2 Uniform II Ag/Ab reference standard and Alere Determine HIV 1/2 non-reference standard for HIV diagnosis, and (ii) Treponema pallidum hemagglutination reference standard and Rapid plasma reagin non-reference standard for syphilis. Sensitivity, specificity, positive predictive value (PPN), negative predictive value (NPV) and kappa (κ) value were calculated for each component against the reference standards within 95% confidence intervals (CIs); agreements between Determine HIV 1/2 and SD Bioline HIV tests were also calculated. Of 442 pregnant women recruited, eight (1.8%) were HIV positive, 22 (5.0%) had evidence of syphilis exposure; 14 (3.2%) had active infection. For HIV diagnosis, the sensitivity, specificity, PPV and NPV were 100% (95% CI: 63.1-100), 100% (95% CI: 99.2-100), 100% (95% CI: 63.1-100) and 100% (95% CI: 99.2-100) respectively with κ value of 1 (95% CI: 0.992-1.000). Overall agreement of the Duo HIV component and Determine test was 99.1% (95% CI: 0.977-0.998) with 66.7% (95% CI: 34.9-90.1) positive and 100% (95% CI: 0.992-1.000) negative percent agreements. For syphilis, the Duo assay sensitivity was 86.4% (95% CI: 65.1-97.1) and specificity 100% (95% CI: 99.1-100) with PPV 100% (95% CI: 82.4-100), NPV 99.2% (95% CI: 97.9-99.9) and κ value 0.92 (95% CI: 0.980-0.999). Our findings suggest the SD Bioline HIV/Syphilis Duo Assay could be suitable for HIV and syphilis testing in women attending antenatal services across South Sudan. Women with positive syphilis results should receive treatment immediately, whereas HIV positive women should undergo confirmatory testing following national HIV testing guidelines.


Eosinophilic angiocentric fibrosis as a cause of nasal obstruction.
We present the tenth case of Eosinophilic Angiocentric Fibrosis (EAF) in the english literature, which presented as nasal obstruction in a patient of Indian descent. The histopathological and clinical features of this underreported condition is discussed as well as other lesions that may show similar features to EAF.


Amplitude-integrated EEG is useful in predicting neurodevelopmental outcome in full-term infants with hypoxic-ischemic encephalopathy: a meta-analysis.
Hypoxic ischemic encephalopathy is a common cause of neurological complications resulting in chronic handicapping conditions, such as cerebral palsy. Amplitude-integrated electroencephalography (EEG) has been used in many European countries for more than a decade in the evaluation of infants with hypoxic ischemic encephalopathy but has not been widely used in the United States. The objective of this study was to evaluate the evidence supporting use of amplitude-integrated EEG as a quantitative predictor of neurodevelopmental outcome in full-term infants with hypoxic ischemic encephalopathy. To assess efficacy, the authors performed a meta-analysis of the literature evaluating the use of the amplitude-integrated EEG or cerebral function monitor in full-term infants with hypoxic ischemic encephalopathy and their neurodevelopmental outcome. A total of 8 studies were eligible for the primary meta-analysis. There was an overall sensitivity of 91% (95% CI 87-95) and a negative likelihood ratio of 0.09 (95% CI .06-.15) for amplitude-integrated EEG tracings to accurately predict poor outcome. Amplitude-integrated EEG is a valuable bedside tool for predicting long-term neurodevelopmental outcome in term infants with hypoxic ischemic encephalopathy. This information is useful in structuring communication and care plans for physicians and parents. Early assessment techniques such as amplitude-integrated EEG provide objective means for determining inclusion in clinical studies evaluating therapies for hypoxic ischemic encephalopathy and for predicting which patients are most likely to respond to treatment.


Action-based memory in Alzheimer's disease: a longitudinal look at tea making.
In this paper we report the results of a longitudinal study which examined memory for a single routine activity of daily living in people with dementia of the Alzheimer type. We assessed memory in a natural setting, visiting volunteers in their homes. We video-taped performance on the selected task and analysed the record for the presence or absence of each of its component actions over a period of 6 years. In this way, we obtained longitudinal data for a small group of people moving from the mild-moderate stages of dementia through to severe dysfunction. In the first section of this paper we examine the nature of the errors which are made in recall of a routine activity by volunteers with dementia of the Alzheimer type and what happens to that routine as the dementia erodes memory. In the second section we examine the consequence of moving the routine from a familiar setting to a novel setting. We observed large differences in the rate of decline of our volunteers, with substantial preservation of performed recall of the everyday task, even in the more severe phases of the disease. The pattern of decline suggests a benign degradation of the memory trace, with omissions comprising the most common category of errors, and this result is contrasted with the more dramatic action disorganization syndrome associated with frontal injury. The results have implications both for theoretical models of action-based memory and intervention programmes aimed at maintaining functional independence for people with dementia.


[The role of human fibroblast growth factor receptor 1-IIIb isoform in proliferation of pancreatic ductal cells and its effects to mitogen-activated protein kinase].
To study the role of IIIb isoform of human fibroblast growth factor receptor 1 (FGFR1-IIIb) in proliferation of pancreatic ductal cells and its effects on mitogen-activated protein kinase (MAPK). Human pancreatic ductal cells of the line TAKA-1 were cultured. The plasmid of human full-length FGFR1-IIIb isoform, pSVK4/FGFR1-IIIb, was stable transfected into the cultured TAKA-1 pancreatic ductal cells facilitated by lipofectamine. Un-transfected TAKA-1 cells and TAKA-1 ductal cells transfected with blank plasmid were used as controls. The expression, distribution and character of protein of FGFR1-IIIb in the TAKA-1 cells were estimated by Western blotting, Northern blotting, immunofluorescence assay, and glycosylation assay. The function and mechanism of FGFR1-IIIb in the transfected pancreatic ductal cells stimulated by FGF were examined by MTT assay and MAPK assay. Tunicamycin, an inhibitor of N-terminal glycoprotein synthesis, was added into the culture fluid of the FGFR1-IIIb transfected TAKA-1 cells to observe the changes of the FGFR1 bands. FGFR1-IIIb, a glycosylated receptor at various levels at 120 kDa and between 130 - 150 kDa, was localized at moderate levels at the cell membrane and cytoplasm and at higher level in the perinuclear region of the cytoplasm of the pSVK4/FGFR1-IIIb-transfected cells. FGF-1, -2, and -4 significantly increased the growth of FGFR1-IIIb-transfected TAKA-1 cells, and at the same time induced the p44/p42 MAPK phosphorylation. Human FGFR1-IIIb receptor is a functional receptor in pancreatic ductal cells. FGF-1, -2, and -4 can increase the growth of FGFR1-IIIb-transfected pancreatic ductal cells, and the mechanism is that they can induce the p44/p42 MAPK phosphorylation.


Mesenchymal stem cell mechanotransduction is cAMP dependent and regulated by adenylyl cyclase 6 and the primary cilium.
Mechanical loading is a potent stimulus of bone adaptation, requiring the replenishment of the osteoblast from a progenitor population. One such progenitor is the mesenchymal stem cell (MSC), which undergoes osteogenic differentiation in response to oscillatory fluid shear. Yet, the mechanism mediating stem cell mechanotransduction, and thus the potential to target this therapeutically, is poorly understood. In this study, we demonstrate that MSCs utilise cAMP as a second messenger in mechanotransduction, which is required for flow-mediated increases in osteogenic gene expression. Furthermore, we demonstrate that this mechanosignalling is dependent on the primary cilium and the ciliary localised adenylyl cyclase 6. Finally, we also demonstrate that this mechanotransduction mechanism can be targeted therapeutically to enhance cAMP signalling and early osteogenic signalling, mimicking the beneficial effect of physical loading. Our findings therefore demonstrate a novel mechanism of MSC mechanotransduction that can be targeted therapeutically, demonstrating a potential mechanotherapeutic for bone-loss diseases such as osteoporosis.This article has an associated First Person interview with the first author of the paper.


The Trichoderma harzianum demon: complex speciation history resulting in coexistence of hypothetical biological species, recent agamospecies and numerous relict lineages.
The mitosporic fungus Trichoderma harzianum (Hypocrea, Ascomycota, Hypocreales, Hypocreaceae) is an ubiquitous species in the environment with some strains commercially exploited for the biological control of plant pathogenic fungi. Although T. harzianum is asexual (or anamorphic), its sexual stage (or teleomorph) has been described as Hypocrea lixii. Since recombination would be an important issue for the efficacy of an agent of the biological control in the field, we investigated the phylogenetic structure of the species. Using DNA sequence data from three unlinked loci for each of 93 strains collected worldwide, we detected a complex speciation process revealing overlapping reproductively isolated biological species, recent agamospecies and numerous relict lineages with unresolved phylogenetic positions. Genealogical concordance and recombination analyses confirm the existence of two genetically isolated agamospecies including T. harzianum sensu stricto and two hypothetical holomorphic species related to but different from H. lixii. The exact phylogenetic position of the majority of strains was not resolved and therefore attributed to a diverse network of recombining strains conventionally called 'pseudoharzianum matrix'. Since H. lixii and T. harzianum are evidently genetically isolated, the anamorph - teleomorph combination comprising H. lixii/T. harzianum in one holomorph must be rejected in favor of two separate species. Our data illustrate a complex speciation within H. lixii - T. harzianum species group, which is based on coexistence and interaction of organisms with different evolutionary histories and on the absence of strict genetic borders between them.


Organizational readiness for change: Preceptor perceptions regarding early immersion of student pharmacists in health-system practice.
To examine preceptors' perceptions regarding readiness for change pre- and post-implementation of a pilot early immersion program engaging student pharmacists in direct patient care. Student pharmacists enrolled in the second professional year of a Doctor of Pharmacy degree program completed a four-week health-system introductory pharmacy practice experience (IPPE) which was modified to include direct patient care roles in operational (drug preparation and dispensing) and clinical (comprehensive medication management) pharmacy environments. Pharmacy preceptors with direct oversight for program implementation completed a pre/post Organizational Readiness for Implementing Change (ORIC) survey and a 50-min interview or focus group post-experience. The ORIC survey evaluates two dimensions of organizational readiness for change - change commitment and change efficacy. Additional items assessed included implementation needs, support, and perceived value of the change. ORIC survey constructs were compared before and after the experience. Interviews and focus groups were audio recorded, transcribed, and evaluated by constant comparative analysis. A mixed methods approach was used to triangulate findings and develop greater understanding of the ORIC survey results. Twenty pharmacy preceptors (37 ± 8 years of age, 60% female, 65% clinical pharmacist position, 70% prior preceptor experience) participated in the study. There were no significant changes in pre/post survey constructs, except for a decline in the perception of organizational change commitment (p < 0.001). Sub-analyses indicated the decline was associated with items assessing individual dedication and individual commitment to the change (p < 0.05 for both). Primary emerging themes from interviews included concerns about implementation requirements, contextual factors of the experience that affected implementation, and varying perceptions about the value of early immersion across preceptor roles. As pharmacy curricula immerse student pharmacists in practice earlier in their education, pharmacy departments can utilize the ORIC survey to identify preceptors' commitment and concerns to support the necessary changes for student pharmacist engagement.


Central nervous system disease in phase III studies for advanced HER2 positive breast cancer: A review.
The introduction of human epidermal growth factor receptor 2 (HER2) directed therapy has transformed the outcomes of patients with advanced breast cancer (BC). However, HER2 positive breast cancer has a predilection for the central nervous system (CNS) which is associated with significant morbidity and mortality. Understanding the intracranial activity of novel HER2 directed agents is key to developing treatments as well as possible preventative strategies for HER2-positive CNS disease. Using protocols and data from published phase III clinical trials for locally advanced/metastatic HER2-positive breast cancer since the licensing of single agent trastuzumab for advanced BC we review the central nervous system related aspects. This includes CNS related entry criteria, use of baseline and on study cross-sectional imaging of the CNS and protocol and non-protocol defined CNS end points and reported data. and Relevance: This review found heterogeneity between studies with regard to the entry criteria, use of CNS imaging and reported end points within the pivotal phase III studies. Based on these data, a standardisation of both entry criteria and end points with regard to the CNS should be developed and applied to future studies of HER2-positive advanced BC. Such an approach would enable the generation of comparable data and allow a meaningful analysis of different treatment approaches with regard to the CNS. This in turn would allow the development of the most optimal treatment approaches for HER2 positive CNS disease and ultimately the development of preventative strategies.


5-HT1A receptor-dependent control of nigrostriatal dopamine neurotransmission in the pharmacotherapy of Parkinson's disease and schizophrenia.
Dysfunctions of the basal ganglia are associated with a number of neurological and psychiatric conditions including Parkinson's disease and schizophrenia. Current treatments of these disorders are mostly symptomatic and inadequate, and are often associated with a number of unwanted side-effects. The striatum, the terminal region of the nigrostriatal dopamine pathway, is the main input nucleus of the basal ganglia, and dopamine neurotransmission through the nigrostriatal pathway plays a crucial role in the modulation of basal ganglia output and mediated behaviors. Evidence suggests a role of 5-hydroxytryptamine (5-HT; serotonin)-1A receptors in the modulation of dopamine neurotransmission and in improving pharmacotherapy in schizophrenia and Parkinson's disease. This review concerns the role of 5-HT1A receptors in the modulation of nigrostriatal dopamine neurotransmission, with the aim of providing guidelines for future research to improve pharmacotherapy. The current state of knowledge suggests that drugs simultaneously targeting dopamine D2 and 5-HT1A receptors may improve pharmacotherapy for schizophrenia and Parkinson's disease. Activation of somatodendritic 5-HT1A receptors in the dorsal raphe nucleus has an important role in the alleviation of extrapyramidal symptoms and levodopa-induced dyskinesia induced by antipsychotic treatment. Drugs acting exclusively through dopamine D2 and 5-HT1A receptors are highly needed to validate the potential role of 5-HT1A receptors in improving therapeutics for Parkinson's disease and schizophrenia.


Regulation of white and brown adipocyte differentiation by RhoGAP DLC1.
Adipose tissues constitute an important component of metabolism, the dysfunction of which can cause obesity and type II diabetes. Here we show that differentiation of white and brown adipocytes requires Deleted in Liver Cancer 1 (DLC1), a Rho GTPase Activating Protein (RhoGAP) previously studied for its function in liver cancer. We identified Dlc1 as a super-enhancer associated gene in both white and brown adipocytes through analyzing the genome-wide binding profiles of PPARγ, the master regulator of adipogenesis. We further observed that Dlc1 expression increases during differentiation, and knockdown of Dlc1 by siRNA in white adipocytes reduces the formation of lipid droplets and the expression of fat marker genes. Moreover, knockdown of Dlc1 in brown adipocytes reduces expression of brown fat-specific genes and diminishes mitochondrial respiration. Dlc1-/- knockout mouse embryonic fibroblasts show a complete inability to differentiate into adipocytes, but this phenotype can be rescued by inhibitors of Rho-associated kinase (ROCK) and filamentous actin (F-actin), suggesting the involvement of Rho pathway in DLC1-regulated adipocyte differentiation. Furthermore, PPARγ binds to the promoter of Dlc1 gene to regulate its expression during both white and brown adipocyte differentiation. These results identify DLC1 as an activator of white and brown adipocyte differentiation, and provide a molecular link between PPARγ and Rho pathways.


Impaired fracture healing with high non-union rates remains irreversible after traumatic brain injury in leptin-deficient mice.
Patients with traumatic brain injury (TBI) and long-bone fractures can show increased callus formation. This effect has already been reproduced in wild-type (wt) mice. However, the mechanisms remain poorly understood. Leptin is significantly increased following TBI, while its role in bone healing remains unclear. The aim of this study was to evaluate fracture healing in leptin-deficient ob/ob mice and to measure any possible impact of TBI on callus formation. 138 female, 12 weeks old, ob/ob mice were divided into four groups: Control, fracture, TBI and combined trauma. Osteotomies were stabilized with an external fixator; TBI was induced with Controlled Cortical Impact Injury. Callus bridging was weekly evaluated with in vivo micro-CT. Biomechanical testing was performed ex vivo. Micro-CT showed high non-union rates after three and four weeks in the fracture and combined trauma group. No differences were observed in callus volume, density and biomechanical properties at any time point. This study shows that bony bridging is impaired in the present leptin-deficient trauma model. Furthermore, the phenomenon of increased callus formation after TBI could not be reproduced in ob/ob mice, as in wt mice. Our findings suggest that the increased callus formation after TBI may be dependent on leptin signaling.


Scalable Fabrication of Modified Graphene Nanoplatelets as an Effective Additive for Engine Lubricant Oil.
The use of nano-additives is widely recognized as a cheap and effective pathway to improve the performance of lubrication by minimizing the energy loss from friction and wear, especially in diesel engines. In this work, a simple and scalable protocol was proposed to fabricate a graphene additive to improve the engine lubricant oil. Graphene nanoplates (GNPs) were obtained by a one-step chemical exfoliation of natural graphite and were successfully modified with a surfactant and an organic compound to obtain a modified GNP additive, that can be facilely dispersed in lubricant oil. The GNPs and modified GNP additive were characterized using scanning electron microscopy, X-ray diffraction, atomic force microscopy, Raman spectroscopy, and Fourier-transform infrared spectroscopy. The prepared GNPs had wrinkled and crumpled structures with a diameter of 10-30 µm and a thickness of less than 15 nm. After modification, the GNP surfaces were uniformly covered with the organic compound. The addition of the modified GNP additive to the engine lubricant oil significantly enhanced the friction and antiwear performance. The highest reduction of 35% was determined for the wear scar diameter with a GNP additive concentration of approximately 0.05%. The mechanism for lubrication enhancement by graphene additives was also briefly discussed.


Exploring Safe Sleep and SIDS Risk Perception in an African-American Community: Focused Ethnography.
Explore the cultural influences of safe sleep practices by African-American caregivers of children under 2 years old. Explore the role of health care professionals in promoting safe sleep. A focused ethnography was used to understand the contextual cultural meaning and experiences of safe sleep practices of African-American caregivers of children under 2 years. Nineteen African-Americans participated in this study. Demographic data were collected and semi-structured interviews were conducted with individuals and small groups. Saturation of the data occurred after 17 interviews. Data were analyzed using Leininger's four Phases of qualitative data analysis. (Themes): (1) The informants expressed both accurate and inaccurate knowledge of Sudden Infant Death Syndrome (SIDS) and safe sleep practices influenced by personal experiences, hospital education, family, extended family and television; (2) Sleeping with infants and children was viewed as a cultural caring behavior promoting comfort, closeness and protection for infants, children, parents and caregivers; (3) The informants want and are seeking collaboration with nurses and health care professionals who are viewed as important in promoting accurate information about SIDS and safe sleep practices. The role of the nurse can impact accurate outcomes about SIDS and safe sleep practices.