Six Sessions of Anterior-to-Posterior Ankle Joint Mobilizations Improve Patient-Reported Outcomes in Patients With Chronic Ankle Instability: A Critically Appraised Topic.
Clinical Scenario: Chronic ankle instability (CAI) is a complex musculoskeletal condition that results in sensorimotor and mechanical alterations. Manual therapies, such as ankle joint mobilizations, are known to improve clinician-oriented outcomes like dorsiflexion range of motion, but their impact on patient-reported outcomes remains less clear. Focused Clinical Question: Do anterior-to-posterior ankle joint mobilizations improve patient-reported outcomes in patients with chronic ankle instability? Summary of Key Findings: Three studies (2 randomized controlled trials and 1 prospective cohort) quantified the effect of at least 2 weeks of anterior-to-posterior ankle joint mobilizations on improving patient-reported outcomes immediately after the intervention and at a follow-up assessment. All 3 studies demonstrated significant improvements in at least 1 patient-reported outcome immediately after the intervention and at the follow-up assessment. Clinical Bottom Line: At least 2 weeks of ankle joint mobilization improves patient-reported outcomes in patients with chronic ankle instability, and these benefits are retained for at least a week following the termination of the intervention. Strength of Recommendation: Strength of recommendation is grade A due to consistent good-quality patient-oriented evidence.


Multivariate analysis of febrile neutropenia occurrence in patients with non-Hodgkin lymphoma: data from the INC-EU Prospective Observational European Neutropenia Study.
Myelosuppression, particularly febrile neutropenia (FN), are serious dose-limiting toxicities that occur frequently during the first cycle of chemotherapy. Identifying patients most at risk of developing FN might help physicians to target prophylactic treatment with colony-stimulating factor (CSF), in order to decrease the incidence, or duration, of myelosuppression and facilitate delivery of chemotherapy as planned. We present a risk model for FN occurrence in the first cycle of chemotherapy, based on a subgroup of 240 patients with non-Hodgkin lymphoma (NHL) enroled in our European prospective observational study. Eligible patients had an International Prognostic Index of 0-3, and were scheduled to receive a new myelosuppressive chemotherapy regimen with at least four cycles. Clinically relevant factors significantly associated with cycle 1 FN were older age, increasing planned cyclophosphamide dose, a history of previous chemotherapy, a history of recent infection, and low baseline albumin (<35 g/l). Prophylactic CSF use and higher weight were associated with a significant protective effect. The model had high sensitivity (81%) and specificity (80%). Our model, together with treatment guidelines, may rationalise the clinical decision of whether to support patients with CSF primary prophylaxis based on their risk factor profile. Further validation is required.


Association of gene polymorphisms and bone density in Japanese girls.
Although some studies have reported a relationship between several candidate polymorphic genes and bone mineral density (BMD), little is known concerning the genetic factors influencing BMD in children. This study examined this relationship in healthy Japanese girls (n=125; age, 13.4 +/- 0.89 years; range, 12-15 years). We investigated allelic variants of the vitamin D receptor (VDR) gene, the estrogen receptor (ER) gene, the parathyroid hormone (PTH) gene, the Ca-sensing receptor (CaSR) gene, and the beta3-adrenergic receptor (beta3-AR) gene. The genotype of the VDR gene (Fok I) correlated with lumbar spine, and femoral neck BMD. The PTH polymorphisms (BstB I, Dra II) were also associated with lumbar spine BMD. No relationship was found between genotypes of the ER gene, CaSR gene, or beta3-AR gene and BMD. The age, height, weight, and body mass index did not differ significantly among girls with different VDR and PTH genotypes. These results suggest that the Fok I polymorphism of the VDR gene and the Dra II polymorphism of the PTH gene are risk factors for low bone density in Japanese girls.


Parenteral nutrition induces organ specific alterations in polymeric immunoglobulin receptor levels.
Secretory immunoglobulin A (IgA) prevents pathogen adherence at mucosal surfaces to prevent infection. Polymeric immunoglobulin receptor (pIgR), located on the basolateral surface of mucosal cells, binds dimeric IgA produced by B cells with the cooperation of T cells in the lamina propria. This IgA-pIgR complex is transported apically, where it is exocytosed as secretory IgA to the mucosal surface. Our prior work shows that parenteral nutrition (PN) impairs both airway and small intestine mucosal immunity by reducing T and B cells and IgA levels. This work examines intestinal and respiratory tissue-specific pIgR responses to PN. Cannulated male Institute of Cancer Research mice were randomized to Chow (n = 10) or PN (n = 10). After 5 days, animals were sacrificed and lavages obtained from the small intestine, lung (BAL = bronchoalveolar lavage), and nasal airways (NAL). Small intestine, lung, and nasal passage tissues were also collected. Lavage and tissue homogenate IgA levels were quantified by enzyme-linked immunosorbent assay and pIgR by Western blot. PN group SIL and NAL IgA levels dropped significantly compared with Chow. PN significantly reduced pIgR levels in the SI while no pIgR change was noted in nasal passages and lung pIgR actually increased with PN. Tissue homogenate IgA levels did not change with PN in the SI while levels in the nasal passage and lung decreased. PN impairs airway mucosal immunity by reduction in IgA available for transport rather than via a reduction in pIgR levels. In the small intestine, diminished pIgR is implicated in the deterioration of antibody-mediated mucosal immunity.


Antibodies labeled with metallic radionuclides: influence of nuclide chemistry on dose distribution.
An antibody with human CEA specificity has been labeled with either yttrium-90, scandium-47, or indium-111, via a diethylenetriamine pentaacetic acid (DTPA) link covalently bound to the protein. The clearance of these proteins from the blood of mice can be described by a single exponential; the half-life decreases in the order indium-111 greater than yttrium-90 greater than scandium-47. Associated with the blood clearance is an uptake of radioactivity into the liver; scandium-47 has the highest concentration, indium-111 has the least, and yttrium-90 is intermediate. There is no correlation between these results and the equilibrium stability constants of the metals with DTPA-like ligands. The results obtained show that, in vivo, scandium-47 and yttrium-90 are more easily displaced from DTPA by other ions than is indium-111. They also show that free DTPA is able to extract yttrium-90 and scandium-47, but not indium-111, from the liver of treated animals, indicating that indium-111 is resistant to ligand exchange reactions in vivo. These data indicate that 1) the equilibrium stability constant is not a good indicator of the in vivo stability of metal-labeled proteins and 2) it is possible to manipulate the ion distribution and therefore the dose from scandium-47 and yttrium-90 after injection of the labeled proteins.


Three-Dimensional Segmented Poincaré Plot Analyses SPPA3 Investigates Cardiovascular and Cardiorespiratory Couplings in Hypertensive Pregnancy Disorders.
Hypertensive pregnancy disorders affect 6-8% of gestations representing the most common complication of pregnancy for both mother and fetus. The aim of this study was to introduce a new three-dimensional coupling analysis methods - the three-dimensional segmented Poincaré plot analyses (SPPA3) - to establish an effective approach for the detection of hypertensive pregnancy disorders and especially pre-eclampsia (PE). A cubic box model representing the three-dimensional phase space is subdivided into 12 × 12 × 12 equal predefined cubelets according to the range of the SD of each investigated signal. Additionally, we investigated the influence of rotating the cloud of points and the size of the cubelets (adapted or predefined). All single probabilities of occurring points in a specific cubelet related to the total number of points are calculated. In this study, 10 healthy non-pregnant women, 66 healthy pregnant women, and 56 hypertensive pregnant women (chronic hypertension, pregnancy-induced hypertension, and PE) were investigated. From all subjects, 30 min of beat-to-beat intervals (BBI), respiration (RESP), non-invasive systolic (SBP), and diastolic blood pressure (DBP) were continuously recorded and analyzed. Non-rotated adapted SPPA3 discriminated best between hypertensive pregnancy disorders and PE concerning coupling analysis of two or three different systems (BBI, DBP, RESP and BBI, SBP, DBP) reaching an accuracy of up to 82.9%. This could be increased to an accuracy of up to 91.2% applying multivariate analysis differentiating between all pregnant women and PE. In conclusion, SPPA3 could be a useful method for enhanced risk stratification in pregnant women.


Risk and protective factors for physical and emotional intimate partner violence against women in a community of lima, peru.
This article shows risk and protective factors for both physical and emotional intimate partner violence (IPV) against women. The study was carried out in a shanty town of Lima, Peru, which has a strong community organization. One hundred ninety-two women between 25 and 59 years old (M = 34.09, SD = 6.5) were interviewed; 44.3% had secondary education, 75.5% were housewives, and 94% lived with their partner. The measurement instrument was a survey especially developed for this project to explore occurrence of physical and emotional IPV and to identify factors associated with them; factors were classified in individual and relational levels according to the ecological nested model (ENM). A logistic regression analysis was used to test the associations; the results showed that for emotional IPV, men's assertiveness was a protective factor, whereas their emotional instability and jealousy were risk factors. For physical IPV, there were no identified risks or protective factors. These results are presented and discussed.


Reverse Stability of Oxyluciferin Isomers in Aqueous Solutions.
We investigated the stability of oxyluciferin anions (keto, enol, and enolate isomers) in aqueous solution at room temperature by performing a nanosecond time scale first-principles molecular dynamics simulation. In contrast to all previous quantum chemistry calculations, which suggested the keto-type to be the most stable, we show that the enol-type is slightly more stable than the keto-type, in agreement with some recent experimental studies. The simulation highlights the remarkable hydrophobicity of the keto-type by the cavity formed at the oxyluciferin-water interface as well as a reduction in hydrophobicity with the number of hydrating water molecules. It is therefore predicted that the isomeric form in a hydrated cluster is size-dependent.


Quantum Mechanics Approaches to Drug Research in the Era of Structural Chemogenomics.
The rapid growth of the available crystallographic information about proteins and binding pockets creates remarkable opportunities for enriching the drug research pipelines with computational prediction of novel protein-ligand interactions. While ab initio quantum mechanical approaches are known to provide unprecedented accuracy in structure-based binding energy calculations, they are limited to only small systems of dozens of atoms. In the structural chemogenomics era, it is critical that new approaches are developed that enable application of QM methodologies to non-covalent interactions in systems as large as protein-ligand complexes and conformational ensembles. This perspective highlights recent advances towards bridging the gap between high accuracy and high volume computations in drug research.


Reduced transdermal absorption of N,N-diethyl-m-toluamide from a new topical insect repellent formulation.
Extensive absorption of the topical insect repellent N, N-diethyl-m-toluamide (DEET) causes systemic and local toxicities. This report describes the preparation and characterization of a new insect repellent formulation (FA), a PEG-polyacrylic acid polymer system, for its DEET release, in vitro skin permeation, and in vivo transdermal absorption properties; and for its relative repellency against Aedes aegypti mosquitoes. DEET release and skin permeation were studied in Franz diffusion cells. DEET transdermal absorption and relative repellency of FA were assessed in beagle dogs. A commercial DEET lotion (FB) and technical DEET (FC) were used as references. FA exhibited 19.5% and 61.7% decrease in DEET steady-state skin flux compared with FB and FC, respectively. At 15 mg DEET/kg, the absolute DEET transdermal bioavailability and Cmax were 13.4% and 154.3 ng/ml, respectively, for FA; and were 17.5% and 196.5 ng/ml, respectively, for FB. DEET half-lives (t1/2) for FA (2.52 hr) and FB (2.73 hr) were similar, while MRT for FA (4.99 hr) was significantly greater (p < 0.05) than that for FB (4.38 hr). FA showed lower mosquito biting rates at 1, 2, 3, 4, 5, and 6 hr postdose at 0.5 mg DEET/cm2. FA exhibited reduced in vitro skin permeation and in vivo transdermal absorption of DEET as well as superior repellency compared with FB. The PEG-polyacrylic acid polymer system is of value in the formulation of DEET lotions.


MicroRNAs in stool samples as potential screening biomarkers for pancreatic ductal adenocarcinoma cancer.
Pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90-95% exocrine malignant tumors of the pancreas. The high prevalence of metastasis and the difficulty of early diagnosis lead to a dismal prognosis. MicroRNAs (miRNAs) play a critical role in extensive biological processes. The purpose of this study was to evaluate the feasibility of stool miRNAs as novel biomarker for PDAC screening. MiRNAs were extracted from clinical specimens which included cancer and matched adjacent benign pancreatic tissues of 30 PDAC patients, pancreatic juice of 20 from the 30 PDAC patients and 10 chronic pancreatitis (CP) patients, stool samples of the 30 PDAC patients, the 10 CP patients and 15 healthy volunteers. Relative expression of a panel of 5 dysregulated miRNAs (miR-21, miR-155, miR-196a, miR-216 and miR-217) was analyzed with qRT-PCR. Receiver operating characteristic curve (ROC) analysis was performed to assess the diagnosing value of stool miRNAs in PDAC patients. The study showed that our methods of extracting and detecting miRNAs from pancreatic juice and stool specimens had high reproducibility. Compared to matched adjacent benign pancreatic tissues and pancreatic juice of CP patients, the expression of miR-21 (P = 0.0021 and P = 0.0027) as well as miR-155 (P = 0.0087 and P = 0.0067) was significantly higher and the expression of miR-216 (P < 0.0001 and P = 0.0044) was significantly lower in primary tumor tissues and pancreatic juice of PDAC patients. PDAC patients had a significantly higher stool miR-21 and miR-155 (P = 0.0049 and P = 0.0112) and lower miR-216 level (P = 0.0002) compared to normal controls. The same results were obtained in the expression levels of stool miR-21, miR-155 and miR-216 between PDAC and CP patients (P = 0.0337, P = 0.0388 and P = 0.0117, respectively). Receiver operating characteristic (ROC) analysis by using stool miRNAs expression indicated that combination of miR-21 and miR-155 had best sensitivity of 93.33% while the combination of miR-21, miR-155 and miR-216 would be best for detecting and screening PDAC with area under the curve (AUC) of 0.8667 (95% CI: 0.7722-0.9612) and a better balance of sensitivity and specificity (83.33% vs. 83.33%). Our data indicate that miRNAs could be extracted and detected from pancreatic juice and stool efficiently and reproducibly. MiR-21, miR-155 and miR-216 in stool have the potential of becoming biomarkers for screening PDAC.


Network-Based Assessment of Adverse Drug Reaction Risk in Polypharmacy Using High-Throughput Screening Data.
The risk of adverse drug reactions increases in a polypharmacology setting. High-throughput drug screening with transcriptomics applied to human cells has shown that drugs have effects on several molecular pathways, and these affected pathways may be predictive proxy for adverse drug reactions. Depending on the way that different drugs may contribute to adverse drug reactions, different options may exist in the clinical setting. Here, we formulate a network framework to integrate the relationships between drugs, biological functions, and adverse drug reactions based on the high-throughput drug perturbation data from the Library of Integrated Network-Based Cellular Signatures (LINCS) project. We present network-based parameters that indicate whether a given reaction may be related to the effect of a single drug or to the combination of several drugs, as well as the relative risk of adverse drug reaction manifestation given a certain drug combination.


Complete mitochondrial genome and the phylogenetic position of the Lesser Cuckoo, Cuculus poliocephalus (Aves: Cuculiformes).
The complete mitochondrial genome of the Lesser Cuckoo Cuculus poliocephalus was determined using next-generation sequencing. Phylogenetic analyses with 20 cuckoo species and six genes (12S, ATP6, CYTb, ND2, ND3, and ND6) strongly verified the identity of our sample as grouping with C. poliocephalus, which was sister to a clade of other Cuculus spp., including C. canorus, C. micropterus, and C. saturatus. The mitogenomic length of C. poliocephalus was 17 508 bp, including 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes, one control region with 48 bp unit tandem repeats close to 3' end, and one short pseudo-control region with 33 tandem repeats of CAACAAA. An extra nucleotide (T) was identified at position 174 of ND3. The mitogenome of C. poliocephalus will contribute to studies of mitogenomic evolution, the phylogenetic relationship of cuckoos, and the co-evolutionary pattern between brood parasitic birds and their hosts.


Diisocyanates and nonoccupational disease: a review.
More than 32 million people in the United States suffer from chronic lung diseases; 12 million experienced at least one asthma attack in 2002. The causes of this "epidemic" are complex and uncertain; however, there is a strong possibility that environmental exposures play a role. The most common and well-studied cause of occupational asthma is diisocyanates, but their use in consumer products as a potential cause of respiratory disease in the general population has been overlooked. These substances are found in or are used to produce an array of polyurethane-containing products, including adhesives, sealants, paints, flexible foams, and rigid foams, among others. The world market for polyurethane products has tripled since 1985 to more than 9.3 billion kg in the year 2000. In this article, the author reviews biologically plausible explanations, as well as the epidemiologic, experimental, and clinical evidence for the role of diisocyanates and polyurethanes in the genesis of nonoccupational allergy and respiratory disease.


A Simple and Practical Bis-N-Heterocyclic Carbene as an Efficient Ligand in Cu-Catalyzed Glaser Reaction.
Conjugated diyne derivatives are important scaffolds in modern organic synthetic chemistry. Using the Glaser reaction involves the coupling of terminal alkynes which can efficiently produce conjugated diyne derivatives, while the use of a stoichiometric amount of copper salts, strong inorganic base, and excess oxidants is generally needed. Developing an environmentally friendly and effective method for the construction of symmetrical 1,3-diynes compounds by Glaser coupling is still highly desirable. In this study, we present an economical method for the production of symmetric diynes starting from various terminal acetylenes in a Glaser reaction. A simple and practical bis-N-heterocyclic carbene ligand has been introduced as efficient ligands for the Cu-catalyzed Glaser reaction. High product yields were obtained at 100 °C for a variety of substrates including aliphatic and aromatic terminal alkynes and differently substituted terminal alkynes including the highly sterically hindered substrate 2-methoxy ethynylbenzene or 2-trifluoromethyl ethynylbenzene and a series of functional groups, such as trifluoromethyl group, ester group, carboxyl group, and nitrile group. The established protocol is carried out in air under base-free condition and is operationally simple. These research work suggest that bis-N-heterocyclic carbene could also an appealing ligand for Glaser reaction and provide a reference for the preparation of symmetric 1,3-diynes in industrial filed.


Is it possible? A different approach to creating a universal influenza vaccine.
The best way to combat influenza virus infection is to prevent it. However, the continual evolution of circulating influenza virus strains and the constant threat of newly emerging viruses forces the public health community to annually update seasonal influenza vaccines while stockpiling potential pandemic virus vaccines. Thus, there is an urgent need to develop a "universal" influenza vaccine that affords protection against all strains. In their recent article, L. M. Schwartzman et al. (mBio 6:e01044-15, 2015, doi:10.1128/mBio.01044-15) demonstrated that intranasal immunization of mice with a cocktail of viral-like particles (VLPs) expressing distinct influenza virus hemagglutinin (HA) proteins can broadly protect against infection not only with the same viral strains but also with unrelated strains. These findings suggest a promising strategy for developing a broadly protective "universal" influenza vaccine.


Depolarization-induced increase in synaptosomal membrane calcium monitored by chlorotetracycline fluorescence.
Chlorotetracycline (CT) was used as a fluorescent probe for membrane calcium with intact synaptosomes. The net increase in fluorescence intensity at 520 nm, which is a measure of membrane-bound Ca, increases with increasing Ca, saturating in the millimolar range. Membrane Ca can also be detected in the absence of added external Ca. Potassium-induced depolarization of synaptosomes leads to an increase in membrane Ca, reaching a new steady-state value within 5 min. Neither opiates nor phenytoin affected synaptosomal membrane Ca. Relatively high concentrations of chlorotetracycline increased depolarization-induced uptake of 45Ca into synaptosomes. The data suggest that the Ca-CT complex binds to synaptic plasma membranes, and that depolarization-induced Ca influx results in increased Ca binding to the internal surface of the plasma membrane and/or other internal membranes.


Duration of corneal anaesthesia following multiple doses and two concentrations of tetracaine hydrochloride eyedrops on the normal equine cornea.
There is a clinical impression that tetracaine hydrochloride (THCl) eyedrops is a suitable topical anaesthetic in horses. To determine the duration of corneal anaesthesia following instillation of multiple doses and 2 concentrations of THCl in 10 healthy horses. The corneal touch threshold (CTT) was determined, in both eyes, before (basal CTT) and after application of one drop of 0.5% THCl, 2 drops at a 1 min interval of 0.5% THCl or one drop of 1% THCl. CTT was measured in mm every 5 min until complete recovery of the basal CTT. Treatments were separated by an interval of at least one week. Corneal sensitivity was significantly reduced from baseline values for 30, 60 and 50 min after application of one drop of 0.5% THCl, 2 drops of 0.5% THCl and one drop of 1% THCl, respectively. Mean maximal anaesthetic effects, corresponding to a CTT of 0 mm, lasted 5.5, 16 and 15.25 min and maximal anaesthetic effect was present in 55, 90 and 80% of eyes, 5 min after application of one drop of 0.5% THCl, 2 drops of 0.5% THCl and one drop of 1% THCl, respectively. The application of a second drop or the use of more concentrated eyedrops significantly increases duration of both anaesthesia and maximal anaesthetic effect. Duration of corneal anaesthesia following tetracaine instillation was established enabling a better use when performing diagnostic and therapeutic procedures. Comparison of tetracaine with other ocular anaesthetics needs to be published in the future.


Immunoglobulins anti-Anisakis simplex in patients with gastrointestinal diseases.
The nematode Anisakis simplex causes anisakidiasis, a disease that often mimics other gastrointestinal diseases. Patients with digestive haemorrhaging, Crohn's disease, digestive cancer and appendicitis were analysed for antibodies to A. simplex. Antibody detection was carried out by enzyme-linked immunosorbent assay (ELISA) and immunoblotting using crude extract (CE) antigen and excretory-secretory (ES) products. Total immunoglobulin (Igs), IgG, IgM, IgA and IgE were studied. The highest percentage was obtained when Igs were tested against CE antigen. A higher percentage of positivity was observed with the appendicitis group. The Crohn's disease group showed the highest levels of IgG against the ES antigen. Using immunoblotting, 24% and 48% of sera from patients with symptoms of Crohn's disease and digestive haemorrhaging, respectively, showed a positive immunorecognition pattern of CE antigen. The prevalence of detectable antibodies against A. simplex is higher in patients with digestive disorders than in the healthy population. A linear correlation was observed between prothrombin activity and Igs-CE, IgA-CE and IgA-ES but not between IgE-CE and the other immunoglobulin levels. Specific IgA is associated with a higher activity index of Crohn's disease. Specific antibodies were observed against A. simplex in patients with appendicitis and gastrointestinal cancer, indicating a higher rate of positivity for IgA.


[Late results of acetabulum fractures].
Of 100 patients with acetabulum fractures treated from 1976 to 1985, 53 were followed up after a mean of 7.9 years. The results were predominantly good in patients with simple fractures, but mainly unsatisfactory in those with combination fractures. The poor results were mainly due to pain generally resulting from posttraumatic coxarthrosis (all grades 18/48) or from persistent nerve lesions (posttraumatic or postoperative 7/51) and functionally relevant ectopic ossifications (2/48). The mobility of the affected hip joint was predominantly good compared to the contralateral side. Results were best after rapid elimination of luxations in luxation fractures and early repositioning and elective internal fixation of fractures of the acetabulum to be operated on.


How a calculated model of sunscreen film geometry can explain in vitro and in vivo SPF variation.
Spectroscopic in vitro assay has recently gained importance for UVA protection, or even for SPF assessment, as manufacturers are increasingly keen to replace in vivo by in vitro tests. These assays are based on transmission UV spectroscopy of a known amount of sunscreen product spread onto an ultraviolet-transparent substrate. In the most recent European publications or methods, the preferred substrate is a roughened PMMA plate. We demonstrated in a previous work the importance of a strict control of plate roughness to ensure reproducibility and repeatability of in vitro results. In the present paper, we studied the effect of varying the thickness of applied sunscreen on low or high plate roughness. Two optimal sunscreen amounts, 0.75 mg cm(-2) for low roughness and 1.2 mg cm(-2) for high roughness, could achieve in vitro SPF close to in vivo SPF. The UV absorption spectra were measured and analyzed, via a mathematical model of irregular film geometry based on a well-known statistical distribution, the gamma law function. Our calculations show the relevance of the model to describe correctly the sunscreen film geometry evolution according to different in vitro spectra changes. Inversely, adjustment of the film geometry to fit with a set of in vivo SPF results allows us to extrapolate the real UV absorption spectra of sunscreens applied on the skin at 2 mg cm(-2). A high plate roughness, preferably a moulded plate for reproducibility, is required to obtain the closest agreement between in vitro and in vivo sunscreen absorption spectra over the entire UV waveband.


Design and operation of a current good manufacturing practices cell-engineering laboratory.
Medical centers and biotechnology companies active in cellular and gene therapy increasingly are working to design and build clinical laboratories capable of performing cellular engineering and vector production using current good manufacturing practices (cGMPs). Because cell engineering is a rapidly changing field, and definitions for cell engineering cGMPs are still being established, a cGMP cell-engineering laboratory most often should be designed with a broad range of potential applications in mind. While the laboratory facility is the most tangible aspect of cGMP, it represents only part of a larger process, which it must be designed and built to support.


The pall ultipor breathing circuit filter--an efficient heat and moisture exchanger.
The Pall bacterial filter was tested as a potential heat and moisture exchanger on a model patient, placed on a circle absorber system, and clinically. The laboratory study was conducted during mechanical ventilation at a V of 6 L/min with fresh gas inflows of 1, 3 and 6 L/min. The model patient introduced carbon dioxide into the circuitry at a rate of 200 ml/min. The resistance of the filter was tested before and after each experiment. With all fresh gas inflows , absolute humidity increased from around 19 mg H2O/L at the start of experimentation to about 27 mg H2O/L within 30 min. Maximum humidities reached were 28 +/- 0.7 mg H2O/L, 27.6 +/- 0.5 mg H2O/L, and 27.7 +/- 0.5 mg H2O/L within 3 hr, with fresh gas inflows of 1, 3, and 6 L/min, respectively. Variations in inspired humidity were also assessed at minute volumes of 4 and 5 L/min with fresh gas inflows of 6 and 3 L/min. Increases in percent dead space were negligible when the filter was inserted between the model patients (assumed to weigh between 70-40 kg) and the circuit. There was no statistically significant increase in pressure with gas flows of 50 L/min when the instrument was dry (0.02 +/- 0.001 cm H2O/L X min-1) or when it was wet (0.02 +/- 0.002 cm H2O/L X min-1). The clinical study was conducted on ten adult anesthetized patients breathing through the bacterial filter and ten controls. The loss of body temperature was 0.2 degrees C when the filter was used and 1.5 degrees C when the filter was not used. Arterial blood gas tensions were within normal limits when the bacterial filter was used as a humidifier.


Pilot Investigation of Blood Pressure Control Using a Mobile App (Cardi.Health): Retrospective Chart Review Study.
The high prevalence of hypertension necessitates effective, scalable interventions for blood pressure (BP) control. Self-monitoring has shown improved adherence to medication and better BP management. Mobile apps offer a promising approach with their increasing popularity and potential for large-scale implementation. Studies have demonstrated associations between mobile app interventions and lowered BP, yet real-world data on app effectiveness and engagement remain limited. In this study, we analyzed real-world user data from the Cardi.Health mobile app, which is aimed at helping its users monitor and control their BP. Our goal was to find out whether there is an association between the use of the mobile app and a decrease in BP. Additionally, the study explored how engagement with the app may influence this outcome. This was a retrospective chart review study. The initial study population comprised 4407 Cardi.Health users who began using the app between January 2022 and April 2022. After applying inclusion criteria, the final study cohort comprised 339 users with elevated BP at the baseline. The sample consisted of 108 (31.9%) men and 231 (68.1%) women (P=.04). This retrospective chart review study obtained permission from the Biomedical Research Alliance of New York Institutional Review Board (June 2022, registration ID 22-08-503-939). The study's main findings were that there is a possible relationship between use of the Cardi.Health mobile app and a decrease in systolic BP. Additionally, there was a significant association between active use of the app and systolic BP decrease (χ21=5.311; P=.02). Finally, active users had an almost 2 times greater chance of reducing systolic BP by 5 mm Hg or more over 4 weeks (odds ratio 1.932, 95% CI 1.074-3.528; P=.03). This study shows a possible relationship between Cardi.Health mobile app use and decreased BP. Additionally, engagement with the app may be related to better results-active use was associated with an almost 2-fold increase in the odds of reducing BP by 5 or more mm Hg.


An adherent subline of a unique small-cell lung cancer cell line downregulates antigens of the neural cell adhesion molecule.
Small-cell lung cancer (SCLC) lines are distinguished from non-small-cell lung cancer (NSCLC) lines by their growth in floating aggregates, in contrast to the adherent monolayers formed by NSCLC cells in culture. Of 50 well-characterized SCLC lines recently described by the National Cancer Institute (NCI)-Navy Medical Oncology Branch, only four variant cell lines (SCLC-v) grew as adherent monolayers. One line, NCI-H446, was unique in growing long-term with coexisting floating and surface adherent subpopulations. We have physically segregated these two populations over many passages in vitro to enrich for relatively pure cultures of floating and adherent cells. No differences in c-myc expression, keratin pattern, or cytogenetic appearance were found between the adherent and floating sublines. However, expression of the neuroendocrine marker neuron-specific enolase in the floating cells was three times that found in the adherent cells. The floating subline also had much greater surface expression of neuroendocrine tumor antigens detected by monoclonal antibodies UJ13A and HNK-1, which have been recently shown to detect the neural cell adhesion molecule (NCAM) on SCLC cells. Two other adherent SCLC-v lines were also found to be unreactive with UJ13A and HNK-1, generalizing the association between NCAM expression and the growth of most SCLC cultures as floating aggregates. In conclusion, we have an interesting model to study expression of NCAM as related to the adhesive properties of SCLC cells.


Basic Proline-Rich Protein-Mediated Microtubules Are Essential for Lobe Growth and Flattened Cell Geometry.
Complex cell shapes are generated first by breaking symmetry, and subsequent polar growth. Localized bending of anticlinal walls initiates lobe formation in the epidermal pavement cells of cotyledons and leaves, but how the microtubule cytoskeleton mediates local cell growth, and how plant pavement cells benefit from adopting jigsaw puzzle-like shapes, are poorly understood. In Arabidopsis (Arabidopsis thaliana), the basic Pro-rich protein (BPP) microtubule-associated protein family comprises seven members. We analyzed lobe morphogenesis in cotyledon pavement cells of a BPP1;BPP2;BPP5 triple knockout mutant. New image analysis methods (MtCurv and BQuant) showed that anticlinal microtubule bundles were significantly reduced and cortical microtubules that fan out radially across the periclinal wall did not enrich at the convex side of developing lobes. Despite these microtubule defects, new lobes were initiated at the same frequency as in wild-type cells, but they did not expand into well-defined protrusions. Eventually, mutant cells formed nearly polygonal shapes and adopted concentric microtubule patterns. The mutant periclinal cell wall bulged outward. The radius of the calculated inscribed circle of the pavement cells, a proposed proxy for maximal stress in the cell wall, was consistently larger in the mutant cells during cotyledon development, and correlated with an increase in cell height. These bpp mutant phenotypes provide genetic and cell biological evidence that initiation and growth of lobes are distinct morphogenetic processes, and that interdigitated cell geometry effectively suppresses large outward bulging of pavement cells.


Impact of surface characteristics on the peri-implant microbiome in health and disease.
Because little is known about the impact of implant surface modifications on the peri-implant microbiome, we aimed to examine peri-implant communities in various surface types in order to better understand the impact of these surfaces on the development of peri-implantitis (PI). One hundred and six systemically healthy individuals with anodized (AN), hydroxyapatite-coated (HA), or sandblasted acid-etched (SLA) implants that were >6 months in function were recruited and categorized into health (H) or PI. Peri-implant biofilm was analyzed using 16S rRNA gene sequencing and compared between health/disease and HA/SLA/AN using community-level and taxa-level metrics. Healthy implants did not demonstrate significant differences in clustering, alpha- or beta-diversity based on surface modification. AN and HA surfaces displayed significant differences between health and PI (p < 0.05); however, such a clustering was not evident with SLA (p > 0.05). AN and HA surfaces also differed in the magnitude and diversity of differences between health and PI. Six species belonging to the genera Shuttleworthia, Scardovia, and Prevotella demonstrated lower abundances in AN implants with PI, and 18 species belonging to the genera Fretibacterium, Tannerella, Treponema, and Fusobacterium were elevated, while in HA implants with PI, 20 species belonging to the genera Streptococcus, Lactobacillus, Veillonella, Rothia, and family Ruminococcaceae were depleted and Peptostreptococcaceae, Atopobiaceae, Veillonellaceae, Porphyromonadaceae, Desulfobulbaceae, and order Synergistales were enriched. Within the limitations of this study, we demonstrate that implant surface can differentially modify the disease-associated microbiome, suggesting that surface topography must be considered in the multi-factorial etiology of peri-implant diseases.


A Social Work Response to the Affordable Care Act: Prevention and Early Intervention.
The Patient Protection and Affordable Care Act represents a reinvestment in primary care, with a focus on prevention of illness and remediation of the impacts of chronic diseases through a behavioral health framework. Licensed social work professionals, specifically those trained in behavioral health, are a natural fit to help implement these new approaches. Though there are many evidence-based interventions that will be helpful, two that come from the field of substance abuse ought to be specifically beneficial: SAMHSA's SBIRT Model and Motivational Interviewing, developed by Miller and Rollnick. In response to the growing need for specially trained social work practitioners, the Social Work Program at Seton Hall University has developed the initial concentration of its MSW Program around these learning needs.


Expression profiles of miRNAs in polarized macrophages.
microRNAs (miRNAs) play a crucial role in tissue development and the pathology of various diseases. However, the effects and roles of miRNAs in macrophage polarization have yet to be investigated. In this study, we analyzed and compared the miRNA expression profiles of bone marrow-derived macrophages (BMDMs) with two distinct polarizing conditions (classical macrophage activation 'M1' and alternative activation 'M2') using miRNA microarray. In total, 109 miRNAs were differentially expressed between M1 and M2. The differential expression of selected miRNAs was validated by real-time qRT-PCR: miR-181a, miR-155-5p, miR-204-5p and miR-451 were upregulated (fold change >2, P<0.05) and miR-125-5p, miR-146a-3p, miR-143-3p and miR-145-5p were downregulated (fold change <-2, P<0.05) in M1 compared with M2. In conclusion, our study may be useful for exploring the precise roles of miRNAs in macrophage differentiation and polarized activation processes in the future.


Stressors and coping measures of hospice nurses.
The nursing care of the dying patient in the home setting is considered highly stressful. As the population ages, the hospice census is expected to increase and the need to attract and retain hospice nurses will be vitally important. Understanding hospice nurses' perceived stress and coping mechanisms can lead to increased retention and higher employee satisfaction. The survey presented in this article identified the perceived stressors of hospice nurses, their stress relief methods, and organizational work issues.


Mechanism of ascaridole activation in Leishmania.
Endoperoxides (EP) are an emerging class of drugs which have potential in antiparasitic therapy, but also in other fields. For malaria therapy the EP artemisinin (Art) and its derivatives are successfully used. We have shown in the past that the EP ascaridole (Asc) is useful for the treatment of cutaneous leishmaniasis in a mouse model. Biomimetic experiments suggested that these drugs need activation in the respective target pathogens to exert their function. In spite of this idea, direct activation of EP to radicals inside cells has never been demonstrated. Therefore, this study was initiated to explore the activation of Asc in biomimetic systems and inside Leishmania in comparison to Art. Using electron paramagnetic resonance spectroscopy (EPR) in combination with spin-trapping we identified the secondary alkyl radical intermediates arising from reduction by Fe2+ in cell-free systems. Combined GC/NMR analysis confirmed the loss of isopropyl residues from Asc during this process as intermediates. This activation of Asc was stimulated by low molecular Fe2+ complexes or alternatively by hemin in conjunction with thiol reductants, such as cysteine (Cys). In Leishmania tarentolae promastigotes (LtP) as model for pathogenic forms of Leishmania carbon-centered radicals were identified in the presence of Asc by EPR spin-trapping. Both Asc and Art inhibited the viability in LtP with IC50 values in the low micromolar range while IC50 values for J774 macrophages were considerably higher. A similar structure without EP bridge (1,4-cineole) resulted in no detectable radicals and possessed much less cytotoxicity in LtP and no selectivity for LtP compared to J774 cells. The Asc-derived radical formation in LtP was inhibited by the iron chelator deferoxamine (DFO), and stimulated by Cys (a suitable reductant for hemin). The IC50 values for LtP viability in the presence of Asc or Art were increased significantly by the spin trap DMPO, while Cys and DFO increased only IC50 values for Art. In a heme association assay Asc demonstrated a lower binding affinity to heme than Art. ICP-OES measurements revealed that in LtP the total iron concentrations were twice as high as values in J774 macrophages. Since low molecular iron was important in Asc activation we studied the influence of Asc on the labile iron pool (LIP) in LtP. Low temperature EPR experiments demonstrated that Asc shifts the redox balance of iron in the LIP to its oxidized state. These data demonstrate that univalent cleavage of Asc/Art in LtP is an essential part of their pharmacological mechanism. The structure of the EP determines whether activation by low molecular iron or heme is favored and the availability of these intracellular activators modulates their cytotoxicity. These findings may be helpful for synthesis of new Asc derivatives and understanding the action of EP in other cell types.


Erdheim-Chester disease presenting with cutaneous involvement: a case report and literature review.
Erdheim-Chester disease (ECD) is a rare, systemic, non-familial histiocytic disorder, first described by Jakob Erdheim and William Chester in 1930. Most patients have multiple sites of involvement at presentation. The most common site of involvement is the long bones of the axial skeleton, which is seen almost universally, followed by the nervous system, heart, lungs, orbit and retroperitoneum, which are seen in up to 50% of cases. Cutaneous involvement is rarely a presenting symptom of ECD, with two reported cases in the English literature. The diagnosis of ECD is rarely made by skin biopsy because of the relative rarity of cutaneous involvement as a presenting feature, and also perhaps because of the difficulty in distinguishing the histopathological appearance from potential mimics. The importance of distinguishing ECD from other cutaneous disorders with similar pathology lies in the implications for both treatment and prognosis. ECD is an aggressive, often fatal disorder, with death from disease occurring in greater than 50% of patients.


Molecular mechanisms governing the progression of nephritis in lupus prone mice and human lupus patients.
Pathologic inflammation is a major driver of kidney damage in lupus nephritis (LN), but the immune mechanisms of disease progression and risk factors for end organ damage are poorly understood. To characterize molecular profiles through the development of LN, we carried out gene expression analysis of microdissected kidneys from lupus-prone NZM2328 mice. We examined male mice and the congenic NZM2328.R27 strain as a means to define mechanisms associated with resistance to chronic nephritis. Gene expression profiles in lupus mice were compared with those in human LN. NZM2328 mice exhibited progress from acute to transitional and then to chronic glomerulonephritis (GN). Each stage manifested a unique molecular profile. Neither male mice nor R27 mice progressed past the acute GN stage, with the former exhibiting minimal immune infiltration and the latter enrichment of immunoregulatory gene signatures in conjunction with robust kidney tubule cell profiles indicative of resistance to cellular damage. The gene expression profiles of human LN were similar to those noted in the NZM2328 mouse suggesting comparable stages of LN progression. Overall, this work provides a comprehensive examination of the immune processes involved in progression of murine LN and thus contributes to our understanding of the risk factors for end-stage renal disease. In addition, this work presents a foundation for improved classification of LN and illustrates the applicability of murine models to identify the stages of human disease.


[Long-term effects of a combination of transdermal nicotine administration with behavior therapy for smoking cessation].
Effects of a transdermal nicotine substitution on psychological smoking cessation were investigated in a double-blind prospective study. 131 smokers have been randomly assigned to three treatment conditions: All smokers underwent nine weeks of self-controlled smoking cessation. During 6 weeks one group was additionally treated with nicotine patches continuously releasing nicotine through the skin into the blood circuit. The second group received placebo patches; while the third group was treated with behavioral training alone. Treatment effects were measured by daily cigarette consumption. Follow-up investigations were performed 3, 6 and 12 months after therapy. Nicotine-treated subjects reached significantly higher abstinence rates during and at the end of treatment as well as during the follow-up period, than both placebo- and control-subjects. No severe side effects of plasters have been reported. The results thus indicate good therapeutic effectiveness of transdermal nicotine substitution.


The association between total phthalate concentration and non-communicable diseases and chronic inflammation in South Australian urban dwelling men.
To investigate associations between urinary total phthalate concentration, chronic low-grade inflammation and non-communicable diseases in a cohort of South Australian men. 1504 men aged 39-84 years who provided a urinary sample at the follow-up visit of the Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) study, a randomly-selected group of urban-dwelling, community-based men from Adelaide, Australia (n = 2038; study participation rate: 78.1%). Total phthalate concentration was quantified in fasting morning urine samples. Chronic diseases were assessed through self-report questionnaire or directly measured using standardised clinical and laboratory procedures. Inflammatory biomarkers were assayed by ELISA or spectroscopy. Multivariable linear and logistic regression models were applied to determine associations of log-transformed urinary phthalate concentration with inflammation and chronic disease. Total phthalates were detected in 99.6% of urinary samples; geometric mean (95% CI) was 114.1 (109.5-118.9)µg/g creatinine. Higher total phthalate levels were associated with higher levels of hs-CRP, IL-6 (all p < 0.05) and TNF-α but not MPO. Urinary total phthalate concentrations were positively associated with cardiovascular disease, type-2-diabetes and hypertension. Comparing extreme quartiles of total phthalate, prevalence ratios were 1.78 (95% CI 1.17 - 2.71, p-trend = 0.001) for cardiovascular disease and 1.84 (95%CI 1.34 - 2.51, p-trend = 0.001) for type-2-diabetes and 1.14 (95%CI 1.01 - 1.29, p-trend = 0.013) for hypertension. Total phthalates and asthma and depression were not significantly associated. A positive association between total phthalates and cardiovascular disease, type-2-diabetes, hypertension and increased levels of chronic low-grade inflammatory biomarkers was observed in urban-dwelling Australian men.


Short-term effect of back school based on cognitive behavioral therapy involving multidisciplinary collaboration.
ObjectivesThe purpose of this study was to develop a comprehensive back school program that included elements of CBT (Cognitive Behavioral Therapy), implement this through multidisciplinary collaboration, and ascertain its effectiveness as a pilot study. DesignThis school was implemented in the form of five 90-minute group sessions held every other week.MethodsParticipants comprised 7 chronic low back pain patients with poor improvement in the usual treatment. Practitioners were orthopaedic surgeon, physical therapist, and a clinical psychologist. This school contents were patient education, self-monitoring, back exercise, relaxation, stress management, cognitive restructuring, activity pacing, and exposure. ResultsFrom the Wilcoxon signed-rank test, each score of four scales or items (sense of control, PCS (pain catastrophizing), PASS-20 (escape/avoidance), FFD (finger-floor distance)) after this program significantly improved. Results of calculating the effect size, sense of control (d=0.55) is 'moderate', the PCS (d=1.12) and the PASS-20 (d=1.64) were 'large'.ConclusionsThis back school may be useful for physical function and psychological variables which much related to pain management and daily disabilities in patients with poor respond to standard orthopaedic treatment.


High-temperature alkaline alpha-amylase from Bacillus iicheniformis TCRDC-B13.
A bacterial strain, Bacillus licheniformis, has been isolated and identified which produces high-temperature alkaline alpha-amylase. Cultural conditions, such as types of carbon and nitrogen sources, temperature, pH, and time of reaction, have been optimized for production of alpha-amylase in shake flask and fermenter. The enzyme produced was quite active even at 100 degrees C; however, it showed optimum activity at 90 degrees C. It exhibited optimum activity in the broad pH range 5.5-10. The effects of Na(+) and Ca(2+) ions on enzyme activity was also studied.


High precision differential measurement of surface photovoltage transients on ultrathin CdS layers.
Time-resolved surface photovoltage (SPV) is an important method for studying charge separation, for example, in nanostructured semiconductors. High precision differential measurement of SPV transients was realized with two identical measurement capacitors and high-impedance buffers. In addition, logarithmic readout and averaging procedures were implemented for single transients over eight magnitudes in time. As a model system ultrathin CdS layers were investigated. The thickness dependencies of the SPV amplitudes and that of the dominating relaxation mechanisms are demonstrated and discussed.


Scanty AFB smears: what's in a name?
A tuberculosis control project in Bangladesh. To document the frequency and diagnostic value of smears with scanty acid-fast bacilli (AFB) (IUATLD/WHO scale, < 10/100 high power fields), and to assess the appropriateness of the current positivity threshold. Analysis of databases of laboratory registers, patient records and the diagnostic yield of sputum collection strategies. Scanty smears constituted about 10% of suspect and almost 50% of follow-up smears. In suspect series, 10% of scanty 1-9/100 were not confirmed by another positive or scanty AFB sputum, compared to 7.5% of results at the current cut-off value of 10/100. Considering such results as positive by adopting a lower cut-off as low as the 1/100 used in the ATS scale added 1.5% false positives at the most. In return, the gain in confirmed positive cases was up to 10%, and that in positive results exceeded the incremental yield of the third diagnostic sputum. Significance of scanty follow-up smears at the end of the intensive phase was suggested by their association with treatment failure and unfavourable outcome overall. Scanty results (IUATLD/WHO scale) are not rare and should not be ignored. Adoption of a considerably lower positivity threshold would be appropriate in control programmes where basic conditions for reliable AFB microscopy, including regular quality assessment, are present.


Interim position statement on doxycycline post-exposure prophylaxis (Doxy-PEP) for the prevention of bacterial sexually transmissible infections in Australia and Aotearoa New Zealand - the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM).
Recent studies have provided evidence for the effectiveness of using doxycycline (Doxy-PEP) to prevent bacterial sexually transmissible infections (STI), namely chlamydia, gonorrhoea, and syphilis, among gay, bisexual, and other men who have sex with men who have experienced multiple STIs. However, there remain several unanswered questions around potential adverse outcomes from Doxy-PEP, including the possibility of inducing antimicrobial resistance in STIs and other organisms, and the possibility of disrupting the microbiome of people who choose to use Doxy-PEP. This interim position statement from the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine aims to outline the current evidence for Doxy-PEP, and to highlight potential adverse outcomes, to enable clinicians to conduct evidence-based conversations with patients in Australia and Aotearoa New Zealand who intend to use Doxy-PEP.


Rhodium(iii)-catalyzed C-H allylation of electron-deficient alkenes with allyl acetates.
Rhodium-catalyzed C-H allylation of acrylamides with allyl acetates is reported. The use of weakly coordinating directing group resulted in high reaction efficiency, broad functionality tolerance and excellent γ-selectivity, which opens a new synthetic pathway for the access of 1,4-diene skeletons.


Peculiarities of the endocrine time structure in noninsulin-dependent adult-onset (type II) diabetes mellitus.
Twenty noninsulin-dependent elderly diabetic patients, ten of whom were treated by oral hypoglycemic agents and ten of whom were regulated by diet alone, and 20 clinically healthy subjects matched for age, sex, height, and weight were examined with six blood and six urine samples at 4-hr intervals over a 24-hr span. Plasma ACTH, cortisol, aldosterone, and dehydroepiandrosterone-sulfate (DHEA-S) were determined by radioimmunoassay (RIA); epinephrine, norepinephrine, and dopamine in urine were determined by high-pressure liquid chromatography (HPLC); and magnesium in urine was determined colorimetrically on a DuPont ACA. There were a number of changes in some of these functions in type II diabetic patients with and without oral hypoglycemic agents that appear to be of interest. The circadian mean in plasma ACTH concentration in diabetic patients with and without oral hypoglycemic agents is significantly higher than in matched nondiabetic controls. The plasma aldosterone concentration is similar in type II diabetics treated by diet only and in matched controls but is statistically significantly elevated in patients on oral hypoglycemic agents. Correspondingly, the urinary excretion of sodium in type II diabetic patients on oral hypoglycemic agents is lower than in matched controls. The plasma cortisol concentration is unchanged in type II diabetic patients treated by diet alone but shows a slight increase in patients on oral hypoglycemic agents. The circadian means of plasma DHEA-S concentration is slightly higher in diabetic patients with and without oral hypoglycemic agents than in matched controls. This elevation, however, does not quite reach the 95% level of statistical significance. Urinary norepinephrine excretion in type II diabetic patients is similar to that in matched controls. The urinary epinephrine excretion in diabetics with and without oral hypoglycemic agents, however, was lower than in controls, and the urinary excretion of dopamine was higher in the diabetics. The urinary magnesium excretion in type II diabetic patients was lower than in matched controls.


Structural Ceramic Nanocomposites: A Review of Properties and Powders' Synthesis Methods.
Ceramic nanocomposites are attracting growing interest, thanks to new processing methods enabling these materials to go from the research laboratory scale to the commercial level. Today, many different types of nanocomposite structures are proposed in the literature; however, to fully exploit their exceptional properties, a deep understanding of the materials' behavior across length scales is necessary. In fact, knowing how the nanoscale structure influences the bulk properties enables the design of increasingly performing composite materials. A further key point is the ability of tailoring the desired nanostructured features in the sintered composites, a challenging issue requiring a careful control of all stages of manufacturing, from powder synthesis to sintering. This review is divided into four parts. In the first, classification and general issues of nanostructured ceramics are reported. The second provides basic structure-property relations, highlighting the grain-size dependence of the materials properties. The third describes the role of nanocrystalline second-phases on the mechanical properties of ordinary grain sized ceramics. Finally, the fourth part revises the mainly used synthesis routes to produce nanocomposite ceramic powders, underlining when possible the critical role of the synthesis method on the control of microstructure and properties of the sintered ceramics.


A Comparative Study on Graphene Oxide and Carbon Nanotube Reinforcement of PMMA-Siloxane-Silica Anticorrosive Coatings.
Carbon nanotubes (CNTs) and graphene oxide (GO) have been used to reinforce PMMA-siloxane-silica nanocomposites considered to be promising candidates for environmentally compliant anticorrosive coatings. The organic-inorganic hybrids were prepared by benzoyl peroxide (BPO)-induced polymerization of methyl methacrylate (MMA) covalently bonded through 3-(trimethoxysilyl)propyl methacrylate (MPTS) to silica domains formed by hydrolytic condensation of tetraethoxysilane (TEOS). Single-walled carbon nanotubes and graphene oxide nanosheets were dispersed by surfactant addition and in a water/ethanol solution, respectively. These were added to PMMA-siloxane-silica hybrids at a carbon (CNT or GO) to silicon (TEOS and MPTS) molar ratio of 0.05% in two different matrices, both prepared at BPO/MMA molar ratios of 0.01 and 0.05. Atomic force microscopy and scanning electron microscopy showed very smooth, homogeneous, and defect-free surfaces of approximately 3-7 μm thick coatings deposited onto A1020 carbon steel by dip coating. Mechanical testing and thermogravimetric analysis confirmed that both additives CNT and GO improved the scratch resistance, adhesion, wear resistance, and thermal stability of PMMA-siloxane-silica coatings. Results of electrochemical impedance spectroscopy in 3.5% NaCl solution, discussed in terms of equivalent circuits, showed that the reinforced hybrid coatings act as a very efficient anticorrosive barrier with an impedance modulus up to 1 GΩ cm(2), approximately 5 orders of magnitude higher than that of bare carbon steel. In the case of GO addition, the high corrosion resistance was maintained for more than 6 months in saline medium. These results suggest that both carbon nanostructures can be used as structural reinforcement agents, improving the thermal and mechanical resistance of high performance anticorrosive PMMA-siloxane-silica coatings and thus extending their application range to abrasive environments.


The symptom cluster-based approach to individualize patient-centered treatment for major depression.
Unipolar major depressive disorder is a common, disabling, and costly disease that is the leading cause of ill health, early death, and suicide in the United States. Primary care doctors, in particular family physicians, are the first responders in this silent epidemic. Although more than a dozen different antidepressants in 7 distinct classes are widely used to treat depression in primary care, there is no evidence that one drug is superior to another. Comparative effectiveness studies have produced mixed results, and no specialty organization has published recommendations on how to choose antidepressants in a rational, evidence-based manner. In this article we present the theory and evidence for an individualized, patient-centered treatment model for major depression designed around a targeted symptom cluster-based approach to antidepressant selection. When using this model for healthy adults with major depressive disorder, the choice of antidepressants should be guided by the presence of 1 of 4 common symptom clusters: anxiety, fatigue, insomnia, and pain. This model was built to foster future research, provide a logical framework for teaching residents how to select antidepressants, and equip primary care doctors with a structured treatment strategy to deliver optimal patient-centered care in the management of a debilitating disease: major depressive disorder.


Body mass index in children with beta-thalassemia major.
Underweight or low body mass index (BMI) is associated with developing many health problems. Despite the presence of many growth abnormalities in patients with beta thalassemia major, BMI has not been adequately studied. All of the thalassemic patients under 18 years of age, registered in thalassemia center of Shiraz, were studied. Medical history was taken and complete physical examination was done. BMI (weight/height2) at different ages was calculated and compared with standardized percentile curves of BMI for children and adolescents. BMI less than 10th percentile for sex and age was observed in 12.4% of thalassemic patients under 10 years of age and in 46.5% of patients above 10 years of age (p< 0.000001). Also the observed difference between girls and boys, specially when they are more than 10 years of age is significant (p< 0.000001). Underweight is a common finding in patients with beta-thalassemia major specially when they are older than 10 years of age. This is possibly because of the occurrence of multiple endocrinopathies and also the presence of under-nutrition in these patients. So growth should be monitored routinely at regular intervals in order to detect any decline in growth velocity and also any derangement in BMI to establish an appropriate protocol for investigation and treatment.


A selective splicing variant of hepcidin mRNA in hepatocellular carcinoma cell lines.
Hepcidin is a main regulator of iron metabolism, of which abnormal expression affects intestinal absorption and reticuloendothelial sequestration of iron by interacting with ferroportin. It is also noted that abnormal iron accumulation is one of the key factors to facilitate promotion and progression of cancer including hepatoma. By RT-PCR/agarose gel electrophoresis of hepcidin mRNA in a hepatocellular carcinoma cell line HLF, a smaller mRNA band was shown in addition to the wild-type hepcidin mRNA. From sequencing analysis, this additional band was a selective splicing variant of hepcidin mRNA lacking exon 2 of HAMP gene, producing the transcript that encodes truncated peptide lacking 20 amino acids at the middle of preprohepcidin. In the present study, we used the digital PCR, because such a small amount of variant mRNA was difficult to quantitate by the conventional RT-PCR amplification. Among seven hepatoma-derived cell lines, six cell lines have significant copy numbers of this variant mRNA, but not in one cell line. In the transient transfection analysis of variant-type hepcidin cDNA, truncated preprohepcidin has a different character comparing with native preprohepcidin: its product is insensitive to digestion, and secreted into the medium as a whole preprohepcidin form without maturation. Loss or reduction of function of HAMP gene by aberrantly splicing may be a suitable phenomenon to obtain the proliferating advantage of hepatoma cells.


Pulmonary vein stenosis following catheter ablation of atrial fibrillation.
This review provides an update on the mechanisms, incidence, and current management of significant pulmonary vein stenosis following catheter ablation of atrial fibrillation. Catheter ablation involving the pulmonary veins and the surrounding left atrial tissue is increasingly used to treat atrial fibrillation. In parallel with the fact that these procedures may cure a substantial proportion of patients, severe complications have been observed. Pulmonary vein stenosis is a new clinical entity produced by radiofrequency energy delivery mainly within or at the orifice of the pulmonary veins. The exact incidence is currently unknown because the diagnosis is dependent on the imaging modality and on the rigor with which patients are followed up. The optimal method for screening patients has not been determined. Stenosis of a pulmonary vein may be assessed by combining anatomic and functional imaging using computed tomographic or magnetic resonance imaging, transesophageal echocardiography, and lung scanning. Symptoms vary considerably and may be misdiagnosed, leading to severe clinical consequences. Current treatment strategies involve pulmonary vein dilatation or stenting; however, the restenosis rate remains high. The long-term outcome in patients with pulmonary vein stenosis is unclear. Strategies under development to prevent pulmonary vein stenosis include alternate energy sources and modified ablation techniques. Pulmonary vein stenosis following catheter ablation is a new clinical entity that has been described in various reports recently. There is much uncertainty with respect to causative factors, incidence, diagnosis, and treatment, and long-term sequelae are unclear.


Reconstitution of biologically active 50S ribosomal subunits with artificial 5S RNA molecules carrying disturbances in the base pairing within the molecular stalk.
Bacillus stearothermophilus 50S ribosomal subunits were reconstituted in vitro using artificial 5S RNA molecules constructed by combining parts of major and minor type (Raué et al. (1976) Europ. J. Biochem. 68, 169-176) B. licheniformis 5S RNA. The artificial 5S RNA molecules carry defined disturbances (A.C juxtapositions and extra G.U pairs) in the base pairing between the 5'- and 3'-terminal sequences of the molecule (the molecular stalk region). The biological activity of the reconstituted subunits was determined in an E. coli cell-free system programmed with poly-U. The results show that conservation of the base pairing within the molecular stalk is not required for biological activity of 5S RNA. Disturbances of the base pairing within this region do reduce the rate of reconstitution, however. Normal base pairing in the molecular stalk is thus required to ensure efficient ribosome assembly.


Genome-Wide Association Analysis Identifies Candidate Genes Regulating Seed Number Per Silique in Arabidopsis thaliana.
Seed weight and number ultimately determine seed yield. Arabidopsis seed number comprised of silique number and seed number per silique (SNS). Comparing seed development and weight, determinants of seed number remain largely uncharacterized. In this study, taking advantage of 107 available Arabidopsis accessions, genome-wide association analysis (GWAS) was employed to identify the candidate genes regulating SNS. GWAS-based genotype and phenotype association analysis identified 38 most significant SNPs marker sites that were mapped to specific chromosomal positions and allowed us to screen for dozens of candidate genes. One of them (PIN3) was selected for functional validation based on gene expression analysis. It is a positive regulator of Arabidopsis SNS. Although silique length of PIN3 loss of function mutant was not significantly changed, its SNS and seed density (SD) were significantly reduced as compared with the wild type. Notably, PIN3 overexpression lines driven by a placenta-specific promoter STK exhibited significantly shorter siliques, slightly reduced SNS, but significant increased SD compared with wild type, suggesting that PIN3 positively regulates SD through inducing ovule primordia initiation regardless of the placenta size. Ovule initiation determines the maximal possibility of SNS, and new genes and mechanism regulating SNS through modulating ovule initiation is worth further investigated.


Modeling the Dynamics of Eukaryotic DNA Synthesis in Remembrance of Tunde Ogunnaike.
Two things Tunde loved were dynamics and probability. The work described herein combined them both, which explains why Tunde invariably asked me each time we talked how this work was proceeding. However, as I've come to appreciate as reminiscent of a surprisingly large amount of work in almost any researcher's career, I did not complete a peer-reviewed article on the matter while he could see it. We were broadly motivated by analysis of data for total DNA content in single cells, across thousands of cells. From such data one can estimate the proportions of cells in different phases of the cell cycle by fitting a mixture model for subpopulations of G0/G1 phase cells (1 relative copy of the genome), S phase cells (between 1 and 2 relative copies of the genome), and G2/M phase cells (2 relative copies of the genome). Given an asynchronously cycling population, Gaussian models are reasonable for the G0/G1 and G2/M subpopulations, but an appropriate functional form for the S-phase subpopulation was unclear. Since the probability of observing an S-phase cell is intimately related to the dynamics of DNA replication, we worked to derive a model for DNA replication dynamics from first principles, resulting in a closed-form, analytic expression for the dynamics of DNA synthesis. While quite arguably a somewhat superfluous effort, there is a certain satisfaction and academic beauty to modeling systems from a first-principles approach, and it can sometimes lead to unexpected scientific insights. Yet, while mathematically elegant, there was a fundamental issue with a key assumption that the so-called inter-origin distance distribution (distances between DNA replication initiation sites) was time-invariant. First, I present the model as developed previously. Then, to address the time-invariant inter-origin distance distribution issue, I provide a treatment of time-varying inter-origin distance distributions that, while mathematically simple, provides (i) mechanistic predictions for how all the DNA in a fertilized frog egg can be replicated "on time" despite some inter-origin distances initially exceeding the corresponding amount of allowable time and (ii) evidence that, based only on data from DNA content versus time and average inter-origin distances, somatic cell DNA is parsed into distinct regions whose replication is temporally separate.


Case series on multimodal endoscopic therapy for gastric antral vascular ectasia, a tertiary center experience.
To study and describe patients who underwent treatment for gastric antral vascular ectasia (GAVE) with different endoscopic treatment modalities. We reviewed patients with GAVE who underwent treatment at University of Alabama at Birmingham between March 1, 2012 and December 31, 2016. Included patients had an endoscopic diagnosis of GAVE with associated upper gastrointestinal bleeding or iron deficiency anemia. Seven out of 15 patients had classic watermelon description for GAVE, 1/15 with diffuse/honeycomb pattern and 6/15 with nodular GAVE per EGD description. Seven out of 15 patients required multimodal treatment. Four out of six of patients with endoscopically nodular GAVE required multimodal therapy. Overall, mean pre- and post-treatment hemoglobin (Hb) values were 8.2 ± 0.8 g/dL and 9.7 ± 1.6 g/dL, respectively (P ≤ 0.05). Mean number of packed red blood cells transfusions before and after treatment was 3.8 ± 4.3 and 1.2 ± 1.7 (P ≤ 0.05), respectively. Patients with nodular variant GAVE required multimodal approach more frequently than non-nodular variants. Patients responded well to multimodal therapy and saw decrease in transfusion rates and increase in Hb concentrations. Our findings suggest a multimodal approach may be beneficial in nodular variant GAVE.


Kinetic isotope effects on the noncovalent flavin mutant protein of pyranose 2-oxidase reveal insights into the flavin reduction mechanism.
Pyranose 2-oxidase (P2O) from Trametes multicolor contains a flavin adenine dinucleotide (FAD) cofactor covalently linked to the N(3) atom of His167. The enzyme catalyzes the oxidation of aldopyranoses by molecular oxygen to generate 2-keto-aldoses and H(2)O(2) as products. In this study, the transient kinetics and primary and solvent kinetic isotope effects of the mutant in which His167 has been replaced with Ala (H167A) were investigated, to elucidate the functional role of the 8a-N(3)-histidyl FAD linkage and to gain insights into the reaction mechanism of P2O. The results indicate that the covalent linkage is mainly important for a reductive half-reaction in which the FAD cofactor is reduced by d-glucose, while it is not important for an oxidative half-reaction in which oxygen reacts with the reduced FAD to generate H(2)O(2). d-Glucose binds to H167A via multiple binding modes before the formation of the active Michaelis complex, and the rate constant of flavin reduction decreases approximately 22-fold compared to that of the wild-type enzyme. The reduction of H167A using d-glucose isotopes (2-d-d-glucose, 3-d-d-glucose, and 1,2,3,4,5,6,6-d(7)-d-glucose) as substrates indicates that the primary isotope effect results only from substitution at the C2 position, implying that H167A catalyzes the oxidation of d-glucose regiospecifically at this position. No solvent kinetic isotope effect was detected during the reductive half-reaction of the wild-type or H167A enzyme, implying that the deprotonation of the d-glucose C2-OH group may occur readily upon the binding to P2O and is not synchronized with the cleavage of the d-glucose C2-H bond. The mutation has no drastic effect on the oxidative half-reaction of P2O, as H167A is very similar to the wild-type enzyme with respect to the kinetic constants and the formation of the C4a-hydroperoxyflavin intermediate. Kinetic mechanisms for both half-reactions of H167A were proposed on the basis of transient kinetic data and were verified by kinetic simulations and steady-state kinetic parameters.


Malignant progression of liver cancer progenitors requires lysine acetyltransferase 7-acetylated and cytoplasm-translocated G protein GαS.
Hepatocarcinogenesis goes through HCC progenitor cells (HcPCs) to fully established HCC, and the mechanisms driving the development of HcPCs are still largely unknown. Proteomic analysis in nonaggregated hepatocytes and aggregates containing HcPCs from a diethylnitrosamine-induced HCC mouse model was screened using a quantitative mass spectrometry-based approach to elucidate the dysregulated proteins in HcPCs. The heterotrimeric G stimulating protein α subunit (GαS) protein level was significantly increased in liver cancer progenitor HcPCs, which promotes their response to oncogenic and proinflammatory cytokine IL-6 and drives premalignant HcPCs to fully established HCC. Mechanistically, GαS was located at the membrane inside of hepatocytes and acetylated at K28 by acetyltransferase lysine acetyltransferase 7 (KAT7) under IL-6 in HcPCs, causing the acyl protein thioesterase 1-mediated depalmitoylation of GαS and its cytoplasmic translocation, which were determined by GαS K28A mimicking deacetylation or K28Q mimicking acetylation mutant mice and hepatic Kat7 knockout mouse. Then, cytoplasmic acetylated GαS associated with signal transducer and activator of transcription 3 (STAT3) to impede its interaction with suppressor of cytokine signaling 3, thus promoting in a feedforward manner STAT3 phosphorylation and the response to IL-6 in HcPCs. Clinically, GαS, especially K28-acetylated GαS, was determined to be increased in human hepatic premalignant dysplastic nodules and positively correlated with the enhanced STAT3 phosphorylation, which were in accordance with the data obtained in mouse models. Malignant progression of HcPCs requires increased K28-acetylated and cytoplasm-translocated GαS, causing enhanced response to IL-6 and driving premalignant HcPCs to fully established HCC, which provides mechanistic insight and a potential target for preventing hepatocarcinogenesis.


Mathematical model of progressive renal disease.
A simple mathematical model is proposed that predicts the dynamics of chronic progressive renal disease. The model consists of coupled linear differential equations formed from three state variables, four control parameters, and three parameters related to initial conditions. All have straightforward physical interpretations. Applied to a population of nephrons, the model predicted the hypertrophic and sclerotic features of parenchyma progressing towards end-stage renal disease. Simulation results compared favorably with measurements obtained from the literature involving the subtotal nephrectomy rat model for renal disease. The time course of disease progression and treatment were considered. Also, the implications of the model for designing new diagnostic techniques using ultrasonic analysis are discussed.


A Graph-Based Approach to Identify Factors Contributing to Postoperative Lung Cancer Recurrence among Patients with Non-Small-Cell Lung Cancer.
The accurate identification of the preoperative factors impacting postoperative cancer recurrence is crucial for optimizing neoadjuvant and adjuvant therapies and guiding follow-up treatment plans. We modeled the causal relationship between radiographical features derived from CT scans and the clinicopathologic factors associated with postoperative lung cancer recurrence and recurrence-free survival. A retrospective cohort of 363 non-small-cell lung cancer (NSCLC) patients who underwent lung resections with a minimum 5-year follow-up was analyzed. Body composition tissues and tumor features were quantified based on preoperative whole-body CT scans (acquired as a component of PET-CT scans) and chest CT scans, respectively. A novel causal graphical model was used to visualize the causal relationship between these factors. Variables were assessed using the intervention do-calculus adjustment (IDA) score. Direct predictors for recurrence-free survival included smoking history, T-stage, height, and intramuscular fat mass. Subcutaneous fat mass, visceral fat volume, and bone mass exerted the greatest influence on the model. For recurrence, the most significant variables were visceral fat volume, subcutaneous fat volume, and bone mass. Pathologic variables contributed to the recurrence model, with bone mass, TNM stage, and weight being the most important. Body composition, particularly adipose tissue distribution, significantly and causally impacted both recurrence and recurrence-free survival through interconnected relationships with other variables.


Remote bednet use monitoring to describe patterns of use and exposure to female Anopheles mosquitoes in an Ugandan cohort.
Long lasting insecticide-treated bednets (LLINs) are the most widely used tool for preventing malaria. There has been a plateau in progress in the highest burden African countries since 2015, leading to questions about the effectiveness of LLINs. In this study, remote LLIN use monitors were deployed in a cohort in Eastern Uganda to explore how LLIN use interacts with mosquito exposure. The SmartNet study included 20 households from May to October 2019. SmartNet devices recorded, every 15 min, whether an LLIN was unfurled or folded up. Unannounced visits were used to assess SmartNet accuracy. Risk factors associated with poor LLIN use were assessed using generalized linear equations. Female Anopheles exposure was estimated by combining hourly probabilities of exposure from human landing catches and measures of density from biweekly CDC light traps in participants rooms. Mosquito exposure averted by LLINs was quantified using SmartNet measurements and age-related differences were estimated using generalized linear equations, adjusting for relevant covariates and household clustering. 96 individuals contributed 5,640 SmartNet observation nights. In 126 unannounced visits, SmartNet had an area under the curve of 0.869 in classifying whether the LLIN was up or down. The rate of non-use was 13.5% of nights (95% CI: 12.6-14.3%). Compared to children under 5, non-use was 1.8 times higher (95% CI: 1.6-2.1; p < 0.001) in children 5-15 years and 2.6 times higher (95% CI: 2.2-3.1; p < 0.001) in participants aged 15-<30years. There was no difference between children under 5 years and adults > 30 years. LLIN use averted 50.3% of female Anopheles mosquito exposure (95% CI: 40.0-60.0%), with decreasing point estimates of efficacy across age groups: from 61.7% (95% CI: 42.6-80.7%) in children under 5 years to 48.0% (95% CI: 29.1-66.8%) in adults over 30. Objective monitors are accurate and can feasibly be deployed to obtain data about LLIN use. LLINs provided protection from only 50% of female Anopheles mosquito exposure in this cohort and protection was dependent upon age. In assessing the role of LLINs in malaria prevention it is crucial to consider the dynamics between mosquito exposure and LLIN use behaviors.


Aerosol penetration study for FFP2 half masks regarding protection against diesel particles in underground mines.
Filtering facepieces (FFP), mainly class FFP2 particle half masks (EN 149:2001#x02009;+ A1:2009), are commonly used in European mines to protect workers from respirable dust, especially from particulate matter (PM) with a diameter of 4 µm or less (PM4). The aerosol associated with diesel exhaust (DE) is dominated by submicrometer particles (with a diameter of less than 1 µm) and nanoparticles (size in the range between 10 and 500 nm). In the European Union (EU), the occupational exposure level (OEL) for DE has been defined in terms of elemental carbon (EC) concentration. Based on measurements in underground mines, on average, 60% of EC associated with PM4 was contained in PM with a diameter of 1 µm or less (PM1). Particle number size distribution (PNSD) of PM1 showed that the most numerous were particles in the size range of 20 to 300 nm. Four popular types of certified FFP2 half masks were tested for penetration. Brand new and thermally conditioned masks of each type were included in the study. NaCl aerosol in the particle size range of 7 to 270 nm was used for tests. Filtration efficiencies of 98.5% (median) or higher were achieved. Aerosol penetration was a function of particle size. Maximum penetration was observed between 20 and 60 nm, depending on the type of mask. During filtration, aerosol characteristics changed. Nanoparticles ranging in size from 7 to about 60 nm were removed to a very limited extent. The change was more noticeable for brand-new masks compared to the thermally conditioned ones. Usually, aerosol penetration through thermally conditioned masks was lower and more consistent. It was confirmed that the half masks of the FFP2 class are capable of filtering submicrometer aerosol in particle size range 7 to 270 nm with an efficiency exceeding 96% and can contribute to achieving compliance with the OEL for DE in the mining sector.


Human prion diseases and the prion protein - what is the current state of knowledge?
Prion diseases and the prion protein are only partially understood so far in many aspects. This explains the continued research on this topic, calling for an overview on the current state of knowledge. The main objective of the present review article is to provide a comprehensive up-to-date presentation of all major features of human prion diseases bridging the gap between basic research and clinical aspects. Starting with the prion protein, current insights concerning its physiological functions and the process of pathological conversion will be highlighted. Diagnostic, molecular, and clinical aspects of all human prion diseases will be discussed, including information concerning rare diseases like prion-associated amyloidoses and Huntington disease-like 1, as well as the question about a potential human threat due to the transmission of prions from prion diseases of other species such as chronic wasting disease. Finally, recent attempts to develop future therapeutic strategies will be addressed.


An Update on the Prevention and Management of Bronchopulmonary Dysplasia.
Bronchopulmonary dysplasia (BPD) is a common morbidity affecting preterm infants and is associated with substantial long-term disabilities. There has been no change in the incidence of BPD over the past 20 years, despite improvements in survival and other outcomes. The preterm lung is vulnerable to injuries occurring as a result of invasive ventilation, hyperoxia, and infections that contribute to the development of BPD. Clinicians caring for infants in the neonatal intensive care unit use multiple therapies for the prevention and management of BPD. Non-invasive ventilation strategies and surfactant administration via thin catheters are treatment approaches that aim to avoid volutrauma and barotrauma to the preterm developing lung. Identifying high-risk infants to receive postnatal corticosteroids and undergo patent ductus arteriosus closure may help to individualize care and promote improved lung outcomes. In infants with established BPD, outpatient management is complex and requires coordination from several specialists and therapists. However, most current therapies used to prevent and manage BPD lack solid evidence to support their effectiveness. Further research is needed with appropriately defined outcomes to develop effective therapies and impact the incidence of BPD.


Statins in Acute Ischemic Stroke: A Systematic Review.
Statins have pleiotropic effects of potential neuroprotection. However, because of lack of large randomized clinical trials, current guidelines do not provide specific recommendations on statin initiation in acute ischemic stroke (AIS). The current study aims to systematically review the statin effect in AIS. From literature review, we identified articles exploring prestroke and immediate post-stroke statin effect on imaging surrogate markers, initial stroke severity, functional outcome, and short-term mortality in human AIS. We summarized descriptive overview. In addition, for subjects with available data from publications, we conducted meta-analysis to provide pooled estimates. In total, we identified 70 relevant articles including 6 meta-analyses. Surrogate imaging marker studies suggested that statin might enhance collaterals and reperfusion. Our updated meta-analysis indicated that prestroke statin use was associated with milder initial stroke severity (odds ratio [OR] [95% confidence interval], 1.24 [1.05-1.48]; P=0.013), good functional outcome (1.50 [1.29-1.75]; P<0.001), and lower mortality (0.42 [0.21-0.82]; P=0.0108). In-hospital statin use was associated with good functional outcome (1.31 [1.12-1.53]; P=0.001), and lower mortality (0.41 [0.29-0.58]; P<0.001). In contrast, statin withdrawal was associated with poor functional outcome (1.83 [1.01-3.30]; P=0.045). In patients treated with thrombolysis, statin was associated with good functional outcome (1.44 [1.10-1.89]; P=0.001), despite an increased risk of symptomatic hemorrhagic transformation (1.63 [1.04-2.56]; P=0.035). The current study findings support the use of statin in AIS. However, the findings were mostly driven by observational studies at risk of bias, and thereby large randomized clinical trials would provide confirmatory evidence.


Conformational calculations of the N-terminal hydrophilic segment of human erythrocyte glycophorin.
The study is focused on the secondary structure of the external N-terminal segment of human erythrocyte glycophorin A (NN) which was determined by applying methods of CHOU et FASMAN and LIM. This hydrophilic glycophorin segment is assumed to consist of 48.5% ordered (alpha-helix, beta-sheet, beta-turn) and 51.5% unordered sequences. From the secondary structure suggestions are made concerning (i) peptide interaction and (ii) binding to the lipid bilayer of the N-terminal segment.


Stimulation of sperm motility and oxygen consumption of fowl spermatozoa by a low molecular weight fraction of seminal plasma.
Washed fowl spermatozoa were incubated in a phosphate buffer containing various concentrations of fowl seminal plasma at 41 degrees C, normal body temperature, and the motility and oxygen consumption of spermatozoa were determined. Immediately after the incubation, spermatozoa showed good motility in the various diluents. However, with concentrations of seminal plasma at or below 20%, spermatozoa quickly became immotile. In contrast, at concentrations higher than 40% seminal plasma, spermatozoa were motile even after 15 min. As the concentration of seminal plasma was increased, oxygen consumption of spermatozoa also increased. A filtrate of the seminal plasma, obtained by passing the fluid through an Amicon YM-2 ultra-filtration membrane (Mr less than 1000), also stimulated the motility and oxygen consumption of spermatozoa. These results suggest that some low molecular weight factor(s) in fowl seminal plasma stimulated motility and oxygen consumption of fowl spermatozoa at 41 degrees C. A physiological role of this factor(s) may be to assist passage of spermatozoa through the vagina after natural mating.


Autoantibodies: the search for origins, target autoantigens and pathogenicity.
The origins of autoantibodies remain largely unknown. Burnet suggested that self-reactive clones of B lymphocytes are deleted during ontogeny and that 'forbidden' clones of autoantibody-producing B lymphocytes arise as a consequence of somatic mutation of the variable regions of immunoglobulin genes. The alternative view, which is gaining increasing support, is that autoreactive B cells are present in all normal individuals but are held in check by control mechanisms, e.g. by the idiotypic network of Jerne. Autoantibodies segregate with clusters of autoimmune diseases and are useful diagnostic markers of these diseases. The autoantigens targeted by these autoantibodies are largely unknown. The precise molecular characteristics of these autoantigens are currently under active investigation by immunochemical and recombinant DNA methods. Precise definition of these autoepitopes should lead to sensitive immunoassays and studies directed at determining the pathogenicity of the autoantigens. The new knowledge gained in this way may lead to successful restoration of tolerance to self antigens.


Factors determining physical activity of Ukrainian students.
Scientific reports provide information concerning an insufficient level of physical activity of societies. The objective of the study is recognition of the level of physical activity among Ukrainian students, and factors which condition this activity: gender, place of residence, self-reported physical fitness, and the BMI. The study was conducted in 2013 among 2,125 Ukrainian students using a long version of the International Physical Activity Questionnaire (IPAQ), supplemented with data concerning the respondents' physical development. The results of the study showed that the mean total physical activity of students was 3.560 MET, and its highest percentage pertained to the area of activity in sports - 1.124 MET. Significantly higher statistically physical activity was observed among males than females. In males, the highest activity was related to participation in sports classes, while in females - engagement in household chores. It was found that males, compared to females, were significantly more physically active in such areas as occupational activity (education) and sports activity, whereas females showed higher activity performing household chores. According to the place of residence, inhabitants of medium-size towns and rural areas obtained the most favourable results in activity, while the inhabitants of large cities the poorest. Self-reported physical fitness was significantly correlated with the results in physical activity obtained by the students. No relationship was found between the BMI and the level of student's physical activity. Considering the very large population of respondents, the results obtained may be considered as an up-to-date pattern of physical activity among Ukrainian students.


Magnetic-dipole transitions in highly charged ions as a basis of ultraprecise optical clocks.
We evaluate the feasibility of using magnetic-dipole (M1) transitions in highly charged ions as a basis of an optical atomic clockwork of exceptional accuracy. We consider a range of possibilities, including M1 transitions between clock levels of the same fine-structure and hyperfine-structure manifolds. In highly charged ions these transitions lie in the optical part of the spectra and can be probed with lasers. The most direct advantage of our proposal comes from the low degeneracy of clock levels and the simplicity of atomic structure in combination with negligible quadrupolar shift. We demonstrate that such clocks can have projected fractional accuracies below the 10^{-20}-10^{-21} level for all common systematic effects, such as blackbody radiation, Zeeman, ac-Stark, and quadrupolar shifts.


Distance travelled to purchase alcohol and the mediating effect of price.
Little research has been done into the distance travelled by consumers to purchase alcohol, whether this is influenced by demographic characteristics or drinking levels of consumers, and the effect of price on purchase distance. This study aimed to explore distances drinkers were prepared to travel to purchase alcohol at on- and off-site outlets and how these decisions were affected by price discounting. Online survey. The study, including 831 alcohol consumers aged 18 years and older living in Australian capital cities, was undertaken in 2012. The survey was used to gather data on the distances which participants anticipated that they usually travelled to purchase alcohol. The data provided insight into which factors influence where participants would choose to purchase alcohol and the possible effects of price discounts on purchase distance. Most participants would choose to travel less than 10 km to purchase alcohol. Data indicated that price discounting might increase the purchase distance that most participants would be prepared to travel to purchase alcohol; this was more marked regarding off-site outlets and among high-risk drinking groups including young males and participants with risky drinking levels. Price discounting affects hypothetical purchase distance choices, indicating the importance of price when implementing alcohol control policies. Purchase distance might be more affected by price discounting among consumers visiting off-site outlets, but less useful when exploring associations with on-site outlets.


Association between the electrophoretically-determined C4M haplotype product and partial inhibition of anti-Cha.
C4-coated Ch(a+) red blood cells (RBC) were used as indicator cells in a serum inhibition reaction of anti-Ch(a), for the determination of the Ch group of serum. This serological study, combined with electrophoretic studies of C4 in a family material, showed that the C4M haplotype product was associated with partial inhibition of anti-Ch(a).


[Poly adenosine diphosphate-ribosylation and neurodegenerative diseases].
The morbidity of neurodegenerative diseases are increased in recent years, however, the treatment is limited. Poly ADP-ribosylation (PARylation) is a post-translational modification of protein that catalyzed by poly(ADP-ribose) polymerase (PARP). Studies have shown that PARylation is involved in many neurodegenerative diseases such as stroke, Parkinson's diseases, Alzheimer's disease, amyotrophic lateral sclerosis and so on, by affecting intracellular translocation of protein molecules, protein aggregation, protein activity, and cell death. PARP inhibitors have showed neuroprotective efficacy for neurodegenerative diseases in pre-clinical studies and phase Ⅰ clinical trials. To find new PARP inhibitors with more specific effects and specific pharmacokinetic characteristics will be the new direction for the treatment of neurodegenerative diseases. This paper reviews the recent progress on PARylation in neurodegenerative diseases.