Neuroradiological Endovascular Intervention for Diplopia in a Case of Aneurysmal Aberrant Regeneration of the Third Nerve.
Aberrant regeneration of the third nerve occurs as a result of synkinetic 'miswiring' of the third nerve following its injury, such as in third cranial nerve palsy due to tumor, trauma, or aneurysm. The case presented is an elderly woman with new vertical diplopia, which led to a diagnosis of a third cranial nerve palsy, thought to be caused by a 5 mm blister aneurysm of the posterior communicating artery. However, neuro-ophthalmological evaluation diagnosed aberrant regeneration of the third nerve, with the cause of her new vertical diplopia being an ipsilateral fourth nerve palsy. The patient underwent endovascular treatment of her aneurysm using stent-assisted coiling. This procedure was complicated by an episode of air embolism, from which the patient made a good recovery. This patient's presentation demonstrates that the cause of any diplopia must be established, and presents a novel, semi-schematic illustration of aberrant regeneration of the third nerve that should aid clinicians in its recognition.


The distribution and number of Leu-7 (CD57) positive cells in lung tissue from patients with pulmonary fibrosis.
Leu-7 positive lymphocytes, including natural killer cells, play an important role in the immune system's surveillance function to prevent the development of cancer. The incidence of lung cancer is significantly high in patients with end-stage pulmonary fibrosis. We hypothesized that the number of Leu-7 positive cells may be decreased in areas of severe pulmonary fibrosis. To demonstrate this, Leu-7 positive cells were immunohistochemically stained in 41 lung specimens obtained from patients with idiopathic pulmonary fibrosis and pulmonary fibrosis associated with collagen vascular disorders. The number of Leu-7 positive cells was evaluated according to the pathological findings. In pathologically normal lung, Leu-7 positive cells were mostly found within the capillaries of the septa and rarely in the alveolar space or the stroma. The number of Leu-7 positive cells was 0.69 +/- 0.15 in areas of advanced fibrosis (n = 41), 2.39 +/- 0.60 in areas that had newly developeing fibrosis (n = 41), 1.14 +/- 0.57 in bronchiolitis obliterans organizing pneumonia (n = 9), and 1.35 +/- 0.87 in diffuse alveolar damage (DAD) (n = 11). The number of Leu-7 positive cells in areas of newly developing fibrosis (2.39 +/- 0.60) was significantly higher than that in areas of established fibrosis (0.69 +/- 0.15, P < 0.05). Our present study demonstrates a significant decrease in the number of Leu-7 positive cells in areas of advanced fibrosis. This evidence may partly explain the high incidence of lung cancer associated with pulmonary fibrosis.


Drug-Drug Interaction Risk Assessment of Esaxerenone as a Perpetrator by In Vitro Studies and Static and Physiologically Based Pharmacokinetic Models.
Esaxerenone (CS-3150) is a novel, oral, nonsteroidal, selective mineralocorticoid receptor blocker approved for the treatment of hypertension in Japan. Here, the drug-drug interaction (DDI) potential of esaxerenone was evaluated in vitro, and its impact in clinical practice was estimated. Esaxerenone exhibited time-dependent inhibition and induction of CYP3A. When the clinical impacts of esaxerenone on the inhibition and induction of CYP3A were estimated separately by using a mechanistic static model, the predicted area under the curve ratios (AUCRs) of midazolam, a typical CYP3A substrate, were 1.80 and 0.31, respectively, suggesting that the DDI potential of esaxerenone cannot be neglected. Because it was suggested that DDIs mainly occur in the intestine, predictions using concentration-time profiles in each segment of the gastrointestinal tract were performed with GastroPlus, a physiologically based pharmacokinetic (PBPK) modeling software. The predicted AUCR of midazolam was approximately 1.2, which is close to that in a clinical study, despite the difficulty of predicting DDIs for compounds with both inhibition and induction effects. When only inhibition or induction was incorporated into a model, the AUCR of midazolam changed depending on the dosing period and dose level of esaxerenone and the timing of midazolam administration. However, the AUCR calculated by incorporating both effects remained almost constant. This study shows the ability of PBPK models to simulate weak DDIs via intestinal CYP3A and that esaxerenone has low DDI potential as a perpetrator because of the offset of inhibition and induction. SIGNIFICANCE STATEMENT: Weak CYP3A inhibition and/or induction sometimes cause DDIs in the intestine but not the liver. Because strong inhibitors maximally inhibit intestinal CYP3A, the predictability of weak DDIs in the intestine should be evaluated further. Here, we simulate the DDIs of esaxerenone as a perpetrator by using physiologically based pharmacokinetic modeling focusing on the intestine and offset of inhibition and induction.


An Advanced NiCoFeO/Polyaniline Composite for High-Performance Supercapacitors.
To reduce the charge-transfer resistance of supercapacitors and achieve faster reversible redox reactions, ternary Ni-Co-Fe layered double hydroxide was prepared by using the urea method and then calcined to give NiCoFe oxide (NiCoFeO). To enhance conductivity, a polyaniline (PANI) conductive layer was assembled on the surface of the NiCoFeO particles by in situ oxidative polymerization of aniline monomers. The as-prepared NiCoFeO/PANI composite was successful employed as a supercapacitor electrode. It was found that the NiCoFeO/PANI composite displayed good cycling stability, with a capacity loss of only 29.54 % after 5000 cycles. Furthermore, the NiCoFeO/PANI composite also exhibited excellent supercapacitor performance, with a high specific capacity of 843 F g-1 at a current density of 2 A g-1 , whereas NiCoFeO showed a specific capacity of only 478 F g-1 . This result was attributed to the synergistic effect between NiCoFeO and PANI. The facile synthesis strategy and excellent electrochemical performance suggest that NiCoFeO/PANI is a promising economical electrode material for applications in supercapacitors.


Human Papilloma Virus vaccine and prevention of head and neck cancer, what is the current evidence?
Human Papilloma Virus is associated with the development of cancers in the head and neck region. We have witnessed, in the last decades, an increase in number of cases directly related to HPV infection, in particular in the Western Countries. Recently the FDA expanded the indications for Gardasil-9® to include the prevention of head and neck cancer. Objective of this paper is to review the evidence supporting its use. Bibliographic review enquiring Medline, Web of Science and the Cochrane Library to assess the efficacy of vaccination against oncogenic HPV in the prevention of head and neck squamous cell carcinoma. Two prospective and 4 retrospective studies have evaluated vaccination in prevention of head and neck cancer, using persistent oral infection as surrogate of efficacy. All studies showed lower prevalence of oral infection up to 4 years following vaccination. Vaccine efficacy was estimated between 88 and 93.3%. Because of low vaccine coverage the estimated population-level effect against oral HPV16/18/6/11 infections was only 17.0%. Antibodies concentration in the oral fluid correlate with serum level, but the threshold to ensure protection is unknown. Duration of protection has not been established. HPV vaccination can provide protection from re-infection (at different mucosal sites) in previously exposed individuals, suggesting possible use of HPV vaccine later in life. Other studies should focus on confirming causal relationship between vaccination and prevention of persistent oral infection and investigate the duration of efficacy, which is crucial in its effectiveness against HNSCC.


Peptide-degrading enzymatic activities in GH3 cells and rat anterior pituitary homogenates.
The activities of a number of peptide-degrading enzymes were compared in homogenates of GH3 cells and rat anterior pituitaries. The enzymes studied were prolyl endopeptidase (EC 188.8.131.52), a soluble metalloendopeptidase, pyroglutamyl peptide hydrolase (EC 184.108.40.206), a multicatalytic protease complex, cathepsin B (EC 220.127.116.11), cathepsin D (EC 220.127.116.11), aminopeptidase (EC 18.104.22.168), and a membrane-bound neutral metalloendopeptidase (EC 126.96.36.199). Specific substrates were used to measure the activities, and active-site-directed inhibitors were used to verify the identities of the enzymes studied. Of the two lysosomal enzymes studied, cathepsin B, the enzyme with the highest activity in both preparations, had 5 times the activity in GH3 cell homogenates as in anterior pituitary homogenates. Cathespin D had a somewhat higher activity in the anterior pituitary homogenates than in the GH3 cell homogenates. Soluble metalloendopeptidase and prolyl endopeptidase, both cytoplasmic enzymes, had about twice the activity in GH3 cell homogenates as in anterior pituitary homogenates. Membrane-bound neutral metalloendopeptidase in the GH3 cell homogenates had 25% of the activity of the anterior pituitary homogenates. Of the two TRH-degrading enzymes, the activity of prolyl endopeptidase in GH3 cell homogenates was about 25 times higher than that of pyroglutamyl peptide hydrolase. Since the secretory function of the pituitary is in part controlled by neuropeptides, the knowledge of the enzyme profiles of the GH3 cells and the anterior pituitary should be of value in studying the metabolism of neuropeptides and peptide hormones in these systems.


[Advances in the surgical treatment of hypoplastic left-heart syndrome].
Hypoplastic left-heart syndrome is a congenital heart malformation that is classified as a univentricular disorder (hearts with only one functioning ventricle). Treatment was first developed in 1977, but a marked improvement in survival was not seen until the last decade. This was due primarily to a better understanding of how to surgically and medically manipulate the balance between pulmonary and systemic circulation. Special attention should be given to cerebral protection before, during and after surgery and to the follow-up of neurocognitive behaviour.


Problems in grading soft tissue sarcomas.
Clinicians, particularly medical oncologists, place increasing importance on histologic grading as a means of informing their treatment decisions in patients with soft tissue sarcoma. Numerous different grading systems (with a variable number of grades) have been described. Although these have often used different parameters, it is nevertheless generally accepted that histologic grade, however derived, is probably the best prognostic indicator in these sarcoma patients. Unfortunately, however, there is no consensus as to the best grading system, and even those schemes that are most widely applied (those of the French National Cancer Centers and the National Cancer Institute in the United States) have important and acknowledged limitations. Furthermore, assessment of many of the most popular grading parameters is necessarily subjective, and, to date, potentially more objective measures of proliferative activity and ploidy (eg, using immunohistochemistry or DNA flow cytometry) have not improved on experienced morphologic grading. In addition, the confounding (and often misleading) effect on histologic grade of preoperative therapy, which is increasingly used, has not been addressed in any meaningful way. This overview highlights the limitations, problems, and concerns regarding histologic grading of soft tissue sarcomas.


The impact of recipient age on the effects of umbilical cord mesenchymal stem cells on HBV-related acute-on-chronic liver failure and liver cirrhosis.
The results of a previous study verified that umbilical cord mesenchymal stem cells (UCMSCs) have good therapeutic effects for the treatment of HBV-related acute-on-chronic liver failure (ACLF) and liver cirrhosis (LC). Nevertheless, it is still unknown whether the effects of UCMSCs are affected by recipient age. Patients treated with UCMSCs who met the criteria of HBV-related ACLF and liver cirrhosis were identified in this retrospective observational study. Patients were divided into subgroups according to the World Health Organization (WHO) age criteria (< 45 vs. ≥ 45 years). Group A included young ACLF patients (< 45 y), and group B included older ACLF patients (≥ 45 y). Young LC patients (< 45 y) were assigned to group C, and group D included older LC patients (≥ 45 y). Patients' clinical characteristics, demographics, biochemical factors, and model for end-stage liver disease (MELD) scores were compared for 24 weeks. Sixty-four ACLF patients and 59 LC patients were enrolled in this study. Compared with patients in groups B and C, patients in group A did not show significant superiority in terms of the levels of ALT, AST, TBIL, AFP, and PTA and MELD scores. However, the median decrease and cumulative decrease in the TBIL and ALT levels of patients in group C were larger than those of patients in group D after four weeks of UCMSC transfusions. For older patients (≥ 45 y), the cumulative decrease and the median decrease in the TBIL of ACLF patients were significantly greater than those of LC patients after UCMSC treatment. However, the median decrease in ALT levels of ACLF patients was significantly greater than that of LC patients during UCMSC treatment, and the cumulative decrease in ALT levels of ACLF patients was significantly greater than that of LC patients at all time points. The therapeutic effects of UCMSCs for HBV-related acute-on-chronic liver failure and liver cirrhosis varied partly by patient age. Assessing patient age is necessary prior to UCMSC clinical use.


Plantar angiomyxolipoma in a child.
Angiomyxolipoma, a lipoma variant with myxoid areas and vascular proliferation was originally described in 1996 and till date has only 12 cases in published literature. Only two cases have been reported in children involving buccal mucosa and knee, respectively. The authors report a case of angiomyxolipoma, on the plantar surface of the left foot, in a 4-year-old male child who presented to our institution in Abha city (Kingdom of Saudi Arabia). The significant differential diagnosis of this neoplasm from other similar lipomatous tumours occurring in adult and paediatric population is discussed. The importance of recognising these tumours lies in their recognition as separate entity and the present case may add to the knowledge, clinical behaviour and prognosis of these less reported lipomatous neoplasms.


[Distribution Characteristics and Ecological Risk Assessment of Soil Heavy Metals in Typical Watersheds of the Qinghai-Tibet Plateau].
The Qinghai-Tibet Plateau is an extremely vulnerable area that is sensitive to human activities. In recent years, more and more human disturbances have been detected in this area. This study analyzed the spatial distribution and ecological risks of 7 heavy metals (Cr, Ni, Cu, Zn, As, Cd, and Pb) in two regions, namely the Bailong River and Yellow River and their two tributaries (BY region) in Gannan and the Yarlung Zangbo River and its two tributaries (YZ region) in Tibet. In terms of spatial distribution, concentrations of the seven heavy metals were higher in the east and lower in the west of the BY region. The average concentrations all exceeded the background value of the Qinghai-Tibet Plateau, especially for Cd (4.50 times) and As (2.83 times). High Pb concentrations were mainly found in water, urban and rural residential land, and industrial and construction land. In the YZ region, heavy metal concentrations were lower along the river, while high-altitude areas exhibited higher heavy metal concentrations. The average concentrations of Ni, Zn, As, and Cd exceeded the background values of the Qinghai-Tibet Plateau, especially that of Cd (3.13 times), which mostly exhibited high values in water coverage areas. The geo-accumulation index method and the potential ecological risk index method show that the degree of As and Cd pollution was relatively high in the BY region in Gannan, with the greatest potential ecological risk occurring in the water coverage area. In the YZ region in Tibet, the degree of Cd pollution was high, with the highest potential ecological risk also occurring in the water coverage area. This study provides significant guidance for the environmental protection, sustainable development, and utilization of soil under different types of land use in the Qinghai-Tibet Plateau.


Study of in Situ Silver Migration in Amorphous Boron Nitride CBRAM Device.
We report the dependence of the thickness of amorphous boron nitride (a-BN) on the characteristics of conductive bridge random access memory (CBRAM) structured with the Ag/a-BN/Pt stacking sequence. The a-BN thin film layers of three different thicknesses of 5.5, 11, and 21.5 nm were prepared by the sputtering deposition. Depending on the thickness of the a-BN layer, the devices are found to be in either low-resistance state (LRS) or high-resistance state (HRS) prior to any consecutive switching cycle. All devices with 5.5 nm thick a-BN switching layer are in LRS as the pristine state, while devices with 21.5 nm thick a-BN layer are found to be in HRS as the pristine state. To attain reliable switching cycles, initial RESET and electroforming process are necessarily required for the devices with 5.5 and 21.5 nm thick a-BN layer, respectively. However, the devices with the a-BN layer of thickness between 5.5 and 21.5 nm in pristine states are in either HRS or LRS. This dependence of the a-BN thickness on different resistance states in the pristine state can be explained by in situ Ag diffusion during its sputter deposition to form a top electrode on the a-BN layer. Our finding shows a detailed investigation and a deep understanding of the switching mechanism of Ag/a-BN/Pt CBRAM devices with respect to different a-BN thicknesses for the future computing system.


Strigolactone and Karrikin Signaling Pathways Elicit Ubiquitination and Proteolysis of SMXL2 to Regulate Hypocotyl Elongation in Arabidopsis.
Strigolactones (SLs) and karrikins (KARs) are related butenolide signaling molecules that control plant development. In Arabidopsis (Arabidopsis thaliana), they are recognized separately by two closely related receptors but use the same F-box protein MORE AXILLARY GROWTH2 (MAX2) for signal transduction, targeting different members of the SMAX1-LIKE (SMXL) family of transcriptional repressors for degradation. Both signals inhibit hypocotyl elongation in seedlings, raising the question of whether signaling is convergent or parallel. Here, we show that synthetic SL analog GR244DO enhanced the interaction between the SL receptor DWARF14 (D14) and SMXL2, while the KAR surrogate GR24 ent-5DS induced association of the KAR receptor KARRIKIN INSENSITIVE2 (KAI2) with SMAX1 and SMXL2. Both signals trigger polyubiquitination and degradation of SMXL2, with GR244DO dependent on D14 and GR24 ent-5DS dependent mainly on KAI2. SMXL2 is critical for hypocotyl responses to GR244DO and functions redundantly with SMAX1 in hypocotyl response to GR24 ent-5DS Furthermore, GR244DO induced response of D14-LIKE2 and KAR-UP F-BOX1 through SMXL2, whereas GR24 ent-5DS induced expression of these genes via both SMAX1 and SMXL2. These findings demonstrate that both SLs and KARs could trigger polyubiquitination and degradation of SMXL2, thus uncovering an unexpected but important convergent pathway in SL- and KAR-regulated gene expression and hypocotyl elongation.


Gender differences in first and secondhand smoke exposure, spirometric lung function and cardiometabolic health in the old order Amish: A novel population without female smoking.
Due to their relatively homogeneous lifestyle and living environment, the Amish offer a novel opportunity to study the health associations of tobacco smoke exposure, particularly secondhand smoke. We hypothesized that secondhand smoke exposure is associated with worse pulmonary and cardiometabolic health. We examined cross-sectional data on 3568 Amish study participants, including tobacco use and secondhand smoke exposure from family members included in the study. Thirty-four percent of Amish men reported ever smoking. Of this proportion, 64% used cigars, 46% cigarettes, and 21% pipes. Less than 1% of women reported ever smoking. Smoking was associated with lower spirometric lung function, higher body mass index, lower HDL cholesterol, higher heart rate, lower ankle-brachial index, and larger aortic diameter in men. A greater number of sources of secondhand smoke exposure (defined from the total of spouses, parents, and siblings who smoke) was associated with higher body mass index (p = 0.03) and with higher fasting glucose in men (p = 0.01), but not in women (p = 0.007 for sex*secondhand smoke interaction). Secondhand smoke exposure was also associated with reduced HDL cholesterol only in women (p = 0.002) and a lower heart rate only in men (p = 0.006). Smoking habits among the Old Order Amish are notable for the absence of female participation and a high proportion of cigar and pipe use. Smoking is associated with decreased spirometric indices of lung function and increased cardiovascular risk in this population and secondhand smoke exposure is associated with a greater burden of risk factors for cardiovascular disease. Sex differences in correlations could reflect differences in exposure patterns, mechanisms, or susceptibilities.


Suppressing Non-Specific Binding of Proteins onto Electrode Surfaces in the Development of Electrochemical Immunosensors.
Electrochemical immunosensors, EIs, are systems that combine the analytical power of electrochemical techniques and the high selectivity and specificity of antibodies in a solid phase immunoassay for target analyte. In EIs, the most used transducer platforms are screen printed electrodes, SPEs. Some characteristics of EIs are their low cost, portability for point of care testing (POCT) applications, high specificity and selectivity to the target molecule, low sample and reagent consumption and easy to use. Despite all these attractive features, still exist one to cover and it is the enhancement of the sensitivity of the EIs. In this review, an approach to understand how this can be achieved is presented. First, it is necessary to comprise thoroughly all the complex phenomena that happen simultaneously in the protein-surface interface when adsorption of the protein occurs. Physicochemical properties of the protein and the surface as well as the adsorption phenomena influence the sensitivity of the EIs. From this point, some strategies to suppress non-specific binding, NSB, of proteins onto electrode surfaces in order to improve the sensitivity of EIs are mentioned.


Role of microRNA-130a in myocardial hypoxia/reoxygenation injury.
The aim of this study was to investigate the role of microRNA (miR)-130a in the pathogenesis of myocardial hypoxia/reoxygenation (H/R) injury. Primary rat cardiomyocytes were cultured and subjected to H/R treatment. Reverse transcription-quantitative polymerase chain reaction was performed to detect the levels of miR-130a, western blot analysis was used to determine the expression of various proteins, and CCK-8 assay was performed to determine cell viability. In addition, flow cytometry was used to assess apoptosis. The cell viability was significantly decreased and the apoptosis rate was significantly increased in H/R-treated primary cardiomyocytes, and the expression level of miR-130a was also elevated in these model cells. Transfection with miR-130a inhibitor significantly elevated the cell viability and reduced the apoptosis rate in H/R-treated cardiomyocytes. Bioinformatics analysis indicated that autophagy-related gene 14 (ATG14) is the target for miR-130a, which was confirmed by dual-luciferase reporter assay and western blot analysis. When the H/R model cells were co-transfected with miR-130a inhibitor and small interfering RNA against ATG14, the cell viability was significantly reduced and the apoptosis rate was significantly elevated, compared with that of cells transfected with miR-130a inhibitor alone. miR-130a inhibitor transfection significantly elevated the levels of ATG14 and phosphorylated (p-)Beclin 1, increased the LC3II/LC3I ratio, and decreased the expression levels of P62 and cleaved caspase-3, while the co-transfection of miR-130a inhibitor and siR-ATG14 attenuated these effects in H/R-induced primary cardiomyocytes. These results indicate that miR-130a is involved in H/R-induced injuries in primary cardiomyocytes, and that the inhibition of miR-130a increases the levels of ATG14 and p-Beclin 1, thereby increasing autophagy and inhibiting apoptosis in these cells.


Smart Fibers and Textiles for Personal Health Management.
Fibers and textiles play key roles in the development and day-to-day activities of human society. Innovations related to flexible electronics-smart fibers and textiles with sensing, thermal regulation, and energy management capabilities-have drawn great interest from both academic and industrial communities. Smart fibers and textiles are anticipated to revolutionize personal health management due to their manifold features and capabilities, providing the foundation for many intelligent wearables. In this Perspective, we provide a brief overview of recent advances in the design and fabrication of smart fibers and textiles for health management applications, focusing primarily on those with sensing, thermal regulation, and energy management functions. We describe the existing challenges and opportunities and propose future development directions.


Modelling sexually transmitted infections: less is usually more for informing public health policy.
Mathematical models have been used to investigate the dynamics of infectious disease transmission since Bernoulli's smallpox modelling in 1760. Their use has become widespread for exploring how epidemics can be prevented or contained. Here we discuss the importance of modelling the dynamics of sexually transmitted infections, the technology-driven dichotomy in methodology, and the need to 'keep it simple' to explore sensitivity, to link the models to reality and to provide understandable mechanistic explanations for real-world policy-makers. The aim of models, after all, is to influence or change public health policy by providing rational forecasting based on sound scientific principles.


[Pharma-Clinics. Medication of the month. Totelle Cycle: new sequential estrogen/progesterone regimen for hormone replacement therapy in menopause].
Totelle Cycle is a sequential regimen containing 2 mg of oestradiol for 28 days associated with a new progestogen, trimegestone, from day 15 to 28. It is indicated for the treatment of climacteric symptoms and the prevention of post-menopausal bone loss. Trimegestone is a new 19-NOR progesterone derivative with an original activity profile, near to--but much more powerful than--progesterone itself, and devoid of androgenic, glucocorticoïd and oestrogenic activity. This particular profile confers to trimegestone its metabolic neutrality and concurs to the high degree of safety and tolerance observed in studies related to Totelle Cycle.


Sources of drinking water in a pediatric population.
The purpose of this study was to determine the primary sources of water used for consumption and cooking by the patients of a university-based pediatric dental practice. A simple, prewritten questionnaire-consisting of seven questions and available in English and Spanish-was conducted verbally with the caregivers of 123 pediatric patients during a designated timeframe. Analysis of responses included descriptive statistics and a chi-square test for a single proportion. Nonfiltered tap water accounted for the primary drinking water source in only 10 percent of the respondents. Firty-two percent of the respondents selected bottled water as the primary source of drinking water, and 24 percent selected vended water stations as a primary drinking water source. Nonfiltered tap water was much more likely to be utilized in cooking (58 percent). The majority of the patients in this study's pediatric dental practice do not consume fluoridated tap water. With the vast majority of the patients primarily consuming bottled or vended water, these patients are likely missing out on the caries-protective effects of water fluoridation.


Web-based tools for microRNAs involved in human cancer.
MicroRNAs (miRNAs/miRs) are a family of small, endogenous and evolutionarily-conserved non-coding RNAs that are involved in the regulation of several cellular and functional processes. miRNAs can act as oncogenes or tumor suppressors in all types of cancer, and could be used as prognostic and diagnostic biomarkers. Databases and computational algorithms are behind the majority of the research performed on miRNAs. These tools assemble and curate the relevant information on miRNAs and present it in a user-friendly manner. The current review presents 14 online databases that address every aspect of miRNA cancer research. Certain databases focus on miRNAs and a particular type of cancer, while others analyze the behavior of miRNAs in different malignancies at the same time. Additional databases allow researchers to search for mutations in miRNAs or their targets, and to review the naming history of a particular miRNA. All these databases are open-access, and are a valuable tool for those researchers working with these molecules, particularly those who lack access to an advanced computational infrastructure.


[Palliative gastric resection].
The surgical treatment of stomach carcinoma is reassessed. Stress is laid on the more aggressive attitude with regard to advanced gastric cancer where total or partial palliative resection is the only operation offering good results. This tendency emerges both from the series presented and those reported in the literature. It is concluded that if more aggressive surgery is justified in IVth stage stomach tumours it must still depend on the patient's general condition.


Traditional diet and food preferences of Australian aboriginal hunter-gatherers.
Until European settlement of Australia 200 years ago, Aborigines lived as nomadic hunter-gatherers all over the continent under widely varying geographic and climatic conditions. Successful survival depended on a comprehensive knowledge of the flora and fauna of their territory. Available data suggest that they were physically fit and lean, and consumed a varied diet in which animal foods were a major component. Despite this, the diet was not high in fat, as wild animal carcasses have very low fat contents through most of the year, and the meat is extremely lean. Everything on an animal carcass was eaten, including the small fat depots and organ meats (which were highly prized), bone marrow, some stomach contents, peritoneal fluid and blood. A wide variety of uncultivated plant foods was eaten in the traditional diet: roots, starchy tubers, seeds, fruits and nuts. The plant foods were generally high in fibre and contained carbohydrates, which was slowly digested and absorbed. Traditional methods of food preparation (usually baked whole or eaten raw) ensured maximum retention of nutrients. In general, traditional foods had a low energy density but high density of some nutrients. The low energy density of the diet and the labour intensity of food procurement provided a natural constraint on energy intake.(ABSTRACT TRUNCATED AT 250 WORDS)


Atopic disposition and bronchial reactivity to inhaled acetylcholine in young adults with a history of asthma in childhood.
The atopic disposition, indicated by positive skin reactions and IgE antibody titers etc., and the bronchial reactivity to inhaled acetylcholine were examined on the following three groups: (1) 20 young adults with a history of childhood asthma who have been symptom-free for more than 4 yr; (2) 20 current asthmatics, and (3) 20 healthy young adults. Young adults with a history of childhood asthma remained atopic in their disposition even after complete clinical remissions of their childhood asthma. However, they had a lower bronchial reactivity as compared with current asthmatics, although the bronchial reactivities of both groups were apparently higher than the control group.


FGF18 in colorectal tumour cells: autocrine and paracrine effects.
Fibroblast growth factors (FGFs) and their high-affinity receptors contribute to the autocrine growth stimulation in several human malignancies. Here, we describe that FGF18 expression is up-regulated in 34/38 colorectal tumours and is progressively enhanced during colon carcinogenesis reaching very high levels in carcinoma. Moreover, our data suggest that FGF18 affects both tumour cells and tumour microenvironment in a pro-tumorigenic and pro-metastatic way. Addition of recombinant FGF18 to the culture media of slowly growing colorectal tumour cell lines LT97 and Caco-2 stimulated proliferation. Phosphorylation of externally regulated kinase 1/2 and S6 was increased already 5 min after growth factor addition. SW480 cells, endogenously producing large amounts of FGF18, were not affected in this setting, but recombinant FGF18 supported tumour cell survival under conditions of serum starvation. Down-modulation of endogenous FGF18 production by small interference RNA (siRNA) significantly reduced clonogenicity of SW480 cells and restored sensitivity to exogenous FGF18. With respect to the tumour microenvironment, both recombinant and tumour-derived FGF18 stimulated growth of colon-associated fibroblasts at 0.1 ng/ml and migration at 10 ng/ml. In addition, recombinant FGF18 (10 ng/ml) induced tube formation in human umbilical vein endothelial cells. siRNA knock down demonstrated that tube-forming activity of colon cancer cell supernatants depended to a large part on tumour cell-derived FGF18. In summary, this study demonstrates that FGF18 is almost generally over-expressed in colon cancer and exerts pro-tumorigenic effects both in the epithelial and the stromal compartments by stimulating growth and survival of tumour cells, migration of fibroblasts and neovascularization. Together, these data strongly support an oncogenic role of FGF18 in colorectal cancer.


Interferon induction by two 2'-modified double-helical RNAs, poly(2'-fluoro-2'-deoxyinosinic acid) x poly(cytidylic acid) and poly(2'-chloro-2'-deoxyinosinic acid) x poly(cytidylic acid).
In addition to the 2'-azido analogue of (I)n x (C)n, (dIn3)n x (C)n, we have found two other (I)n x (C)n analogues, (dIfl)n x (C)n and (dIcl)n x (C)n, in which the 2'-hydroxyls of the (I)n strand are replaced by either fluorine or chlorine, to be highly effective in inducing interferon. This contrasted with the lack of interferon-inducing activity noted for various other 2'-halogeno analogues of (I)n x (C)n and (A)n x (U)n, i.e. (I)n x (dCcl)n, (dAfl)n x (U)n, (dAcl)n x (U)n, (A)n x (dUfl)n and (A)n x (dUcl)n. In most assay systems, viz. primary rabbit kidney cells, human diploid fibroblasts, HeLa cells, interferon-primed mouse L-929 cells, and intact rabbits, (dIfl)n x (C)n and (dIcl)n x (C)n induced interferon levels that were comparable to those induced by (I)n x (C)n. There was one particular system (L-929 cells treated with DEAE-dextran), however, in which (dIfl)n x (C)n and (dIcl)n x (C)n, unlike (I)n x (C)n, failed to stimulate interferon production. As monitored by both radiochemical and biological means, (dIfl)n x (C)n and, to a lesser extent, (dIcl)n x (C)n were more resistant to degradation by ribonuclease A, T1 and human serum nucleases than was (I)n x (C)n. In their reactivity towards antibodies to double-stranded RNA (dIfl)n x (C)n and (dIcl)n x (C)n conformed more closely to (I)n x (C)n than did other 2'-substituted (e.g. 2'-O-methyl or 2'-O-ethyl) analogues of (I)n x (C)n. The high interferon-inducing potency of (dIfl)n x (C)n and (dIcl)n x (C)n has both theoretical and practical implications. While our findings suggest that (dIfl)n x (C)n and (dIcl)n x (C)n should be further explored for their therapeutic potentials, they also strengthen the notion that the interferon-inducing capacity, and possibly other biological functions of double-stranded RNAs is dependent on the recognition of the overall conformation of the polynucleotide rather than on the binding of specific functional groups such as the 2'-hydroxyl group.


A comparison of stereological and computer-assisted histomorphometric analysis as tools for histological quantification in regenerative studies.
This study was designed to compare computer-assisted histomorphometric analysis (CAHA) and stereology (STER) as measurement tools for evaluating the repair response during periodontal wound healing. Thirty-six histological sections derived from 4 surgically created defects in the furcation of mandibular second premolars of sheep were measured by each technique to determine the furcation area and volume, and the percentage of new bone formation at 7 wk postoperatively. Slides were viewed in random order with the source unknown to the examiner (JL). One section from each of the 4 specimens was flagged for triplicate measurement by each technique. Intraexaminer error was determined to be low as the coefficient of variation in each of the 2 techniques was between 1% and 4%. A consistently higher percentage of bone was identified using stereology. The coefficient of agreement was plotted to determine how closely these 2 techniques were matched in their respective estimations of bone fill in a furcation defect. This analysis revealed statistical bias between the 2-techniques and a low degree of agreement between them. This study demonstrates that the 2 techniques are not interchangeable. It also emphasizes that the reader must be cautious when comparing results from studies in which different systems of measurement and analysis have been used. Stereology was determined to be the measurement tool of choice due to its high degree of reproducibility, ease of use and efficient use of time.


The mouse cornea as a transplantation site for live imaging of engineered tissue constructs.
The field of tissue engineering aims to recapitulate healthy human organs and 3-D tissue structures in vitro and then transplant these constructs in vivo where they can be effectively integrated within the recipient patient and become perfused by the host circulation. To improve the design of materials for artificial tissue scaffolds, it would be ideal to have a high-throughput imaging system that allows one to directly monitor transplanted tissue constructs in live animals over an extended period of time. By combining such an assay with transgenic, cell-specific fluorescent reporters, one could monitor such parameters as tissue construct perfusion, donor cell survival, and donor-host cell interaction/integration. Here, we describe a protocol for a modified version of the classical corneal micropocket angiogenesis assay, employing it as a live imaging "window" to monitor angiogenic poly(ethylene glycol) (PEG)-based hydrogel tissue constructs.


Evaluation of the implementation of advanced practice nursing roles in France: A multiple case study.
The aims of the study were to describe the processes used to introduce advanced practice nursing roles and factors that facilitated or hindered role implementation, examine the time advanced practice nurses (APNs) spend in role activities and how these activities relate to domains of advanced practice nursing and examine how implementation processes influenced APN integration within healthcare teams. A multiple case study was conducted. Five cases were included, representing the four population areas approved for advanced practice nursing in France. Data were collected from January to March 2021 using observation, interview and document analysis methods. Data were examined using thematic analysis. Participants included APNs (n = 5), nurses/allied health providers (n = 5), physicians (n = 5), managers (n = 4) and decision-makers (n = 4). Stakeholder engagement and leadership provided by decision-makers, managers, physicians and APNs facilitated role implementation. Poor stakeholder role understanding, uncertain role funding, and the COVID-19 pandemic hindered role implementation. APNs spent the most time in clinical activities. Participants perceived the integration of APNs within the healthcare team and their impact on patient care to be positive. Stakeholder engagement and organizational and APN leadership facilitated the implementation of the roles, especially related to team-based patient care. Further efforts are needed to strengthen APN involvement in non-clinical activities and address role barriers. Systematic and system-wide approaches are needed to improve role clarity, role autonomy and health systems integration of APNs. Research should examine patient perspectives about APNs in France. The results highlight how policies can create favourable conditions for advanced practice nursing role implementation in France. Internationally, this study serves as a reminder to APNs and nurse leaders about the strategies for and importance of implementation evaluation to support the optimal development of advanced practice nursing roles. The study reporting followed the Consolidated Criteria for Reporting Qualitative Research. No Patient or Public Contribution.


Nebulized Fentanyl for Dyspnea in a Hospice Patient with True Allergy to Morphine and Hydromorphone.
An 86-year-old white female was admitted to hospice care with lung cancer. Even with optimal medical management, she suffered from dyspnea and required opioid therapy. However, the patient had a true morphine and hydromorphone allergy. She was administered nebulized fentanyl for symptomatic relief of dyspnea with good effect and she did not experience any allergic response.


Unfavourable environment limits social conflict in Yuhina brunneiceps.
Identifying the factors that modulate cooperative and competitive behaviours is the key to understanding social evolution. However, how ecological factors affect social conflict and their fitness consequences remain relatively unexplored. Here, using both a game-theoretical model and empirical data, we show that Taiwan yuhinas (Yuhina brunneiceps)--a joint-nesting species in which group members are unrelated--employ more cooperative strategies in unfavourable environmental conditions. Fighting duration was lower, fewer total eggs were laid and incubation was more likely to start after all females completed egg laying (which causes more synchronous egg hatching). Surprisingly, as a consequence, there were more surviving offspring in unfavourable conditions because the cooperative strategies resulted in fewer dead nestlings. To our knowledge, this study is the first theoretical analysis and empirical study demonstrating that an unfavourable environment reduces social conflict and results in better fitness consequences in social vertebrates.


Identification of a contact region between the tridecapeptide alpha-factor mating pheromone of Saccharomyces cerevisiae and its G protein-coupled receptor by photoaffinity labeling.
Saccharomyces cerevisiae haploid cells communicate with their opposite mating type through peptide pheromones (alpha-factor and a-factor) that activate G protein-coupled receptors (GPCRs). S. cerevisiaewas used as a model system for the study of peptide-responsive GPCRs. Here, we detail the synthesis and characterization of a number of alpha-factor (Trp-His-Trp-Leu-Gln-Leu-Lys-Pro-Gly-Gln-Pro-Met-Tyr) pheromone analogues containing the photo-cross-linkable group 4-benzoyl-L-phenylalanine (Bpa). Following characterization, one analogue, [Bpa(1), Tyr(3), Arg(7), Phe(13)]alpha-factor, was radioiodinated and used as a probe for Ste2p, the GPCR for alpha-factor. Binding of the di-iodinated probe was saturable (K(d) = 200 nM) and competable by alpha-factor. Cross-linking into Ste2p was specific for this receptor and reversed by the wild-type pheromone. Chemical and enzymatic cleavage of the receptor/radioprobe complex indicated that cross-linking occurred on a portion of Ste2p spanning residues 251-294 which encompasses transmembrane domain 6, the extracellular loop between transmembrane domains 6 and 7, and transmembrane domain 7. This fragment was verified using T7-epitope-tagged Ste2p and a biotinylated, photoactivatable alpha-factor. After cross-linking with the biotinylated photoprobe and trypsin cleavage, the cross-linked receptor fragment was revealed by both an anti T7-epitope antibody and a biotin probe. This is the first determination of a specific contact region between a Class IV GPCR and its ligand. The results demonstrate that Bpa alpha-factor probes are useful in determining contacts between alpha-factor and Ste2p and initiate mapping of the ligand binding site of this GPCR.


Intimate partner violence screening in the emergency department: U.S. medical residents' perspectives.
Intimate Partner Violence (IPV) is physical, psychological, or sexual harm committed by a current or former partner, spouse, boy/girlfriend. In the United States, the National Center for Injury Prevention and Control (2003) estimates that 1.5 million women experience physical assault each year while the lifetime prevalence rate of IPV for women reaches almost 30%. Given the frequency and range of injuries and other health-related problems that result from IPV, the medical system shows promise as a central source of service provision for large numbers of abused women and their children. However, identification rates of IPV in many medical settings are low. This article describes a study that examined focus group data from 25 physicians in residency training at an urban hospital in the United States. Physicians discussed their knowledge and attitudes about IPV screening in the emergency department (ED) setting and suggestions to address perceived barriers to such screening. These data depict multiple barriers to physician screening of IPV in the ED. Findings substantiate previous research and provide new direction for enhancing IPV identification, referral, and treatment mechanisms in the ED setting including alternatives to physician mandated universal screening.


Archaic introjects and the cosmology of H.G. Wells.
The roles of the archaic loving and hating introjects are traced in the early scientific romances and the life work of H.G. Wells. The preambivalent polarization of the early loving introjects of an archaic ego ideal (giving rise to utopian fantasies and, later, to promulgations of a new world state) and the early hostile introjects of an archaic superego (giving rise to fears of death and, later, to fears of cosmic dissolution) is represented in eschatological preoccupations with death, the Last Judgment, heaven and hell. These religious preoccupations are derivatives of wishes for maternal union and bliss on the one hand, and of castration anxiety and fears of personal annihilation on the other. Further transformations of the archaic introjects are traced through an indentification with the role of redeemer, and later, through his scientific studies, to an espousal of T.H. Huxley's teachings of organic evolution and to the development of cosmological themes in his work.


Levodopa-resistant freezing of gait and executive dysfunction in Parkinson's disease.
We examined executive functioning in patients with Parkinson's disease exhibiting, or not, levodopa-resistant freezing of gait (L-FOG). 38 advanced-stage patients with L-FOG were identified in a consecutive series of 400 patients. They were matched with 38 patients without L-FOG. All patients underwent prospective evaluations of cognitive and motor functioning before subthalamic nucleus surgery, and 1 year after. A composite frontal score, a measure of executive functioning, was compared between the two groups. We also examined correlations between the frontal score and the score on the FOG item of the Unified Parkinson Disease Rating Scale II. Results show that after surgery, patients with L-FOG, as a group, were more impaired in executive functioning than control patients. However, individual data analysis showed preserved executive functions in 11 patients with L-FOG. In addition, there was no correlation between L-FOG severity and the degree of executive impairment. Therefore, frontal dysfunction may be one mechanism underlying L-FOG in a number of patients with Parkinson's disease. However, since some patients develop L-FOG despite the preservation of executive functions, lesions or dysfunction of other neuronal structures are likely to be involved.


Nicotiana (Nicotiana tobaccum, Nicotiana benthamiana).
Agrobacterium-mediated transformation of Nicotiana species, namely, Nicotiana tobaccum and Nicotiana benthamiana, using leaf disks as the target explant has provided the plant community with a valuable tool for rapid evaluation of transgenes in higher plants. This protocol has a number of desirable attributes: readily available explant material, high efficiency, and a relatively quick turnaround time. The in vitro regeneration scheme of the leaf disks is prolific and follows an indirect organogenic differentiation. N. tobaccum and N. benthamiana are highly susceptible to a variety of disarmed A. tumefaciens strains, and the transformation system is amenable to a number of selection agents. This protocol has proved to be easily transferable to a point at which a single investigator with minimal training can generate thousand of events per year. Moreover, seed size and quantity per event permit monitoring of segregation in Petri plates, and sufficient biomass can be accrued from an individual plant, which can be either clonally propagated or allowed to self-pollinate or easily outcrossed.


Supramolecular Assays for Mapping Enzyme Activity by Displacement-Triggered Change in Hyperpolarized (129)Xe Magnetization Transfer NMR Spectroscopy.
Reversibly bound Xe is a sensitive NMR and MRI reporter with its resonance frequency being influenced by the chemical environment of the host. Molecular imaging of enzyme activity presents a promising approach for disease identification, but current Xe biosensing concepts are limited since substrate conversion typically has little impact on the chemical shift of Xe inside tailored cavities. Herein, we exploit the ability of the product of the enzymatic reaction to bind itself to the macrocyclic hosts CB6 and CB7 and thereby displace Xe. We demonstrate the suitability of this method to map areas of enzyme activity through changes in magnetization transfer with hyperpolarized Xe under different saturation scenarios.


Detection of Streptococcus species by polymerase chain reaction in infectious crystalline keratopathy.
Investigation of a positive polymerase chain reaction (PCR) for Streptococcus species from an excised cornea of a patient with infectious crystalline keratopathy. Samples microdissected from corneal intrastromal aggregates present in infectious crystalline keratopathy were subjected to PCR for 3 primer pairs respectively specific for Streptococcus, Staphylococcus, and several kinds of fungi. The PCR detected DNA from Streptococcus but not from Staphylococcus or fungi. Direct sequencing of the PCR products showed that the PCR products had the highest identity (99.8%) with Streptococcus mitis and Streptococcus gordoni, indicating that these species were the most probable causes of infectious crystalline keratopathy in this patient. Our findings suggest that PCR provides a good adjunct technique in the diagnosis of corneal infection.


[Ultrasound-guided cytopuncture and hepatic microbiopsy in focal lesions of the liver. Apropos of 160 cases].
A retrospective study was carried out in 160 patients explored by ultrasound guided cytopuncture and hepatic microbiopsy for focal lesions of liver over a 5 1/2 year period. Results are analyzed as a function of clinical and ultrasound findings, the frequency of unexpected histology (20 cases) being emphasized and justifying the wide use of hepatic microbiopsy.


Territorial issues addressed through regionalization.
Possibly no structural issue in blood banking is as problematic as that of service "territory." The Regionalization Program of the American Blood Commission has worked with numerous regions in an effort to achieve a rational resolution of territorial issues. This paper discusses approaches utilized by these regions and results achieved. It provides a discussion of an alternate model that facilitates resolution of some problems. This information may be beneficial to regions that encounter similar problems.


[Health education and people's participation in health in Nicaragua: research on the profile, role and function of the "brigadistas populares" in health].
The Nicaraguan democratic government has been building, since the defeat of somozism in 1979, a very extensive and uniform health system in the whole country, giving special attention to the problems of prevention and health education, promoting and utilizing a wide participation of the population. The most emblematic representative of the Nicaraguan model of participation is the Brigadista Popular en Salud, a voluntary figure in urban and rural areas, working along side the Sole National Health System. The work and role of the Brigadista is integrated in a health education action defined "Educaciòn Popular en Salud", intended as a dialogue through which the educator and educated, beginning with the specific political and economical social reality, accomplish work of observation, analysis and syntesis of the different phenomena that deal with health-sickness. The Brigadista is a member of the community that works voluntarily for the community to carry out health actions, in coordination with the "Puesto de Salud" of the community. The authors refer to a research study done in the field in 1987, geared to study the profile, role and activities of the Brigadista. The research was done in the "Las Segovias" Region, in the Northern part of the country, in two Health Areas, involving three urban centers and six rural communities: 73 Brigadistas were interviewed, of which 50 (predetermined) of urban centers and 23 (total population) in rural communities. The article represents in a comparative manner the operative Brigadista respectively, in urban areas on the one hand and in rural areas on the other. The article examines: sex; age; schooling; work activity; social-cultural background; collective systems background; participation in Literacy Campaigns; motivation; length and continuity of activities; relationship with the territory; activities done. The Brigadista that works in rural areas seems actually to be more attached, even to the formal image of his role, that the urban Brigadista. This is shown by the reduced turn-over, the wider span of functions, the closer relationship with collective systems that represent categories, a more intense relationship with colleagues of the health system as well as with other Brigadistas, the operative reference to specificity defined territories, more continuity in the functions of the Brigadista Popular en Salud.


3D printing of modified-release aminosalicylate (4-ASA and 5-ASA) tablets.
The aim of this study was to explore the potential of fused-deposition 3-dimensional printing (FDM 3DP) to produce modified-release drug loaded tablets. Two aminosalicylate isomers used in the treatment of inflammatory bowel disease (IBD), 5-aminosalicylic acid (5-ASA, mesalazine) and 4-aminosalicylic acid (4-ASA), were selected as model drugs. Commercially produced polyvinyl alcohol (PVA) filaments were loaded with the drugs in an ethanolic drug solution. A final drug-loading of 0.06% w/w and 0.25% w/w was achieved for the 5-ASA and 4-ASA strands, respectively. 10.5mm diameter tablets of both PVA/4-ASA and PVA/5-ASA were subsequently printed using an FDM 3D printer, and varying the weight and densities of the printed tablets was achieved by selecting the infill percentage in the printer software. The tablets were mechanically strong, and the FDM 3D printing was shown to be an effective process for the manufacture of the drug, 5-ASA. Significant thermal degradation of the active 4-ASA (50%) occurred during printing, however, indicating that the method may not be appropriate for drugs when printing at high temperatures exceeding those of the degradation point. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of the formulated blends confirmed these findings while highlighting the potential of thermal analytical techniques to anticipate drug degradation issues in the 3D printing process. The results of the dissolution tests conducted in modified Hank's bicarbonate buffer showed that release profiles for both drugs were dependent on both the drug itself and on the infill percentage of the tablet. Our work here demonstrates the potential role of FDM 3DP as an efficient and low-cost alternative method of manufacturing individually tailored oral drug dosage, and also for production of modified-release formulations.


Neuropeptide-gated perception of appetitive olfactory inputs in Drosophila larvae.
Understanding how smell or taste translates into behavior remains challenging. We have developed a behavioral paradigm in Drosophila larvae to investigate reception and processing of appetitive olfactory inputs in higher-order olfactory centers. We found that the brief presentation of appetitive odors caused fed larvae to display impulsive feeding of sugar-rich food. Deficiencies in the signaling of neuropeptide F (NPF), the fly counterpart of neuropeptide Y (NPY), blocked appetitive odor-induced feeding by disrupting dopamine (DA)-mediated higher-order olfactory processing. We have identified a small number of appetitive odor-responsive dopaminergic neurons (DL2) whose activation mimics the behavioral effect of appetitive odor stimulation. Both NPF and DL2 neurons project to the secondary olfactory processing center; NPF and its receptor NPFR1 mediate a gating mechanism for reception of olfactory inputs in DL2 neurons. Our findings suggest that eating for reward value is an ancient behavior and that fly larvae are useful for studying neurobiology and the evolution of olfactory reward-driven behavior.


Quantitative Structure Activity Relationship study of the Anti-Hepatitis Peptides employing Random Forests and Extra-trees regressors.
Antimicrobial peptides are host defense peptides being viewed as replacement to broad-spectrum antibiotics due to varied advantages. Hepatitis is the commonest infectious disease of liver, affecting 500 million globally with reported adverse side effects in treatment therapy. Antimicrobial peptides active against hepatitis are called as anti-hepatitis peptides (AHP). In current work, we present Extratrees and Random Forests based Quantitative Structure Activity Relationship (QSAR) regression modeling using extracted sequence based descriptors for prediction of the anti-hepatitis activity. The Extra-trees regression model yielded a very high performance in terms coefficient of determination (R2) as 0.95 for test set and 0.7 for the independent dataset. We hypothesize that the developed model can further be used to identify potentially active anti-hepatitis peptides with a high level of reliability.


The relationship between glomerular filtration rate and sodium reabsorption by the proximal tubule of the rat nephron.
We have tested two of the hypotheses proposed to explain the adjustment in sodium reabsorption in the proximal tubule that follows a change in the rate of glomerular filtration (glomerulotubular balance). Using the recollection micropuncture technique, we were able to measure the immediate and late changes in reabsorptive rate after an acute alteration in filtration rate produced by aortic constriction and release of constriction. It was found that fractional reabsorption, as measured by the inulin tubule fluid to plasma (TF/P) ratio, increased after aortic constriction and decreased after release, but that in most instances, absolute reabsorptive rate changed in parallel to glomerular filtration rate. The change was similar whether the collections were made less than 1 or more than 5 min after the change in blood pressure. The rapid time course of this adjustment in reabsorptive rate is viewed as evidence against an intrarenal humoral feedback mechanism. In the same experiments we measured the (TF/P)(In), transit time, and flow rate of fluid in single nephrons before and during aortic constriction or release of aortic constriction. The change in reabsorptive rate and the simultaneous change in calculated cross-sectional area of the tubule lumen were rarely proportional, i.e., C/pir(2) was not constant. In other experiments, these same measurements were made before and during periods of increased ureteral pressure. Despite large increments in calculated cross-sectional area, the absolute rate of reabsorption either remained relatively unchanged or fell in proportion to the change in filtration rate. It is concluded that under these conditions, reabsorptive rate is governed by some factor other than tubule geometry.


Akt is a major angiogenic mediator downstream of the Ang1/Tie2 signaling pathway.
Tie2 and VEGF receptors (VEGFRs) are tyrosine kinases that play essential roles in angiogenesis. Activation of both receptors leads to the activation of Akt, an important mediator of cell survival and cell motility. In this study, we compared the role of Akt in Tie2-mediated versus VEGF-mediated endothelial cell (EC) survival and EC sprouting. Our data show that Akt is required and sufficient to mediate Ang1-induced EC survival in response to growth factor depletion. Blocking Akt function abolishes angiopoietin 1 (Ang1), a ligand for Tie2, mediated EC survival, and activating Akt rescues a Tie2 blockade-induced EC apoptosis. In contrast, activating Akt rescues EC apoptosis induced by a VEGF blockade, but interestingly, blocking Akt function has no effects on VEGF-induced EC survival, demonstrating that Akt is sufficient but not required for VEGF-mediated EC survival. In addition, we show that both Ang1 and VEGF induce EC sprouting in a three-dimensional collagen gel, which depends on the activation of Akt. Blocking Akt action inhibited EC sprouting induced by Ang1 or VEGF. Therefore, the data show that Akt is the primary mediator of Ang1-induced EC survival while multiple pathways are involved downstream of VEGF responsible for EC survival. However, Akt is required and sufficient to mediate the EC sprouting induced by both Ang1 and VEGF.


Streptococcal infections and their sequelae in the upper respiratory tract.
Local sequelae of group A beta-hemolytic streptococci (GABHS) are common and can vary from otitis media, sinusitis, cervical adenitis associated with generalized adenopathy, peritonsillitis and persisting symptoms in spite of therapy, GABHS is one of the pathogens isolated in acute or chronic otitis media and in acute maxillary sinusitis. In cervical adenitis associated with generalized adenopathy GABHS is, along with S. aureus, the most commonly recovered bacteria. In peritonsillitis, GABHS can be recovered alone or in combination with anaerobes in 50% of the cases. These sequelae are usually associated with a slow clinical response to therapy and a high percentage of relapses, reinfections, and chronic infections in the presence of a penicillin-sensitive GABHS. One of the possible causes of these so-called failures is the interference that beta-lactamase producing bacteria can have on the activity of penicillin and similar compounds. When to select a beta-lactamase-resistant antibiotic for the treatment of an apparent penicillin-sensitive infection remains an important area for further research.


Performance of Momguard, a new non-invasive prenatal testing protocol developed in Korea.
To evaluate the performance of Momguard, non-invasive prenatal test (NIPT) for detecting trisomy (T) 21, T18, T13, and sex-chromosome abnormalities recently developed in Korea. This preliminary study formed part of a large prospective cohort study conducted at Asan Medical Center, Seoul, Korea. Only pregnant women who underwent both NIPT and confirmatory karyotyping were included in this study. NIPT results were compared with those of karyotype analyses. Among 93 eligible cases, NIPT results could not be obtained in one case due to a low fetal cell-free DNA fraction. Based on NIPT, eight cases of fetal aneuploidies, including T21 (n=5), T18 (n=2), and T13 (n=1), were identified. For T21 and T18, the sensitivity and specificity of NIPT were both 100%, with a false-positive and false-negative rate of 0% and a positive-predictive value of 100%. One patient classified as having intermediate risk for T13 by NIPT was confirmed to have T13 by karyotyping, and there were no false-negative cases. No cases of sex-chromosome anomalies were detected by NIPT or karyotyping during the study period. Momguard is a reliable screening tool for detecting T21 and T18. For T13 and sex-chromosome anomalies, further prospective studies are necessary to confirm its utility.


Search for the presence of glucocorticoid receptors in dopaminergic neurons of rat ventral tegmental area and substantia nigra.
Using non-fluorescent immunocytochemical double-labelling procedure and specific antibodies visualizing GR (glucocorticoid receptors) and TH (tyrosine hydroxylase) we have been looking for the co-localization of both antigens in neurons of the rat ventral tegmental area and adjacent substantia nigra. This experimental direction has been inspired by the available data showing that alterations in the level of circulating glucocorticosteroids have distinct effects on the intensity of dopaminergic neurotransmission. Thus, it was of interest to find the anatomical background for the above interaction. It has been found that the rat ventral tegmental area and substantia nigra possess a relatively moderate number of cells with active GR, i.e. receptors which are condensed in the nuclei. Further, we found that dopaminergic neurons (TH-positive) of the ventral tegmental area and substantia nigra were not immunopositive for GR. This observation was in the sharp contrast to the results from the locus coeruleus, where the co-localization of GR with TH was a general rule. Above anatomical data indicate that glucocorticoid receptors influence the dopaminergic neurotransmission by an indirect mechanism, which possibly involves intermittent neurotransmitter.


Characterizing the role of MDM2 in diethylnitrosamine induced acute liver damage and development of pre-neoplastic lesions.
Pre-neoplastic lesions in rodent liver often express high levels of MDM2 and lack a p53 response to DNA damage. The question we posed was whether there is a liver-specific regulation of the p53/MDM2 feedback loop and if it can be related to the development of pre-neoplastic lesions, referred to as enzyme altered foci (EAF) in rats. Acute responses of p53 and MDM2 to diethylnitrosamine (DEN) were characterized by employing immunohistochemistry, western blotting, RT-PCR and in situ hybridization. A single dose of DEN induced a centrilobular p53 response that peaked at 24 h. It was associated with transcriptional activation of MDM2 and signs of apoptosis. However, in midzonal hepatocytes, which constitutively expressed high levels of cytoplasmic MDM2, there was a rapid-onset but transient p53 response. It was terminated at 24 h and there were no signs of apoptosis. The rapidly declining p53 levels in midzonal areas was preceded by a transient peak in MDM2 mRNA levels at 6 h. Rats pre-treated with repeated low or high weekly doses of DEN exhibited EAF and these lesions expressed high levels of cytoplasmic MDM2. Using MDM2 as a marker for EAF gave similar results as using glutathione transferase-P (GST-P) as a marker. Furthermore, small EAF, elicited by low doses of DEN, were preferentially localized to midzonal areas. It is concluded that in centrilobular areas DEN-induced alterations in p53/MDM2 levels are compatible with a previously described feedback loop. An attenuated p53 response in midzonal hepatocytes can be related to a high constitutive expression of MDM2 in these cells. The localization of small EAF to midzonal areas, and the fact that EAF cells expressed high levels of MDM2, indicates that MDM2 expression is a factor governing initiation and early development of EAF. The data support the hypothesis that EAF hepatocytes are initiated via epigenetic mechanisms.


In vivo regulation of chromogranin A messenger ribonucleic acid in the parathyroid by 1,25-dihydroxyvitamin D: studies in normal rats and in chronic renal insufficiency.
Chromogranin-A (CgA) and PTH are the two major secretory products of the parathyroid gland. In vitro, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] increases CgA, but decreases PTH messenger RNA (mRNA) levels. We investigated the physiological significance of the induced changes in CgA expression by examining the effects of 1,25-(OH)2D3 on parathyroid CgA mRNA levels in vivo. Normal rats were injected with 1,25-(OH)2D3 at 48 and 24 h before blood sampling and isolation of both parathyroid glands. Parathyroid total RNA was extracted and CgA and PTH mRNA quantified by Northern blot analysis. CgA mRNA levels increased 1.6-, 3.2- and 5.6-fold, whereas PTH mRNA levels decreased by 37, 63 and 97%, respectively, with 1,25-(OH)2D3 doses of 10, 50, and 250 pmol/100 g BW. Parathyroid gland CgA expression also was examined in rats with mild chronic renal insufficiency, induced by a 5/6 nephrectomy 5 weeks earlier. Chronic renal insufficiency rats, fed normal chow, had elevated serum urea, creatinine, and PTH levels and reduced 1,25-(OH)2D3 but normal serum levels of calcium and phosphate. PTH mRNA levels were elevated 4-fold and CgA mRNA levels were 50% lower in the uremic animals. This indicates that the regulation of CgA expression in normocalcemic rats occurs at physiological 1,25-(OH)2D3 concentrations. In summary, increases and decreases in serum 1,25-(OH)2D3 levels are associated with corresponding increases and decreases in CgA mRNA levels in the parathyroid glands of rats. Therefore, this study is the first to demonstrate the physiological relevance of the earlier in vitro observations.


[Spatial temporal differentiation of product-based and consumption-based CO2 emissions and balance in the Beijing-Tianjin-Hebei region: an economic input- output analysis].
Distinguishing product-based and consumption-based CO2 emissions in the open economic region is the basis for differentiating the emission responsibility, which is attracting increasing attention of decision-makers'attention. The spatial and temporal characteristics of product-based and consumption-based CO2 emissions, as well as carbon balance, in 1997, 2002 and 2007 of JING- JIN-JI region were analyzed by the Economic Input-Output-Life Cycle Assessment model. The results revealed that both the product- based and consumption-based CO2 emissions in the region have been increased by about 4% annually. The percentage of CO2 emissions embodied in trade was 30% -83% , to which the domestic trading added the most. The territorial and consumption-based CO2 emissions in Hebei province were the predominant emission in JING-JIN-JI region, and the increasing speed and emission intensity were stronger than those of Beijing and Tianjin. JING-JIN-JI region was a net inflow region of CO2 emissions, and parts of the emission responsibility were transferred. Beijing and Tianjin were the net importers of CO2 emissions, and Hebei was a net outflow area of CO2 emissions. The key CO2 emission departments in the region were concentrated, and the similarity was great. The inter-regional mechanisms could be set up for joint prevention and control work. - Production and distribution of electricity, gas and water and smelting and pressing of metals had the highest reliability on CO2 emissions, and took on the responsibility of other departments. The EIO-LCA model could be used to analyze the product-based and consumption-based CO2 emissions, which is helpful for the delicate management of regional CO2 emissions reduction and policies making, and stimulating the reduction cooperation at regional scale.


RNase H1 can catalyze RNA/DNA hybrid formation and cleavage with stable hairpin or duplex DNA oligomers.
Cleavage of a RNA target site by RNase H1 from Escherichia coli was examined in the presence of complementary DNA sequences in the form of single-stranded, duplex, and hairpin structures. The target site was a 15 nt sequence in the middle of a 79 nt RNA transcript. DNA molecules employed included seven single-stranded oligodeoxynucleotides 10 or 15 nt long, and five hairpin DNAs each with a 10 bp stem and 5 nt loop. The loop and 3' side of the stem of two of the hairpin DNAs were fully complementary to the target site, while the other hairpin DNAs had sequence changes. A 10 bp duplex DNA with one strand complementary to the target site was also employed. A gel electrophoresis mobility shift assay examined hybrid formation between the RNA and the single-stranded 15 nt DNA and two hairpin DNAs that contained 15 complementary bases. RNA titration of the 32P-labeled single-stranded DNA produced a shifted band indicative of RNA/DNA complex formation. No RNA/DNA complex was detected when the more stable (Tm = 71 degrees C) hairpin DNA was combined with excess RNA. The less stable hairpin DNA (Tm = 62 degrees C) showed a small amount ( approximately 8%) of hybrid formation. Thermodynamic analysis of RNA binding to the DNAs was in qualitative agreement with the results. Although no RNA/DNA hybrid was expected from thermodynamic calculations, a RNase H assay at 25 degrees C showed that hairpin or duplex DNAs with a 10 nt complementary sequence catalyzed RNA degradation. A complementary loop sequence in the hairpin DNA was not required. Cleavage of the RNA did not occur with hairpin DNAs containing three or four noncomplementary bases in the stem. The results show that RNase H can promote the formation and cleavage of a RNA/DNA hybrid between an RNA site and a base paired strand of a stable hairpin or duplex DNA at temperatures below their Tm.


Structural insights of a SusD-like protein in marine Bacteroidetes bacteria reveal the molecular basis for chitin recognition and acquisition.
Efficient recognition and transportation of chitin oligosaccharides are crucial steps for the utilization of chitin by heterotrophic bacteria. In this study, we employed structural biological and biochemical approaches to investigate the substrate recognition and acquisition mechanism of a novel chitin-binding SusD-like protein, AqSusD, which is derived from the chitin utilization gene cluster of a marine Bacteroides strain (Aquimarina sp. SCSIO 21287). We resolved the crystal structures of the AqSusD apo-protein and its complex with chitin oligosaccharides. Our results revealed that some crucial residues (Gln67, Phe87, and Asp276) underwent significant conformational changes to form tighter substrate binding sites for ligand binding. Moreover, we identified the functions of key amino acid residues and discovered that π-π stacking and hydrogen bonding between AqSusD and the ligand played significant roles in recognition of the protein for chitin oligosaccharide binding. Based on our findings and previous investigations, we put forward a model for the mechanism of chitin oligosaccharide recognition, capture, and transport by AqSusD, in collaboration with the membrane protein AqSusC. Our study deepens the understanding of the molecular-level "selfish" use of polysaccharides such as chitin by Bacteroides.


Syndrome of inappropriate antidiuretic hormone secretion induced by the phytotherapy Harpagophytum procumbers: case report.
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the inability of antidiuretic hormone (ADH) suppression, compromising the mechanisms of water excretion and urinary concentration. It manifests as hyponatremia and its symptoms, especially neurological. There are many causes that trigger such disease, notably: central nervous system disorders, malignant neoplasm, drugs and others. A 65 years female hypertensive patient presented clinical and laboratory manifestations of hyponatremia due to SIADH. It happened twice under use of herbal medication for osteoarthritis treatment. The drug-related hyponatremia can be triggered by direct effect of the drug or by association with SIADH. The clinical manifestations presented could have been related to psychiatric condition and may have severe outcome if not properly diagnosed. The association of an herbal medicine to SIADH could be confirmed after a new episode of hyponatremia related to Harpagophytum procumbers reintroduction. Our literature review did not find this herbal medicine associated with SIADH, so far. SIADH may be caused by herbal medicine described from now on their association in the literature.


Glycemic control with continuous subcutaneous insulin infusion with use of U-500 insulin in a pregnant patient.
To demonstrate the benefits and to advocate the safety and efficacy of using an insulin pump with U-500 insulin in comparison with U-100 insulin for a pregnant patient with diabetes requiring massive doses of insulin. We present a detailed case report about the use of continuous subcutaneous insulin infusion with U-500 insulin during pregnancy. Dose calculation is reviewed, and the benefits of insulin pump therapy in patients with diabetes are discussed. A 34-year-old white woman, with a history of type 2 diabetes for 7 years, was seen at 17 weeks of gestation because of episodes of hyperglycemia and hypoglycemia accompanied by a very high insulin requirement. At the time of initial assessment, the patient was hospitalized with diabetic ketoacidosis and was being treated with 400 U/day of intravenously administered insulin. She responded well to intravenous therapy, but when switched to a regimen of NPH and regular insulin, she continued to have high blood glucose levels (despite 4 to 5 insulin injections a day, with a total daily dose up to 400 to 450 U). Use of an insulin pump was instituted, which presented another challenge because of the limited reservoir capacity and the need to change sites at least once or twice a day. We decided to initiate U-500 insulin therapy with a total basal rate of 40 U/day. Her meal carbohydrate insulin ratio and correction bolus were calculated on a U-100 scale. Then each estimated dose for meal coverage, depending on her carbohydrate intake, as well as the appropriate corrections were totaled and divided by 5 to convert to U-500. Throughout the rest of her pregnancy, the patient was able to maintain tight glycemic control, with no further hospitalizations for stabilization of hyperglycemia or hypoglycemia. To our knowledge, this is the first report of successful management of difficult to control diabetes by means of an insulin pump with use of U-500 insulin in a pregnant patient who required massive doses of insulin.


Alkaloids of Ocotea brachybotra.
Aporphine, proaporphine and morphinane alkaloids were isolated from the leaves of a Brazilian Lauracea, Ocotea brachybotra (Meiss.) Mez. The known alkaloids were identified through their physico-chemical properties as: (I) (+/-)-glaziovine, (II) dicentrine, (III) ocopodine, (IV) cassynthicine, (V) predicentrine, (VI) leucoxine, (IX) sinacutine and (X) pallidine. The structure of (VI) leucoxine was confirmed by a detailed analysis of the N.M.R. spectra recorded in various conditions. New morphinane alkaloids, (XI) ocobotrine and (XII) 14-espisinomenine, having the unusual B/C-trans configuration were also isolated. Their structures were determined using spectroscopic methods and chemical correlations.


[Comparison of color character of VITA shade guide and the custom shade guide].
To compare the color character of VITA shade guide and the custom shade guide with metal substrate. Color of 9 sites of 5 series of VITA shade guides and custom shade guides with metal substrate were measured by means of PR-650 spectrophotometer. The color range of VITA shade guide were that L* was 56.86-73.86, a* was-1.29-3.69, b* was 7.09-21.94, and the transparence was 3.20-7.59. The color range of the custom shade guide was that L* was 60.59-78.54, a* was -1.09-4.99, b* was 7.60-22.35, and the transparence was 0.23-10.98. L*, a* and b* of the custom shade guide with metal substrate were higher than VITA shade guide, and the transparence was differet. The color difference of homonymy shade tab between custom shade guide and VITA shade guide was larger than 1.5 NBS. There is color difference between VITA shade guide and custom shade guide. Metal substrate has effects on the color of cero-metal prosthesis, and color selection in clinic should be carefully considered.


Outpatient theophylline determinations.
The indications and usefulness of outpatient serum theophylline determinations were prospectively evaluated by doing 151 of these studies in 137 consecutive cases of chronic obstructive pulmonary disease. We found that evaluations were done for the following three groups of indications: group A, worsening bronchospasm; group B, stable asymptomatic cases, and group C, symptoms suggesting theophylline toxicity. When the three clinical groups were compared for frequency of nontherapeutic values, only an increased frequency of subtherapeutic values in patients with bronchospasm (group A) was significant (P<.01). Increasing the dosage up to 15 mg per kg of body weight a day while theophylline determinations are pending appears to be safe in this group of patients. Toxic symptoms were rarely associated with concentrations greater than 20 mug per ml (3/13) and infrequently occurred in patients with concentrations greater than 20 mug per ml (3/29). Nontherapeutic theophylline values did not always result in an adjustment of theophylline dosage. This was influenced by a correlation of symptoms, timing of the theophylline determination and the use of other bronchodilators.


Measuring agreement between diagnostic devices.
There is growing interest in using portable monitoring for investigating patients with suspected sleep apnea. Research studies typically report portable monitoring results in comparison with the results of sleep laboratory-based polysomnography. A systematic review of this research has recently been completed by a joint working group of the American College of Chest Physicians, the American Thoracic Society, and the American Academy of Sleep Medicine. The methods for comparing the results of portable monitors and polysomnography include product-moment correlation, intraclass correlation, mean differences/limits of agreement, sensitivity, specificity, and likelihood ratios. Each approach has advantages and limitations, which are highlighted in this review.


Intracellular thiol concentration modulating inflammatory response: influence on the regulation of cell functions through cysteine prodrug approach.
Oxidative stress is defined as the consequence of overpowering of the immune system's reaction, which causes increased production of the reactive oxidative species (ROS) greater than the antioxidant protection. Tissue injury and oxidation of the circulating molecules may be the consequences. Moreover, the sulphur-containing amino acids (SAA) fate is perturbed during stress. The altered biochemical rules during inflammation weaken the anti-oxidant mechanism, and the extra-supply of SAA under inflammatory conditions can help to restore homeostasis. In brief, the main biochemical steps during inflammation are: The production of Cytokines, Acute Phase Protein, and Glutathione (GSH) pool are strongly modified during inflammation. The GSH participates in many important physiological processes controlling the homeostasis of the cells. A higher demand of Cysteine (Cys) supply causes difficulties in maintaining a constant GSH level. The role of GSH as a key regulator of thiol redox intracellular balance is established. This reveals that GSH is essential in regulating the cell's life cycle and that the reduction of intracellular GSH contributes to chronic inflammation. The fact that Cys availability is generally a limiting factor for the GSH synthesis stimulated the development of a pharmacologically useful Cys pro-drug. The simplest derivative is N-acetylcysteine (NAC), which appears to be the prototype of all Cys suppliers. Different approaches are presented here.


Defective group-II metaboropic glutamate receptors in the hippocampus of spontaneously depressed rats.
Spontaneously depressed flinders sensitive line (FSL) rats showed a reduced expression of mGlu2/3 metabotropic glutamate receptors in the hippocampus, as compared to "non-depressed" flinders resistant line (FRL) rats. No changes in mGlu2/3 receptor protein levels were found in other brain regions, including the amygdala, hypothalamus, and cerebral cortex. Biochemical analysis of receptor signalling supported the reduction of mGlu2/3 receptors in the hippocampus of FSL rats. Accordingly, the selective mGlu2/3 receptor agonist, LY379268 (1microM) reduced forskolin-stimulated cAMP formation by 56% and 32% in hippocampal slices from FRL and FSL rats, respectively. In addition, LY379268 enhanced 3,5-dihydroxyphenylglycine-stimulated inositol phospholipid hydrolysis from 65% to 215% in hippocampal slices from FRL rats, whereas it was inactive in slices from FRL rats. We also examined the behavioural response of FSL rats to systemic injection of LY379268 (0.5mg/kg, i.p., once a day for 1-21 days) by measuring the immobility time in the forced swim test, which is known to be increased in these rats. LY379268 was administered alone or combined with the classical antidepressant, chlorimipramine (10mg/kg, i.p.). LY379268 alone had no effect at any of the selected time-points, whereas chlorimipramine alone reduced the immobility time only after 21 days of treatment. In contrast, when combined with LY379268, chlorimipramine reduced the immobility time during the first 14 days of treatment. These data support the view that mGlu2/3 receptors might be involved in the pathophysiology of depressive disorders, and that pharmacological activation of these receptors may shorten the latency of antidepressant medication.


The Crosstalk between Hypoxia and Innate Immunity in the Development of Obesity-Related Nonalcoholic Fatty Liver Disease.
Nonalcoholic fatty liver disease (NAFLD) has become a major health issue in western countries in parallel with the dramatic increase in the prevalence of obesity and all obesity related conditions, including respiratory diseases as obstructive sleep apnea-hypopnea syndrome (OSAHS). Interestingly, the severity of the liver damage in obesity-related NAFLD has been associated with the concomitant presence of OSAHS. In the presence of obesity, the proinflammatory state in these patients together with intermittent episodes of hypoxia, characteristic of OSAHS pathogenesis, may lead to an enhanced inflammatory response mediated by a positive feedback loop mechanism that implicates HIF-1 and NFκB. Thus, the severity of liver involvement in obese NAFLD patients with a concomitant diagnosis of OSAHS could be explained. In this review, we focus on the molecular mechanisms underlying the hepatic response to chronic intermittent hypoxia and its interaction with innate immunity in obesity-related NAFLD.


Characterization of Rat NTPDase1, -2, and -3 ectodomains refolded from bacterial inclusion bodies.
The ecto-nucleoside triphosphate diphosphohydrolases or NTPDases are a family of membrane-bound enzymes that catalyze the sequential removal of gamma- and beta-phosphate from ATP, ADP, and other nucleotides. NTPDase1, -2, -3, and -8 are the enzymes responsible for signal conversion and termination in purinergic signaling. They are anchored to the cytoplasmic membrane by two transmembrane helices with a large catalytic domain pointing toward the extracellular space. Here we report the first successful expression and purification of the soluble extracellular domains of rat NTPDase1, -2, and -3 from bacterial inclusion bodies. The refolded proteins show characteristics similar to the wild type enzymes, for example in that they are dependent on divalent metal ions for catalysis and hydrolyze a wide variety of nucleoside tri- and diphosphates, whereas the monophosphate AMP is not further degraded. Nucleoside triphosphates are hydrolyzed at a higher rate than the corresponding diphosphates. Other characteristics of the recombinant enzymes however reflect the absence of transmembrane regions and side chain glycosylation. For example all three enzymes are monomeric and only subtly activated by Mg2+ ions as compared to Ca2+ ions. Although having a considerably higher specificity constant kcat/Km for ADP as for ATP, the bacterially expressed variant of NTPDase1 in contrast to its wild type counterpart releases intermediate ADP to a substantial amount. The presented expression system will allow large scale production of active protein suitable for structural studies, development of inhibitors, and even clinical application.


Hitting with a BAM: Selective Killing by Lectin-Like Bacteriocins.
Lectin-like bacteriocins (LlpAs) are secreted by proteobacteria and selectively kill strains of their own or related species, and they are composed of two B-lectin domains with divergent sequences. In Pseudomonas spp., initial binding of these antibacterial proteins to cells is mediated by the carboxy-terminal domain through d-rhamnose residues present in the common polysaccharide antigen of their lipopolysaccharide, whereas the amino-terminal domain accounts for strain selectivity of killing. Here, we show that spontaneous LlpA-resistant mutants carry mutations in one of three surface-exposed moieties of the essential β-barrel outer membrane protein insertase BamA, the core component of the BAM complex. Polymorphism of this loop in different Pseudomonas groups is linked to LlpA susceptibility, and targeted cells all share the same signature motif in this loop. Since heterologous expression of such a bamA gene confers LlpA susceptibility upon a resistant strain, BamA represents the primary bacteriocin selectivity determinant in pseudomonads. Contrary to modular bacteriocins that require uptake via the Tol or Ton system, parasitism of BamA as an LlpA receptor advocates a novel bacteriocin killing mechanism initiated by impairment of the BAM machinery.IMPORTANCE Bacteria secrete a variety of molecules to eliminate microbial rivals. Bacteriocins are a pivotal group of peptides and proteins that assist in this fight, specifically killing related bacteria. In Gram-negative bacteria, these antibacterial proteins often comprise distinct domains for initial binding to a target cell's surface and subsequent killing via enzymatic or pore-forming activity. Here, we show that lectin-like bacteriocins, a family of bacteriocins that lack the prototypical modular toxin architecture, also stand out by parasitizing BamA, the core component of the outer membrane protein assembly machinery. A particular surface-exposed loop of BamA, critical for its function, serves as a key discriminant for cellular recognition, and polymorphisms in this loop determine whether a strain is susceptible or immune to a particular bacteriocin. These findings suggest a novel mechanism of contact-dependent killing that does not require cellular uptake. The evolutionary advantage of piracy of an essential cellular compound is highlighted by the observation that contact-dependent growth inhibition, a distinct antagonistic system, can equally take advantage of this receptor.


Out-of-hospital cardiac arrests in the city of Cape Town, South Africa: a retrospective, descriptive analysis of prehospital patient records.
While prospective epidemiological data for out-of-hospital cardiac arrest (OHCA) exists in many high-income settings, there is a dearth of such data for the African continent. The aim of this study was to describe OHCA in the Cape Town metropole, South Africa. Observational study with a retrospective descriptive design. Cape Town metropole, Western Cape province, South Africa. All patients with OHCA for the period 1 January 2018-31 December 2018 were extracted from public and private emergency medical services (EMS) and described. Description of patients with OHCA in terms of demographics, treatment and short-term outcome. A total of 929 patients with OHCA received an EMS response in the Cape Town metropole, corresponding to an annual prevalence of 23.2 per 100 000 persons. Most patients were adult (n=885; 96.5%) and male (n=526; 56.6%) with a median (IQR) age of 63 (26) years. The majority of cardiac arrests occurred in private residences (n=740; 79.7%) and presented with asystole (n=322; 34.6%). EMS resuscitation was only attempted in 7.4% (n=69) of cases and return of spontaneous circulation (ROSC) occurred in 1.3% (n=13) of cases. Almost all patients (n=909; 97.8%) were declared dead on the scene. To our knowledge, this was the largest study investigating OHCA ever undertaken in Africa. We found that while the incidence of OHCA in Cape Town was similar to the literature, resuscitation is attempted in very few patients and ROSC-rates are negligible. This may be as a consequence of protracted response times, poor patient prognosis or an underdeveloped and under-resourced Chain of Survival in low- to middle-income countries, like South Africa. The development of contextual guidelines given resources and disease burden is essential.


Stroop interference, practice, and aging.
We report two experiments that investigate practice effects on Stroop color-word interference in older and younger adults. Both experiments employed a computerized, single-item version of the Stroop task with a voice response, and both involved practice over hundreds of trials. Both experiments showed generally similar practice patterns, including a practice-related reduction in the size of the color-word interference effect. However, the older group continued to show a larger interference effect throughout practice. These findings indicate that older adults show the same trend in practice-related improvement on the Stroop task as younger adults.


Diabetes is associated with an increased risk of wound complications and readmission in patients with surgically managed pressure ulcers.
The effect of diabetes on postoperative outcomes following surgical management of pressure ulcers is poorly defined despite evidence showing that patients with diabetes are at increased risk for developing pressure ulcers, as well as postoperative wound complications including delayed healing and infection. This study aimed to examine the impact of diabetes on postoperative outcomes following surgical management of pressure ulcers using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. In this retrospective analysis all CPT codes with ICD-9 diagnoses of pressure ulcers were reviewed. A total of 3,274 patients who underwent surgical management of pressure ulcers were identified, of which 1,040 (31.8%) had diabetes. Overall primary outcomes showed rates of superficial and deep incisional surgical site infection (SSI) were 2.0 and 4.2%, respectively, while the rate of wound dehiscence was 2.1%. Univariate analysis of primary outcomes stratified by diabetes status showed that patients with diabetes had significantly higher rates of superficial incisional SSI (3.9 vs. 2.3%; p = 0.01), deep incisional SSI (7.0 vs. 4.3%; p = 0.001), wound dehiscence (5.2 vs. 2.7%; p < 0.001), as well as significantly higher rates of readmission (12.8 vs. 8.9%; p = 0.001). Multivariate analysis for significant outcomes between groups on univariate analysis demonstrated that diabetes was an independent risk factor for superficial incisional SSI (OR = 2.7; 95% CI: 1.59-4.62; p < 0.001), deep incisional SSI (OR = 1.85; 95% CI: 1.26-2.70; p = 0.002), wound dehiscence (OR = 4.09; 95% CI: 2.49-6.74; p < 0.001), and readmission within 30 days (OR = 1.38; 95% CI: 1.05-1.82; p = 0.02). These findings emphasize the importance of preoperative prevention, and vigilant postoperative wound care and monitoring in patients with diabetes to minimize morbidity and optimize outcomes. Future prospective studies are needed to establish causality between diabetes and these outcomes.


Predictors of Anxiety Before and After Diagnostic Procedures in Women with Abnormal Papanicolaou Smear in Cervical Cancer Screening Program.
Anxiety is one of the most common causes of withdrawal from follow-up among women with abnormal Papanicolaou screening results. The purpose of this study was to investigate predictors of anxiety in women with abnormal Papanicolaou smear in cervical cancer screening program. A population-based, cross-sectional study concerning the factors related to anxiety was carried out during 2017 in a cohort of women (N = 172) with positive Papanicolaou screening test before and after diagnostic procedures (colposcopy/biopsy/endocervical curettage) at one university Clinical Center in Serbia. Women completed a socio-demographic questionnaire and scale concerning anxiety (Hospital Anxiety and Depression Scale, subscale HADS-Anxiety) immediately before and 2-4 weeks after the diagnostic procedures. Multivariate logistic regression was applied in the data analysis. In our study, 35.2% (n = 52) of women had abnormal anxiety scores before the diagnostic procedures and 40.1% (n = 69) after the diagnostic procedures. Predictors of anxiety before diagnostic procedures were family history of noncervical gynecological cancers, higher level of worry and high burden of depressive symptoms. Significant independent predictors of anxiety after diagnostic procedures in women were rural residence, tension and discomfort during medical procedures, and less satisfaction with information/support. Although there was no significant difference in the prevalence of anxiety before and after diagnostic procedures in women with abnormal Papanicolaou screening results, results of this research will enable doctors to successfully make decisions concerning timely psychological support for women with positive screening test for cervical cancer that is necessary to decrease anxiety in our population.