The Direct Interaction between Two Morphogenetic Proteins Is Essential for Spore Coat Formation in Bacillus subtilis.
In Bacillus subtilis the protective layers that surround the mature spore are formed by over seventy different proteins. Some of those proteins have a regulatory role on the assembly of other coat proteins and are referred to as morphogenetic factors. CotE is a major morphogenetic factor, known to form a ring around the forming spore and organize the deposition of the outer surface layers. CotH is a CotE-dependent protein known to control the assembly of at least nine other coat proteins. We report that CotH also controls the assembly of CotE and that this mutual dependency is due to a direct interaction between the two proteins. The C-terminal end of CotE is essential for this direct interaction and CotH cannot bind to mutant CotE deleted of six or nine C-terminal amino acids. However, addition of a negatively charged amino acid to those deleted versions of CotE rescues the interaction.


Nanopore-facilitated, voltage-driven phosphatidylserine translocation in lipid bilayers--in cells and in silico.
Nanosecond, megavolt-per-meter pulses--higher power but lower total energy than the electroporative pulses used to introduce normally excluded material into biological cells--produce large intracellular electric fields without destructively charging the plasma membrane. Nanoelectropulse perturbation of mammalian cells causes translocation of phosphatidylserine (PS) to the outer face of the cell, intracellular calcium release, and in some cell types a subsequent progression to apoptosis. Experimental observations and molecular dynamics (MD) simulations of membranes in pulsed electric fields presented here support the hypothesis that nanoelectropulse-induced PS externalization is driven by the electric potential that appears across the lipid bilayer during a pulse and is facilitated by the poration of the membrane that occurs even during pulses as brief as 3 ns. MD simulations of phospholipid bilayers in supraphysiological electric fields show a tight association between PS externalization and membrane pore formation on a nanosecond time scale that is consistent with experimental evidence for electropermeabilization and anode-directed PS translocation after nanosecond electric pulse exposure, suggesting a molecular mechanism for nanoelectroporation and nanosecond PS externalization: electrophoretic migration of the negatively charged PS head group along the surface of nanometer-diameter electropores initiated by field-driven alignment of water dipoles at the membrane interface.


Comparative Cerebroprotective Potential of d- and l-Carnosine Following Ischemic Stroke in Mice.
l-carnosine is an attractive therapeutic agent for acute ischemic stroke based on its robust preclinical cerebroprotective properties and wide therapeutic time window. However, large doses are needed for efficacy because carnosine is rapidly degraded in serum by carnosinases. The need for large doses could be particularly problematic when translating to human studies, as humans have much higher levels of serum carnosinases. We hypothesized that d-carnosine, which is not a substrate for carnosinases, may have a better pharmacological profile and may be more efficacious at lower doses than l-carnosine. To test our hypothesis, we explored the comparative pharmacokinetics and neuroprotective properties of d- and L-carnosine in acute ischaemic stroke in mice. We initially investigated the pharmacokinetics of d- and L-carnosine in serum and brain after intravenous (IV) injection in mice. We then investigated the comparative efficacy of d- and l-carnosine in a mouse model of transient focal cerebral ischemia followed by in vitro testing against excitotoxicity and free radical generation using primary neuronal cultures. The pharmacokinetics of d- and l-carnosine were similar in serum and brain after IV injection in mice. Both d- and l-carnosine exhibited similar efficacy against mouse focal cerebral ischemia. In vitro studies in neurons showed protection against excitotoxicity and the accumulation of free radicals. d- and l-carnosine exhibit similar pharmacokinetics and have similar efficacy against experimental stroke in mice. Since humans have far higher levels of carnosinases, d-carnosine may have more favorable pharmacokinetics in future human studies.


THE GENETIC STRUCTURE OF A GYNODIOECIOUS PLANT: NUCLEAR AND CYTOPLASMIC GENES.
Sex expression in gynodioecious plants is often determined by an interaction between biparentally and maternally inherited genes. Their relative rates of gene flow should be considered when modeling the evolution of the sex ratio in structured populations. In order to understand patterns of gene flow in Silene vulgaris, a gynodioecious plant, genetic structure was estimated from biparentally inherited genetic markers (allozymes) and a maternally inherited marker (chloroplast DNA) using Wright's Fst . Based on data from 16 local populations, chloroplast DNA showed considerably more genetic structure than did allozymes (Fst values of 0.62 and 0.22, respectively). This suggests that the rate of gene flow is about three times greater for nuclear genes.


Sapphire optical viewport for high pressure and temperature applications.
We describe the design of a soldered sapphire optical viewport, which is useful for spectroscopic applications of samples at high temperatures and high pressures. The sapphire window is bonded via active soldering to a metal flange with a structure of two c-shaped rings made of different metallic materials in between, so as to mitigate thermally induced stress. A spectroscopic cell equipped with two of the optical viewports has been successfully operated with alkali metals in a noble gas environment at temperatures in the range of 20-450 °C at noble gas pressures from 10-6 mbar to 330 bars. In the upper pressure range, we observe a leakage rate smaller than our readout accuracy of 30 mbar per day.


Factors associated with family caregiver dissatisfaction with acute hospital care of older cognitively impaired relatives.
To identify patient and caregiver characteristics associated with caregiver dissatisfaction with hospital care of cognitively impaired elderly adults. Secondary analysis of data from a randomized controlled trial. An 1,800-bed general hospital in England providing the only emergency medical services in its area. Cognitively impaired individuals aged 65 and older randomly assigned to a specialist unit or standard geriatric or internal medical wards (N = 600) and related caregivers (N = 488). Patient and caregiver health status was measured at baseline, including delirium, cognitive impairment, behavioral and psychological symptoms, activities of daily living, and caregiver strain. Caregiver satisfaction with quality of care was ascertained after hospital discharge or death. Four hundred sixty-two caregivers completed satisfaction questionnaires. Regardless of assignment, 54% of caregivers were dissatisfied with some aspects of care, but overall 87% were satisfied with care. The main areas of dissatisfaction were communication, discharge planning, and medical management. Dissatisfaction was associated with high levels of patient behavioral and psychological symptoms on admission, caregiver strain and poor psychological well-being at admission, a diagnosis of delirium, and the relationship between the caregiver and the patient. There was less dissatisfaction from caregivers of patients managed on the specialist Medical and Mental Health Unit than those on standard wards, after controlling for multiple factors. Dissatisfaction was associated with patient behavioral and psychological symptoms and caregiver strain but was not immutable to efforts to improve care.


Bi nanoparticles confined in N,S co-doped carbon nanoribbons with excellent rate performance for sodium-ion batteries.
Bismuth (Bi) has emerged as a promising candidate for sodium-ion battery anodes because of its unique layered crystal structure, superior volumetric capacity, and high theoretical gravimetric capacity. However, the large volume expansion and severe aggregation of Bi during the alloying/dealloying reactions are extremely detrimental to cycling stability, which seriously hinders its practical application. To overcome these issues, we propose an effective synthesis of composite materials, encapsulating Bi nanoparticles in N,S co-doped carbon nanoribbons and composites with carbon nanotubes (N,S-C@Bi/CNT), using Bi2S3 nanobelts as templates. The uniform distribution of Bi nanoparticles and the structure of carbon nanoribbons can reduce the diffusion path of ions/electrons, efficiently buffer the large volume change and prevent Bi from aggregating during cycles. As expected, the N,S-C@Bi/CNT electrode shows superior sodium storage performance in half cells, including a high specific capacity (345.3 mA h g-1 at 1.0 A g-1), long cycling stability (1000 cycles), and superior rate capability (336.0 mA h g-1 at 10.0 A g-1).


Effects of pioglitazone on renal calcium excretion.
Glitazones increase fracture risk in long-term users and in postmenopausal women. Studies have demonstrated deleterious effects of glitazones on bone metabolism. Glitazones also have direct renal tubular effects increasing sodium reabsorption. We hypothesized that glitazones may also regulate renal calcium excretion. In this double-blind, randomized, placebo-controlled, four-way, crossover study, we examined the effects of pioglitazone (45 mg/d for 6 wk) or placebo on renal calcium and phosphate excretion and PTH levels during different sodium intakes in 16 individuals (eight with type 2 diabetes and eight with essential hypertension). Pioglitazone had no effect on corrected plasma calcium and phosphate levels but decreased significantly the alkaline phosphatase and PTH levels. Pioglitazone induced on average a 45% increase in urinary calcium excretion. The fractional excretion of calcium rose to the same extent, suggesting a glomerular filtration rate-independent effect. Sodium intake did not influence the calciuric effect of pioglitazone. Changes in diurnal and nocturnal calciuria were similar. There was no effect of pioglitazone on phosphate excretion. Pioglitazone decreases PTH levels and increases urinary calcium excretion, independently from changes in glomerular filtration rate and from the sodium load, suggesting an inhibitory effect of pioglitazone on the tubular reabsorption of calcium. These effects may contribute to the increased fracture risk with glitazone treatment.


Lineage-specific duplication and loss of pepsinogen genes in hominoid evolution.
Fourteen different pepsinogen-A cDNAs and one pepsinogen-C cDNA have been cloned from gastric mucosa of the orangutan, Pongo pygmaeus. Encoded pepsinogens A were classified into two groups, i.e., types A1 and A2, which are different in acidic character. The occurrence of 9 and 5 alleles of A1 and A2 genes (at least 5 and 3 loci), respectively was anticipated. Respective orthologous genes are present in the chimpanzee genome although their copy numbers are much smaller than those of the orangutan genes. Only A1 genes are present in the human probably due to the loss of the A2 gene. Molecular phylogenetic analyses showed that A1 and A2 genes diverged before the speciation of great hominoids. Further reduplications of respective genes occurred several times in the orangutan lineage, with much higher frequencies than those occurred in the chimpanzee and human lineages. The rates of non-synonymous substitutions were higher than those of synonymous ones in the lineage of A2 genes, implying the contribution of the positive selection on the encoded enzymes. Several sites of pepsin moieties were indeed found to be under positive selection, and most of them locate on the surface of the molecule, being involved in the conformational flexibility. Deduced from the known genomic structures of pepsinogen-A genes of primates and other mammals, the duplication/loss were frequent during their evolution. The extreme multiplication in the orangutan might be advantageous for digestion of herbaceous foods due to the increase in the level of enzymes in stomach and the diversification of enzyme specificity.


Definition of Iron Deficiency Based on the Gold Standard of Bone Marrow Iron Staining in Heart Failure Patients.
The most commonly used definition of iron deficiency (ID; ferritin <100 ng/mL or ferritin 100-300 ng/mL and transferrin saturation [TSAT] <20%) has not been validated in patients with heart failure (HF). We aimed to define and validate the biomarker-based definition of ID in HF, using bone marrow iron staining as the gold standard. Second, we aimed to assess the prognostic value of the optimized definition. Bone marrow aspiration with iron staining was performed in 42 patients with HF and a reduced left ventricular ejection fraction (≤45%) undergoing median sternotomy for coronary artery bypass grafting. Patients were mostly male (76%) with mild-to-moderate HF and a mean age of 68±10 years. Bone marrow ID was found in 17 (40%) of the HF patients. The most commonly used definition of ID had a sensitivity of 82% and a specificity of 72%. A definition solely based on TSAT ≤19.8% or serum iron ≤13 µmol/L had a sensitivity of 94% and specificity of 84% and 88%, respectively (P<0.05 compared with the former definition). Subsequently, we assessed the incidence of all-cause mortality in 387 consecutive outpatient HF patients (left ventricular ejection fraction ≤45%). In these patients, TSAT ≤19.8% and serum iron ≤13 µmol/L, and not ferritin, were independently associated with mortality. A TSAT ≤19.8% or a serum iron ≤13 µmol/L shows the best performance in selecting patients with ID and identifies HF patients at the highest risk of death. Our findings validate the currently used TSAT cutoff of <20% for the identification of ID in HF patients, but question the diagnostic value of ferritin.


A low-power bio-potential acquisition system with flexible PDMS dry electrodes for portable ubiquitous healthcare applications.
This work describes a bio-potential acquisition system for portable ubiquitous healthcare applications using flexible polydimethylsiloxane dry electrodes (FPDEs) and a low-power recording circuit. This novel FPDE used Au as the skin contact layer, which was made using a CO2 laser and replica method technology. The FPDE was revised from a commercial bio-potential electrode with a conductive snap using dry electrodes rather than wet electrodes that proposed reliable and robust attachment for the purpose of measurement, and attaching velcro made it wearable on the forearm for bio-potential applications. Furthermore, this study proposes a recording device to store bio-potential signal data and provides portability and low-power consumption for the proposed acquisition system. To acquire differential bio-potentials, such as electrocardiogram (ECG) signals, the proposed recording device includes a low-power front-end acquisition chip fabricated using a complementary metal-oxide-semiconductor (CMOS) process, a commercial microcontroller (MSP430F149), and a secure digital (SD) card for portable healthcare applications. The proposed system can obtain ECG signals efficiently and are comfortable to the skin. The power consumption of the system is about 85 mW for continuous working over a 3 day period with two AA batteries. It can also be used as a compact Holter ECG system.


Regional nerve injury after intra-arterial chemotherapy.
Eleven patients at M.D. Anderson Hospital were referred for neurologic evaluation after having their internal or external iliac arteries catheterized for the treatment of localized pelvic or lower extremity tumors. Nine patients developed lumbosacral plexopathies and two patients, mononeuropathies. All symptoms occurred within 48 hours of the intra-arterial infusion. All patients received cis-dichlorodiammine-platinum (cisplatin; CDDP) intra-arterially, alone or in combination with other agents. Follow-up examinations revealed that only one patient had made partial recovery from the neurologic dysfunction. Chemotherapy-induced small vessel injury, with subsequent plexus or nerve infarction, appears to be the most likely cause, although a direct neurotoxic effect of CDDP cannot be excluded.


Use of an oral phosphodiesterase-4 inhibitor (apremilast) for the treatment of chronic, severe atopic dermatitis: a case report.
Atopic dermatitis (AD) is a common inflammatory dermatosis characterized by pruritus, erythema, induration, and lichenification. Current treatment options for generalized atopic dermatitis are limited and have potentially serious adverse effects, especially in patients with severe, chronic AD who frequently require systemic anti-inflammatory agents. Apremilast, an oral phosphodiesterase-4 inhibitor, was FDA approved in September 2014 for the treatment of moderate-to-severe plaque psoriasis. However, its upstream anti-inflammatory effects, ease of use as an oral agent, and mild side-effect profile make it an interesting treatment option for AD as well. Herein, we present a patient with a life-long history of AD recalcitrant to topical steroids and cyclosporine who attained subjective and objective improvement in pruritus and erythema after 10-week treatment with apremilast.


Physiology of mastitis and factors affecting somatic cell counts.
Inflammation of the mammary gland that results from the introduction and multiplication of pathogenic microorganisms in the mammary gland is a complex series of events leading to reduced synthetic activity, compositional changes, and elevated SCC. The magnitude and temporal relationships of these responses vary with nutritional status, other animal factors, and the pathogen involved. Because the elevation of SCC is a response to an insult to the mammary gland and is modulated by inflammatory mediators, the major factor influencing SCC is infection status. The effects of stage of lactation, age, season, and various stresses on SCC are minor if the gland is uninfected. Except for normal diurnal variation, few factors other than infection status have a significant impact on milk SCC.


Optochemical Control of mRNA Translation in Eukaryotes.
A major stage in the expression of genes is the translation of messenger RNA (mRNA), and the regulation of this process is essential for protein production in cells. How tightly controlled gene expression can be spatially and temporally, is particularly evident in polar cells and embryonic development. We need tools to dissect these complex processes, if we wish to understand the underlying links, especially the difficulties brought on by malfunction. External bioorthogonal triggers are very helpful in this area, if they let us precisely control where and when a process is started. Equipping nucleic acids with light-responsive groups has proven to be an effective approach to examine the dynamic regulatory route of mRNA translation in living cells. In this review, we present an overview of the most recent methods for optochemically controlling translation, focusing on cis-acting technologies.


Using context to train time-domain echolocation click detectors.
This work demonstrates the effectiveness of using humans in the loop processes for constructing large training sets for machine learning tasks. A corpus of over 57 000 toothed whale echolocation clicks was developed by using a permissive energy-based echolocation detector followed by a machine-assisted quality control process that exploits contextual cues. Subsets of these data were used to train feed forward neural networks that detected over 850 000 echolocation clicks that were validated using the same quality control process. It is shown that this network architecture performs well in a variety of contexts and is evaluated against a withheld data set that was collected nearly five years apart from the development data at a location over 600 km distant. The system was capable of finding echolocation bouts that were missed by human analysts, and the patterns of error in the classifier consist primarily of anthropogenic sources that were not included as counter-training examples. In the absence of such events, typical false positive rates are under ten events per hour even at low thresholds.


Novel robust hepatitis C virus mouse efficacy model.
The lack of a robust small-animal model for hepatitis C virus (HCV) has hindered the discovery and development of novel drug treatments for HCV infections. We developed a reproducible and easily accessible xenograft mouse efficacy model in which HCV RNA replication is accurately monitored in vivo by real-time, noninvasive whole-body imaging of gamma-irradiated SCID mice implanted with a mouse-adapted luciferase replicon-containing Huh-7 cell line (T7-11). The model was validated by demonstrating that both a small-molecule NS3/4A protease inhibitor (BILN 2061) and human alpha interferon (IFN-alpha) decreased HCV RNA replication and that treatment withdrawal resulted in a rebound in replication, which paralleled clinical outcomes in humans. We further showed that protease inhibitor and IFN-alpha combination therapy was more effective in reducing HCV RNA replication than treatment with each compound alone and supports testing in humans. This robust mouse efficacy model provides a powerful tool for rapid evaluation of potential anti-HCV compounds in vivo as part of aggressive drug discovery efforts.


The contributions of Sam Greenhouse to research on psychiatric diagnosis and psychopharmacology.
Sam Greenhouse began his involvement in mental disorders research in 1954 when appointed chief of the Theoretical Statistics and Mathematics section at the National Institute of Mental Health. He remained with the NIMH until 1966. Despite moving on to several other positions at the NIH and at the university during the ensuing years, he continued as a consultant to NIMH investigators. He also participated actively as an advisor and co-investigator on a number of important collaborative research programmes launched by the Institute in the 1970s and 1980s. His contributions to the design and methodology of the first clinical trials of drugs for the treatment of schizophrenia, to research aimed at revising the national and international classification systems for the mental disorders, and his participation in the planning of the first attempt to use the collaborative research model to test hypotheses about the genesis of a specific mental disorder (depression), are described. Finally, the signal importance of the 'profile analysis of variance' method that he and Seymour Geisser developed, to research on personality and mental disorders, is examined in detail. The authors describe applications of the method in their own research on the classification of the mental disorders, predicting response to drug treatment and the variations in the expression of mental illness across different cultures. Sam worked in mental health during an era of revolutionary changes in the diagnosis and treatment of mental disorders. The field was acutely aware of his many contributions to the progress of research and his colleagues are very grateful to have had the opportunity to work with him.


[Evaluation of the Unicel DXC 600 (Beckman Coulter) and comparison with Integra 800 (Roche Diagnostics)].
The Unicel DXC 600 is an automated analytical system from Beckman Coulter for measuring usual biochemistry parameters (electrolytes, substrates and enzymatic activities), therapeutic drugs, drugs of abuse and specific proteins. According to the "Société française de biologie clinique (SFBC)" validation protocol, we tested the following parameters: electrolytes (sodium, potassium, chloride, total CO2), substrates (uric acid, calcium, phosphate, glucose, creatinine, urea, cholesterol, HDL cholesterol, bilirubin, iron, triglycerides), enzymes (ALAT, ASAT, amylase, CK, GGT, LDH, lipase, ALP), total proteins and specific proteins (albumin, CRP, haptoglobin). The results confirm the excellent analytical performances regarding imprecision. The comparison study shows differences between values obtained with Unicel DXC 600 and Integra 800 (Roche diagnostics), leading to the use of correcting factors for some parameters.


Transcatheter pulmonary valve implantation: valve technology and procedural outcome.
Procedural technique and short-term outcomes of transcatheter pulmonary valve implantation (TPVI) have been widely described. The purpose of this article is to provide an update on current valve technology, and to focus on recent data surrounding TPVI in the dilated right ventricular outflow tract (RVOT), hybrid interventions, significant outcomes, and procedural costs. Transcatheter valve technology has expanded with current trials evaluating self-expandable valves that can be implanted in dilated RVOTs. Until those valves are widely available, hybrid techniques have been shown to offer a potential alternative in these patients, as well as in patients of small size. Although medium-term results of TPVI have shown 5-year freedom from reintervention or replacement of 76%, new data have underlined some concerns relating to bacterial endocarditis after the procedure. Procedural costs remain a concern, but vary greatly between institutions and healthcare systems. TPVI has emerged as one of the most innovative procedures in the treatment of patients with dysfunctional RVOT and pulmonary valves. Further device development is likely to expand the procedure to patients of smaller size and with complex, dilated RVOTs.


Lipid nanoparticles-loaded with toxin mRNA represents a new strategy for the treatment of solid tumors.
Background and rationale: Cancer therapy have evolved remarkably over the past decade, providing new strategies to inhibit cancer cell growth using immune modulation, with or without gene therapy. Specifically, suicide gene therapies and immunotoxins have been investigated for the treatment of tumors by direct cancer cell cytotoxicity. Recent advances in mRNA delivery also demonstrated the potential of mRNA-based vaccines and immune-modulators for cancer therapeutics by utilizing nanocarriers for mRNA delivery. Methods: We designed a bacterial toxin-encoding modified mRNA, delivered by lipid nanoparticles into a B16-melanoma mouse model. Results: We showed that local administration of LNPs entrapping a modified mRNA that encodes for a bacterial toxin, induced significant anti-tumor effects and improved overall survival of treated mice. Conclusions: We propose mmRNA-loaded LNPs as a new class of anti-tumoral, toxin-based therapy.


Organic Donor-Acceptor System Exhibiting Electrical Bistability for Use in Memory Devices.
An all-organic electrically bistable device and its application in non-volatile memory is reported. The switching mechanism is attributed to electric-field-induced charge transfer from an organic electron donor to an acceptor, so that the device switches from a low- to a high-conductivity state. This device provides a new direction for data-storage technology based on organic composites.


CRISPRclassify: Repeat-Based Classification of CRISPR Loci.
Detection and classification of CRISPR-Cas systems in metagenomic data have become increasingly prevalent in recent years due to their potential for diverse applications in genome editing. Traditionally, CRISPR-Cas systems are classified through reference-based identification of proximate cas genes. Here, we present a machine learning approach for the detection and classification of CRISPR loci using repeat sequences in a cas-independent context, enabling identification of unclassified loci missed by traditional cas-based approaches. Using biological attributes of the CRISPR repeat, the core element in CRISPR arrays, and leveraging methods from natural language processing, we developed a machine learning model capable of accurate classification of CRISPR loci in an extensive set of metagenomes, resulting in an F1 measure of 0.82 across all predictions and an F1 measure of 0.97 when limiting to classifications with probabilities >0.85. Furthermore, assessing performance on novel repeats yielded an F1 measure of 0.96. Although the performance of cas-based identification will exceed that of a repeat-based approach in many cases, CRISPRclassify provides an efficient approach to classification of CRISPR loci for cases in which cas gene information is unavailable, such as metagenomes and fragmented genome assemblies.


Pyrene-Bridged Expanded Carbaporphyrin Nanobelts.
Two belt-like expanded carbaporphyrins (NB1 and NB2) were prepared via a one-pot procedure that involves a [6 + 3] condensation between a pyrene-bearing tetrapyrrole precursor (2) and pentafluorobenzaldehyde, followed by oxidation. Single crystal X-ray diffraction analyses revealed that NB1 and NB2 both contain six dipyrromethene moieties and three bridging pyrene units. In the structure of NB1, there are two vertically orientated pyrene units and one transverse orientated pyrene unit; however, in NB2 all three pyrene units are vertically orientated. The structural differences between NB1 and NB2 are reflected in their respective physical properties as revealed by proton NMR, UV-vis, and fluorescence spectroscopies. In contrast to all-carbon nanobelts, NB1 and NB2 contain multiple pyrrolic nitrogen donors that could serve as potential metal coordination sites. As a test of this possibility, NB2 was used to prepare an unprecedented Zn complex containing 7 Zn2+ metal centers connected by a network of bridging atoms, as confirmed by a single crystal X-ray diffraction analysis. To the best of our knowledge, this is the first example of a belt-like molecular system that can coordinate multiple metal ions both along the backbone and within its central cavity.


Patient-Directed Vasectomy Information: How Readable Is It?
To assess the quality and readability of online health information on vasectomy using validated readability and quality assessment tools. The top 50 search results for "vasectomy" on Google, Bing, and Yahoo were selected. Duplicate links, advertisements, blog posts, paid webpages, and information intended for healthcare providers were excluded. Flesch Reading Ease score, Flesch-Kincaid Grade level, Gunning Fog Index, and Simple Measure of Gobbledygook (SMOG) index were used to assess readability, with optimal readability level for online health information established as being at sixth grade reading level. DISCERN Instrument and JAMA Benchmark were used to assess the quality of selected webpages. Inter-assessment score correlation and results by webpage type were analyzed. We analyzed 44 webpages, including 16 academic, 5 hospital-affiliated, 6 commercial, 13 non-profit health advocacy, and 4 uncategorized sources. The average readability of the evaluated webpages was at a 10th grade reading level as measured by the Flesch Kincaid Assessment tool, and an undergraduate reading level per the SMOG and Gunning Fog indices. Non-profit health advocacy webpages had the best reading level but still was not at the recommended level of grade 6 to 7. The overall DISCERN quality of the webpages was "fair", with non-profit health advocacy pages performing best. The assessed webpages offer education on vasectomy in a language that is too complex for the general population to understand. Furthermore, several sources for online health information, such as non-profits, outperformed webpages by academic institutions. Increased healthcare collaboration and dedication to producing quality online patient resources is necessary to address these shortcomings and build trust among patients to increase utilization of vasectomy and decrease decisional regret.


Hidden Hemibonding in the Aqueous Hydroxyl Radical.
The existence of a two-center, three-electron hemibond in the first solvation shell of •OH(aq) has long been a matter of debate. The hemibond manifests in ab initio molecular dynamics simulations as a small-r feature in the oxygen radial distribution function (RDF) for H2O···•OH, but that feature disappears when semilocal density functionals are replaced with hybrids, suggesting a self-interaction artifact. Using periodic simulations at the PBE0+D3 level, we demonstrate that the hemibond is actually still present (as evidenced by delocalization of the spin density) but is obscured by the hydrogen-bonded feature in the RDF due to a slight elongation of the hemibond. Computed electronic spectra for •OH(aq) are in excellent agreement with experiment and confirm that hemibond-like configurations play an outsized role in the spectroscopy due to an intense charge-transfer transition that is strongly attenuated in hydrogen-bonded configurations. Apparently, 25% exact exchange (as in PBE0) is insufficient to eliminate delocalization of unpaired spins.


Integrating health services research into nursing doctoral programs: the evolution of nursing research.
Traditionally, nursing research has focused on the effect of an intervention on selected patients without considering the influence of the system of care and its myriad characteristics. Health services research (HSR) focuses on organization and financing of health services; access to health care; quality of care; clinical evaluation and outcomes research; informatics and clinical decision making; practitioner, patient, and consumer behavior; health professions workforce; health policy formulation and analyses; and health care model and service use. Doctoral students can benefit from HSR's broad perspective if it is included in existing nursing curricula. Ultimately, HSR could help the nursing profession achieve the capacity to develop health policy and new systems of health care for the 21st century.


Novel Nongenetic Murine Model of Hyperglycemia and Hyperlipidemia-Associated Aggravated Atherosclerosis.
Atherosclerosis, the main pathology underlying cardiovascular diseases is accelerated in diabetic patients. Genetic mouse models require breeding efforts which are time-consuming and costly. Our aim was to establish a new nongenetic model of inducible metabolic risk factors that mimics hyperlipidemia, hyperglycemia, or both and allows the detection of phenotypic differences dependent on the metabolic stressor(s). Wild-type mice were injected with gain-of-function PCSK9D377Y (proprotein convertase subtilisin/kexin type 9) mutant adeno-associated viral particles (AAV) and streptozotocin and fed either a high-fat diet (HFD) for 12 or 20 weeks or a high-cholesterol/high-fat diet (Paigen diet, PD) for 8 weeks. To evaluate atherosclerosis, two different vascular sites (aortic sinus and the truncus of the brachiocephalic artery) were examined in the mice. Combined hyperlipidemic and hyperglycemic (HGHCi) mice fed a HFD or PD displayed characteristic features of aggravated atherosclerosis when compared to hyperlipidemia (HCi HFD or PD) mice alone. Atherosclerotic plaques of HGHCi HFD animals were larger, showed a less stable phenotype (measured by the increased necrotic core area, reduced fibrous cap thickness, and less α-SMA-positive area) and had more inflammation (increased plasma IL-1β level, aortic pro-inflammatory gene expression, and MOMA-2-positive cells in the BCA) after 20 weeks of HFD. Differences between the HGHCi and HCi HFD models were confirmed using RNA-seq analysis of aortic tissue, revealing that significantly more genes were dysregulated in mice with combined hyperlipidemia and hyperglycemia than in the hyperlipidemia-only group. The HGHCi-associated genes were related to pathways regulating inflammation (increased Cd68, iNos, and Tnfa expression) and extracellular matrix degradation (Adamts4 and Mmp14). When comparing HFD with PD, the PD aggravated atherosclerosis to a greater extent in mice and showed plaque formation after 8 weeks. Hyperlipidemic and hyperglycemic mice fed a PD (HGHCi PD) showed less collagen (Sirius red) and increased inflammation (CD68-positive cells) within aortic plaques than hyperlipidemic mice (HCi PD). HGHCi-PD mice represent a directly inducible hyperglycemic atherosclerosis model compared with HFD-fed mice, in which atherosclerosis is severe by 8 weeks. We established a nongenetically inducible mouse model allowing comparative analyses of atherosclerosis in HCi and HGHCi conditions and its modification by diet, allowing analyses of multiple metabolic hits in mice.


Severe aortic stenosis and subarachnoid hemorrhage: Anesthetic management of lethal combination.
Despite advances in various modalities of management, subarachnoid hemorrhage (SAH) continues to be associated with high mortality, which is further increased by associated comorbidities. Aortic stenosis (AS) is one such disease which can further complicate the course of SAH. We recently managed a known patient of severe AS, who presented with aneurysmal SAH. Patient was planned for eurovascular intervention. With proper assessment and planning, patient was managed with favorable outcome despite the restrictions faced in the neurovascular intervention laboratory.


Prediction of fetal sex in cattle by testosterone levels in allantoic fluid.
The testosterone concentration in allantoic fluid between 90 and 150 days of gestation in cattle can be used to determine the fetal sex; values were 442 +/- 20-3 (S.E.M.) pg testosterone/ml for males fetuses and 215 +/- 8-2 pg/ml for female fetuses.


[Amyloid Positron Emission Tomography in the Therapeutic Strategies for Alzheimer's Disease].
Amyloid positron emission tomography (PET) has been developed as a non-invasive neuroimaging technique that enables us to visualize the accumulation of fibrillar amyloid-beta (Aβ) in the living human brain with histopathological confirmation. As the deposition of fibrillar Aβ is the earliest detectable biomarker of Alzheimer's disease (AD), amyloid PET is useful not only to increase the probability of a correct diagnostic in clinical practice and clinical studies, but also to enrich appropriate participants in the clinical trials of disease modifying drugs for early stage of AD. The amyloid positivity has been shown to be affected by age and APOE ε4 allele presence. In combination with the emerging technique of tau imaging, amyloid PET will reveal details of the early pathophysiological mechanism of AD, which will lead to the development of effective disease modifying therapies and prevention strategies. Amyloid negativity by amyloid PET is the most reliable marker to exclude the possibility of AD in the differential diagnosis of dementia diseases. Therefore, amyloid imaging is also essential for the clinical studies and clinical trials targeting non-AD dementia diseases such as frontotemporal lobar degeneration, argyrophilic grain disease and neurofibrillary tangle dominant disease. Establishing an in vivo imaging technique to visualize tau and alpha synuclein will accelerate further understanding of non-AD dementias.


[In vitro activity of roxithromycin compared to 5 other macrolides against staphylococci].
This study aimed to compare the bacteriostatic activity of roxithromycin (RU) to those of erythromycin (ERY), troleandomycin (TAO), spiramycin (SPI), josamycin (JOS) and midekamycin (MID) against staphylococci strains. 239 strains of hospital origin were analysed: S. aureus (139), coagulase negative staphylococci (CNS) (100). The MIC were determined by the agar dilution method. The modal MIC, the MIC 50 and 90 observed for the both groups of strains are given according to species and antibiotics. This study gives the opportunity to classify the 6 antibiotics in a decreasing order considering their antistaphylococcal activity: RU = ERY, TAO = SPI, JOS = MID. No difference was noticeable between S. aureus and CNS strains.


Phenylbutazone toxicosis in the horse: a clinical study.
In a retrospective study of 269 horses that had been treated with phenylbutazone, horses receiving less than or equal to 8.8 mg/kg of body weight/day for less than or equal to 4 days or 2 to 4 mg/kg of body weight/day for up to 50 days remained clinically normal. Anorexia, depression, colic, hypoproteinemia, diarrhea, melena, weight loss, ventral edema, petechial hemorrhages of mucous membranes, oral and gastrointestinal tract erosions and ulcers, renal papillary necrosis, and death were among the complications seen in horses that had received greater than 8.8 mg/kg of body weight/day. In 2 cases, signs suggestive of gastrointestinal-related shock were also evident.


Underuse of statins for secondary prevention of atherosclerotic cardiovascular disease events among ambulatory surgical patients.
Although statins are highly effective for reducing cardiovascular disease events, prior studies demonstrate their significant underuse in the US population, including among those with known atherosclerotic disease. It is unknown whether this finding applies to the subset of patients who present for outpatient surgery, as such patients would be expected to have recent exposures to healthcare providers during the preoperative referral period. The primary aim of this manuscript was to ascertain the prevalence of statin underuse and associated risk-factors for such underuse among ambulatory surgical patients with documented atherosclerotic cardiovascular disease. This was a retrospective observational study of a random sample of 600 patients ages 40-75 years presenting for ambulatory surgery within a 6-month period in 2016, at one of three ambulatory surgical centers affiliated with a large, tertiary care hospital. Compilation and analysis of data occurred in 2018-2019. Of the 600 subjects, 117 (19.5%) had documented atherosclerotic cardiovascular disease. Within this high-risk group, only 71 (60.7%) carried a prescription for any statin, and only 30 (25.6%) were prescribed a recommended high intensity statin dose for secondary prevention. In a multivariable logistic regression analysis, older age, male sex, and treatment for hypertension were positively associated with statin use. In conclusion, statin underuse among ambulatory surgical patients is common and mirrors what has been observed in non-surgical populations. Future trials are needed to investigate the possible role of surgical teams to promote guideline-based statin therapy, including the role of preoperative screening interventions to impact long term cardiovascular morbidity and mortality.


Cluster Analysis of Clinical Features of Children Suspected to Have Neurodevelopmental Disorders.
Early identification of neurodevelopmental disabilities (NDDs) is critical to a good prognosis. Several factors such as overlapping diagnoses can complicate this process and thus delay access to services. This study sought to identify meaningful clinical profiles, beyond diagnostic labels, in 194 children with NDDs referred to an assessment clinic. Cluster analyses were applied to eight selected behavioral and cognitive variables. Results suggested a cluster structure in which three homogenous groups differed significantly from one another: children who presented either (1) heterogeneous diagnoses and ambiguous profiles, (2) a clinical profile closely aligned to a classic presentation of ASD, and (3) emotional and behavioral challenges. These distinct profiles may have implications for assessment and clinical practices.


Piscine Vitamin D Receptors Vdra/Vdrb in the Absence of Vitamin D Are Utilized by Grass Carp Reovirus for Promoting Viral Replication.
The vitamin D receptor (VDR) plays a pivotal role in the biological actions of vitamin D (VitD). However, little is known about the functions of VDR in the production of viral inclusion bodies (VIBs). Using a representative strain of grass carp reovirus (GCRV) genotype I, GCRV-873, we show that GCRV-873 recruits grass carp Vdrs for promoting the production of VIBs in the absence of VitD. Inhibition of cholesterol synthesis by lovastatin impairs the production of VIBs and blocks the effects of grass carp Vdrs in promoting the production of VIBs in the absence of VitD. Furthermore, grass carp Vdrs are found to form the Vdra-Vdrb heterodimer, which is vital for 3-hydroxy-3-methylglutaryl-coenzyme A reductase (hmgcr)-dependent cholesterol synthesis and GCRV replication. Intriguingly in the presence of VitD, grass carp Vdra but not Vdrb forms the heterodimer with the retinoid X receptor beta b (Rxrbb), which induces the transcription of those genes involved in the RIG-I-like receptor (RLR) antiviral signaling pathway for inhibiting GCRV infection. Furthermore, the VitD-activated Vdra-Vdrb heterodimer attenuates the transcription of the RLR antiviral signaling pathway induced by VitD. In the presence of VitD, a balance between the Vdra-Rxrbb heterodimers as coactivators and Vdra-Vdrb heterodimers as corepressors in affecting the transcriptional regulation of the RLR antiviral signaling pathway may eventually determine the outcome of GCRV infection. Transfection with VitD can abolish the effect of grass carp Vdrs in promoting GCRV replication in a dose-dependent manner. Taken together, these findings demonstrate that GCRV utilizes host Vdrs to increase hmgcr-dependent cholesterol synthesis for promoting its replication, which can be prevented by VitD treatment. IMPORTANCE Grass carp reovirus (GCRV) is the causative agent of grass carp hemorrhagic disease, which seriously harms freshwater fish. Although many positive or negative regulators of GCRV infection have been identified in teleosts, little is known about the molecular mechanisms by which GCRV utilizes host factors to generate its infectious compartments beneficial for viral replication and infection. Here, we show that in the absence of VitD, the GCRV-873 strain utilizes host vitamin D receptors Vdra/Vdrb to increase hmgcr-dependent cholesterol synthesis for promoting the production of VIBs, which are important functional sites for aquareovirus replication and assembly. The negative regulation of Vdrs during viral infection can be prevented by VitD treatment. Thus, this present work broadens understanding of the pivotal roles of Vdrs in the interaction between the host and GCRV in the absence or presence of VitD, which might provide a rational basis for developing novel anti-GCRV strategies.


The contribution of proteinase-activated receptors to intracellular signaling, transcellular transport and autophagy in Alzheimer's disease.
The etiopathogenesis of Alzheimer´s disease is characterized by beta amyloid Aβ(1-42) toxic fragment aggregation and its association with impaired autophagy. In mitochondria, chronic damage due to transport and enzymatic processes together with the production of reactive oxygen species (ROS) are followed by the subsequent accumulation of Aβ in the form of senile plaques and the accumulation of hyperphosphorylated tau protein in intracellular deposits called tangles. Proteinase-activated receptors (PARs), members of the G protein-coupled receptor (GPCR) family, facilitate and modulate the transcellular transport and distribution of a variety of subcellular molecular components to the lysosomal system and, thus, influence their degradation. A review of the data shows that the activation or inhibition of PARs leads to changes in the process of autophagy, which may influence ROS production and Aβ (1-42) degradation in lysosomes and result in AD pathogenesis.


What social determinants will cause ethical challenges in geriatric care? Comments from South Africa.
Social determinants are defined as those nonmedical factors that influence health. Their influence is especially evident in vulnerable communities, such as the geriatric one. However, which social determinants will cause ethical challenges in geriatric healthcare in South Africa are not yet confirmed. This study first identified which social determinants influence geriatric care. The study then established which of these social determinants raises ethical challenges in geriatric care. Twenty statements were identified from the literature review and were grouped into 3 indexes, focusing respectively on i) a general view on public health and social determinants; ii) social determinants influencing geriatric people's health; iii) the consequences of social determinants on geriatric people's health. The rating was based on presenting the statements employing a 5- point Likert scale. The rating of statements confirmed the generally accepted view that social determinants impact geriatric people's health. The responses to the statements were an additional confirmation that the quality and access to healthcare services influence geriatric care and lead to ethical challenges. Matters such as corruption, limited resources, and the COVID-19 pandemic contribute to the influence of social determinants and the expected but failed ethical behavior toward the geriatric community. The geriatric community is vulnerable because of the ongoing social factors that have a negative impact on health, of which healthcare quality and provision are significant contributing factors. These factors contribute to ethical challenges in healthcare for the geriatric community.


Severe complicated neutropenia in two patients with metastatic non-small-cell lung cancer treated with nivolumab.
Checkpoint inhibitors effectively enhance the natural immune response against cancer, but they are also known to induce a unique spectrum of immune-related adverse events. Here, we report the first case of isolated neutropenia subsequent to nivolumab therapy. Prominent activated T-cells were found in the patient's serum and bone marrow alongside evidence of maturational defects in neutrophil precursors. Antineutrophil antibodies were not detected despite reliable testing techniques. A T-cell-mediated response is probable, consistent with the established mechanism for the development of other immune-related toxicities. Awareness of this rare and severe side effect reinforces the importance of early diagnosis and prompt initiation of proper treatment.


Zoom Zoom: racing CARs for multiple myeloma.
Chimeric antigen receptors redirect T cells to surface antigens. Discovery and validation of appropriate target antigens expand the possible indications for chimeric-antigen receptor (CAR)-T cells. B-cell maturation antigen (BCMA) is expressed only on mature B cells and plasma cells and promotes their survival. BCMA is a promising target for CAR-T cells in multiple myeloma.


Inhibition of human alcohol dehydrogenases by formamides.
Human alcohol dehydrogenase (HsADH) comprises class I (alpha, beta, and gamma), class II (pi), and class IV (sigma) enzymes. Selective inhibitors of the enzymes could be used to prevent the metabolism of alcohols that form toxic products. Formamides are unreactive analogues of aldehydes and bind to the enzyme-NADH complex [Ramaswamy, S.; Scholze, M.; Plapp, B. V. Biochemistry 1997, 36, 3522-3527]. They are uncompetitive inhibitors against varied concentrations of alcohol, and this makes them effective even with saturating concentrations of alcohols. Molecular modeling led to the design and synthesis of a series of cyclic, linear, and disubstituted formamides. Evaluation of 23 compounds provided structure-function information and selective inhibitors for the enzymes, which have overlapping but differing substrate specificities. Monosubstituted formamides are good inhibitors of class I and II enzymes, and disubstituted formamides are selective for the alpha enzyme. Selective inhibitors, with Ki values at pH 7 and 25 degrees C of 0.33-0.74 microM, include N-cyclopentyl-N-cyclobutylformamide for HsADH alpha, N-benzylformamide for HsADH beta1, N-1-methylheptylformamide for HsADH gamma2, and N-heptylformamide for HsADH sigma and HsADH beta1.


To reduce the maximum stress and the stress shielding effect around a dental implant-bone interface using radial functionally graded biomaterials.
In a dental implant system, the value of stress and its distribution plays a pivotal role on the strength, durability and life of the implant-bone system. A typical implant consists of a Titanium core and a thin layer of biocompatible material such as the hydroxyapatite. This coating has a wide range of clinical applications in orthopedics and dentistry due to its biocompatibility and bioactivity characteristics. Low bonding strength and sudden variation of mechanical properties between the coating and the metallic layers are the main disadvantages of such common implants. To overcome these problems, a radial distributed functionally graded biomaterial (FGBM) was proposed in this paper and the effect of material property on the stress distribution around the dental implant-bone interface was studied. A three-dimensional finite element simulation was used to illustrate how the use of radial FGBM dental implant can reduce the maximum von Mises stress and, also the stress shielding effect in both the cortical and cancellous bones. The results, of course, give anybody an idea about optimized behaviors that can be achieved using such materials. The finite element solver was validated by familiar methods and the results were compared to previous works in the literature.


CRP in Outpatients with Inflammatory Bowel Disease Is Linked to the Blood Microbiota.
The circulation is a closed system that has been assumed to be free from bacteria, but evidence for the existence of a low-density blood microbiota is accumulating. The present study aimed to map the blood microbiota of outpatients with Crohn's disease (CD) or with ulcerative colitis (UC) by 16S metagenomics. A diverse microbiota was observed in the blood samples. Regardless of the type of disease, the alpha diversity of the microbiota was positively associated with C-reactive protein (CRP). The blood microbiota had a surprisingly high proportion of Proteobacteria in comparison with human oral and colonic microbiotas. There was no clear difference in the overall pattern of the microbiota between CD and UC. A non-template control (NTC) was included in the whole process to control for the potential contamination from the environment and reagents. Certain bacterial taxa were concomitantly detected in both blood samples and NTC. However, Acinetobacter, Lactobacillus, Thermicanus and Paracoccus were found in blood from both CD and UC patients but not in NTC, indicating the existence of a specific blood-borne microbiota in the patients. Achromobacter dominated in all blood samples, but a minor amount was also found in NTC. Micrococcaceae was significantly enriched in CD, but it was also detected in high abundance in NTC. Whether the composition of the blood microbiota could be a marker of a particular phenotype in inflammatory bowel disease (IBD) or whether the blood microbiota could be used for diagnostic or therapeutic purposes deserves further attention.


A steady state model of agricultural waste pyrolysis: A mini review.
Agricultural waste is one of the main renewable energy resources available, especially in an agricultural country such as Serbia. Pyrolysis has already been considered as an attractive alternative for disposal of agricultural waste, since the technique can convert this special biomass resource into granular charcoal, non-condensable gases and pyrolysis oils, which could furnish profitable energy and chemical products owing to their high calorific value. In this regard, the development of thermochemical processes requires a good understanding of pyrolysis mechanisms. Experimental and some literature data on the pyrolysis characteristics of corn cob and several other agricultural residues under inert atmosphere were structured and analysed in order to obtain conversion behaviour patterns of agricultural residues during pyrolysis within the temperature range from 300 °C to 1000 °C. Based on experimental and literature data analysis, empirical relationships were derived, including relations between the temperature of the process and yields of charcoal, tar and gas (CO2, CO, H2 and CH4). An analytical semi-empirical model was then used as a tool to analyse the general trends of biomass pyrolysis. Although this semi-empirical model needs further refinement before application to all types of biomass, its prediction capability was in good agreement with results obtained by the literature review. The compact representation could be used in other applications, to conveniently extrapolate and interpolate these results to other temperatures and biomass types.


Electronic circular dichroism of chiral alkenes: B3LYP and CAM-B3LYP calculations.
Time-dependent density functional theory (TDDFT) calculations of electronic circular dichroism (ECD) are widely used to determine absolute configurations (ACs) of chiral molecules. Two very popular DFT exchange-correlation functionals, one hybrid (B3LYP) and one long-range corrected (CAM-B3LYP), along with a hierarchical sequence of basis sets were investigated, and the ECD spectra predicted for eight alkenes and compared to gas-phase experimental spectra. Little variation in predicted ECD spectra was found with the basis set size enlargement, but the sensitivity to the functional is greater. Good agreement was obtained only with the CAM-B3LYP functional, leading to the conclusion that TDDFT calculations of ECD spectra can routinely provide reliable ACs if and only if an appropriate functional is used. For camphene, twistene, syn-(E)-bisfenchylidene, and phyllocladene, solvent effects were estimated.


Development of cervical cancer control interventions for Chinese immigrants.
The objective of the study was to develop a culturally relevant video and a pamphlet for use as a cervical cancer screening educational intervention among North-American Chinese women. The project conducted 87 qualitative interviews and nine focus groups to develop a culturally tailored intervention to improve Pap testing rates. The intervention consisted of an educational/motivational video, a pamphlet, and home visits. Less acculturated Chinese women draw on a rich tradition of herbal knowledge and folk practices historically based on Chinese medical theory, now mixed with new information from the media and popular culture. The video, the pamphlet, and the outreach workers knowledge base were designed using these results and combined with biomedical information to address potential obstacles to Pap testing. Culturally relevant information for reproductive health promotion was easily retrieved through qualitative interviews and used to create educational materials modeling the integration of Pap testing into Chinese women's health practices.


Developing and evaluating an intervention to improve care and reduce costs of rabies postexposure therapy: an observational quality improvement initiative in selected vaccination units in Sri Lanka.
Exposure to the rabies virus is fatal unless a patient is treated with a timely, accurate and complete administration of postexposure prophylaxis (PEP). The level of adherence to PEP guidelines by health service providers is therefore critical in providing high-quality care as well as preventing unnecessary costs. We developed a simple user-friendly decision aid based on Sri Lankan national guidelines for the administration of PEP and trialed it over a 5-month period in three study settings. Pre and post levels of adherence to the national guidelines by service providers was measured in each setting. Changes to per patient cost for rabies medications and hospital admissions were also collected. A significant improvement in adherence to the guidelines was observed in two settings with a nonsignificant improvement observed in the third setting. We estimated a total cost saving of LKR 158 476 across the three sites, comprising LKR 14 418 in admissions cost savings and LKR 144 058 in medication savings. We conclude that the development of a decision aid for the administration of PEP is likely to be an effective and cost-saving intervention in the Sri Lankan setting. Further research is required to inform the generalizability of our findings.


Understanding the Mechanisms of Action and Effects of Drugs of Abuse.
Drug abuse and addiction are major public health concerns, with millions of people worldwide affected by the negative consequences of drug use. To better understand this complex issue, a review was conducted to examine the mechanisms of action and effects of drugs of abuse, including their acute and chronic effects, the symptoms of abstinence syndrome, as well as their cardiovascular impacts. The analyzed data were obtained after surveying an electronic database, namely PubMed, with no time limit, grey literature sources, and reference lists of relevant articles. The review highlights the different categories of drugs of abuse, such as opioids, stimulants, depressants, hallucinogens, and cannabis, and discusses the specific ways that each drug affects the brain and body. Additionally, the review explores the short-term and long-term effects of drug abuse on the body and mind, including changes in brain structure and function, physical health problems, and mental health issues, such as depression and anxiety. In addition, the review explores the effects of drug abuse on cardiovascular health, focusing on electrocardiogram changes. Moreover, the analysis of relevant literature also highlighted possible genetic susceptibility in various addictions. Furthermore, the review delves into the withdrawal symptoms that occur when someone stops using drugs of abuse after a period of chronic use. Overall, this review provides a comprehensive overview of the current state of knowledge on drug abuse and addiction. The findings of this review can inform the development of evidence-based prevention and intervention strategies to address this critical public health issue.


Transcription elements and factors of RNA polymerase B promoters of higher eukaryotes.
The promoter for eukaryotic genes transcribed by RNA polymerase B can be divided into the TATA box (located at -30) and startsite (+1), the upstream element (situated between -40 and about -110), and the enhancer (no fixed position relative to the startsite). Trans-acting factors, which bind to these elements, have been identified and at least partially purified. The role of the TATA box is to bind factors which focus the transcription machinery to initiate at the startsite. The upstream element and the enhancer somehow modulate this interaction, possibly through direct protein-protein interactions. Another class of transcription factors, typified by viral proteins such as the adenovirus EIA products, do not appear to require binding to a particular DNA sequence to regulate transcription. The latest findings in these various subjects are discussed.


Recombinant prion protein does not possess SOD-1 activity.
A considerable body of evidence now shows that PrP (prion protein) binds metal ions with high affinity and it has been claimed that the binding of copper (II) ions to PrP confers SOD (superoxide dismutase) activity. In turn, it has been suggested that PrP is a synaptic dismutase and that loss of this function, as a result of the conversion of PrP(C) into PrP(Sc), results in pathology and hence morbidity associated with prion disease. However, contrary to previous reports, in the present study we have found that PrP exhibits no detectable dismutase activity above baseline levels measured for copper (II) ions in water when assayed using a reliable procedure with a detection limit of at least 2 units of activity/mg of protein. This was true when the assay was performed with either PrP refolded from a denatured state in the presence of copper, as in previous studies, or native PrP loaded with copper. Thus if PrP has any role in oxidative stress, it must be indirect as a regulator of protective cellular responses.


Local mu and delta opioid receptors regulate amphetamine-induced behavior and neuropeptide mRNA in the striatum.
The purpose of this study was to investigate the role that mu and delta opioid receptor blockade has upon stimulant-induced behavior and neuropeptide gene expression in the striatum. Acute administration of amphetamine (2.5 mg/kg i.p.) caused an increase in behavioral activity and preprodynorphin, substance P, and preproenkephalin mRNA expression. Intrastriatal infusion of the mu opioid antagonist, H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP), or the delta opioid antagonist, H-Tyr-Tic[CH(2)NH]-Phe-Phe-OH (TIPPpsi), significantly decreased amphetamine-induced vertical activity. However, only CTAP reduced amphetamine-induced distance traveled. Quantitative in situ hybridization histochemistry revealed that CTAP blocked amphetamine-induced preprodynorphin and substance P mRNA. However, preproenkephalin mRNA levels in the dorsal striatum were increased to the same extent by CTAP, amphetamine, or a combination of the two drugs. In contrast, TIPPpsi significantly decreased amphetamine-induced mRNA expression of all three neuropeptides. These data indicate that both mu and delta receptor subtypes differentially regulate amphetamine-induced behavior and neuropeptide gene expression in the rat striatum.


Influence of small ruminant lentivirus infection on cheese yield in goats.
Three-year cohort study was carried out to investigate the influence of small ruminant lentivirus (SRLV) infection on cheese yield in goats. For this purpose records of milk yield, milk composition and cheese yield were collected in a dairy goat herd. Cheese yield was recorded as the amount of fresh cheese obtained from 1 kg milk. All goats were serologically tested for SRLV infection twice a year. The analysis included 247 records in total (71 for seropositive and 176 from seronegative individuals) and was carried out with the use of the four-level hierarchical linear model (α = 0·05). SRLV infection proved to be a statistically significant independent factor reducing cheese yield (P = 0·013)--when other covariates were held constant cheese yield was reduced by 4·6 g per each 1 kg milk in an infected goat compared with an uninfected goat. Other statistically significant covariates positively associated with cheese yield were protein contents, fat contents and the 3rd stage of lactation (P < 0·001 for all).


Effect of carcinogens and analogs on interferon induction.
Pretreatment of mouse embryo fibroblasts with several chemicals, including 7,12-dimethylbenz-(a)-anthracene, 2-aminofluorene, aflatoxin B1, benzo-(a)-pyrene, styrene oxide, and the No. 4 fraction of tobacco smoke condensate, resulted in severely reduced production of interferon when the cells were challenged with Newcastle disease virus. All of the above chemicals are proven or strongly suggested carcinogens. When the analogs methyl methanesulfonate, a potent carcinogen, and ethyl methanesulfonate, a weak carcinogen, were applied to cells, interferon induction was only inhibited by the methyl methanesulfonate. Therefore, carcinogens may directly inhibit the induction of interferon by Newcastle disease virus.


Growth and differentiation of a murine interleukin-3-producing myelomonocytic leukemia cell line in a protein-free chemically defined medium.
We established the continuous growth of WEHI-3B D+ cells in protein-free chemically defined F-12 medium by stepwise decreases in the concentration of fetal calf serum. This cell line, designated as WEHI-3B-Y1, has now been propagated in protein-free F-12 medium for 3 years. The population-doubling time of the cells in culture is about 24 hr. WEHI-3B-Y1 cells are immature undifferentiated cells which show positive staining for naphthol ASD chloroacetate esterase and alpha-naphthyl butyrate esterase and spontaneously exhibit a low level of differentiation to mature granulocytes and macrophages. Medium conditioned by WEHI-3B-Y1 cells stimulated the proliferation of an interleukin-3 (IL-3)-dependent FDCP-2 cell line. This conditioned medium was shown to have erythroid burst-promoting activity when assayed using normal murine bone marrow. The colony formation of WEHI-3B-Y1 cells in semi-solid agar culture was not stimulated by purified recombinant human granulocyte colony-stimulating factor (rhG-CSF). However, in the presence of human transferrin, rhG-CSF enhanced the number of colonies of WEHI-3B-Y1 cells but did not induce their differentiation. These results suggest that WEHI-3B-Y1 cells cultured in protein-free medium produced murine IL-3. In addition, human G-CSF enhanced the clonal growth but did not induce the differentiation of WEHI-3B-Y1 cells cultured in serum-free medium.


Prognostic Clinical Phenotypes of Patients with Acute Decompensated Heart Failure.
Acute decompensated heart failure (AHF) is a clinical syndrome with a poor prognosis. This study was conducted to identify clusters of inpatients with acute decompensated heart failure that shared similarities in their clinical features. We analyzed data from a cohort of patients with acute decompensated heart failure hospitalized between February 2013 and January 2017 in a Department of Cardiology. Patients were clustered using factorial analysis of mixed data. The clusters (phenotypes) were then compared using log-rank tests and profiled using a logistic model. In total, 458 patients (255; 55.7% male) with a mean (SD) age of 72.7 (11.1) years were included in the analytic dataset. The demographic, clinical, and laboratory features were included in the cluster analysis. The two clusters were significantly different in terms of time to mortality and re-hospitalization (all P < 0.001). Cluster profiling yielded an accurate discriminating model (AUC = 0.934). Typically, high-risk patients were elderly females with a lower estimated glomerular filtration rate and hemoglobin on admission compared to the low-risk phenotype. Moreover, the high-risk phenotype had a higher likelihood of diabetes type 2, transient ischemic attack/cerebrovascular accident, previous heart failure or ischemic heart disease, and a higher serum potassium concentration on admission. Patients with the high-risk phenotype were of higher New York Heart Association functional classes and more positive in their medication history. There are two phenotypes among patients with decompensated heart failure, high-risk and low-risk for mortality and re-hospitalization. They can be distinguished by easy-to-measure patients' characteristics.


Regulation of Glutamine Synthetase Activity.
Detailed studies of the glutamine synthetase (GS) in Escherichia coli and other bacteria have shown that the activity of this enzyme is regulated by at least five different mechanisms: (i) cumulative feedback inhibition by multiple end products of glutamine metabolism, (ii) interconversion between taut and relaxed protein configurations in response to binding and dissociation of divalent cations at one of its two metal binding sites, (iii) dynamic interconversion of the enzyme between covalently modified (adenylylated) and unmodified forms by a novel bicyclic cascade system, (iv) repression and derepression of glutamine synthetase formation by cyclic phosphorylation and dephosphorylation of an RNA factor that governs transcription activities, and (v) regulation of glutamine synthetase turnover by the coupling of site specific metal ion-catalyzed oxidation with proteolytic degradation of the enzyme. Glutamine synthetase activity in E. coli is subject to inhibition by seven different end products of glutamine metabolism, namely, by tryptophan, histidine, carbamyl-phosphate, CTP, AMP, glucose-6-phosphate, and NAD+, and also by serine, alanine, and glycine. The cascade theory predicts that the steady-state level of glutamine synthetase adenylylation and therefore its catalytic activity is determined by the combined effects of all metabolites that affect the kinetic parameters of one or more of the enzymes in the cascade. Furthermore, under conditions where the supplies of ATP and glutamate are not limiting and the production of glutamine exceeds the demand, GS is no longer needed, then it will be converted to the catalytically inactive adenylylated form that is not under protection of ATP and glutamate.


Do exercise-induced increases in muscle size contribute to strength in resistance-trained individuals?
Previous work in non-resistance-trained individuals has found that an increase in muscle size has no additive effect on changes in strength. However, it is thought that muscle growth is of increased importance for resistance-trained individuals. Experiment 1: To examine changes in muscle thickness (MT) and one repetition maximum (1RM) strength following 8 weeks of bi-weekly 1RM practice or traditional training. Experiment 2: To determine whether increasing muscle size increases strength potential when followed by 4 weeks of 1RM training. Participants performed biceps curls for 8 weeks (Experiment 1). One arm performed 4 sets of as many repetitions as possible with approximately 70% of 1RM (TRAD), and the other arm performed a single 1RM. For experiment 2, both arms trained for muscle size and strength. Experiment 1 (n = 25): for MT, the posterior probabilities favoured the hypothesis that MT changed more in the TRAD condition [mean difference: 50% site 0.15 (-0.09, 0.21) cm; 60% site 0.14 (0.06, 0.23) cm; 70% site 0.17 (0.10, 0.23) cm]. For 1RM strength, each condition changed equivalently. Experiment 2 (n = 18): for MT, the posterior probabilities favoured the hypothesis that MT changed similarly between conditions following a 4-week strength phase. For changes in 1RM strength, the evidence favoured neither hypothesis (i.e. null vs. alternative). Of note, the mean difference between conditions was small [0.72 (4.3) kg]. 1RM training produces similar increases in strength as traditional training. Experiment 2 suggests that increases in muscle mass may not increase the 'potential' for strength gain.


Effect of 7,12-dimethylbenz(a)anthracene on onco/suppressor gene action in vivo: a short-term experiment.
Dimethylbenz[a]anthracene is a pluripotent carcinogenic chemical, which acts as an initiator by causing point mutations in certain oncogenes and tumor suppressor genes. Changes in their expression may be another possible area of investigation the carcinogenic effect of DMBA. Elevated expression of oncogenes was previously has been shown after treatment with carcinogenic compounds. In the present study, expression of c-myc, c-Ha-ras and p53 24 hours after a single dose treatment of DMBA in the spleen and in the liver of Long-Evans rats was investigated. Control animals were injected with the solvent corn oil only. We could not find any significant change on the transcriptional level of the investigated oncogenes in the liver. In the spleen, the overexpression of Ha-ras was 2-fold and c-myc was 3-fold higher in the DMBA-treated rats than in the corresponding control group. Since DMBA is a typical environmental carcinogen, the results of animal experiments may serve as a basis for application of gene expression investigations as a screening method in humans.


Relation between uncorrected astigmatism and visual acuity in pseudophakia.
PURPOSE.: The end point of astigmatic correction after cataract surgery will depend on how uncorrected astigmatism impacts distance and near vision of pseudophakic eyes. This study determined the impact of induced astigmatism and pupil size on the distance and near acuity of otherwise emmetropic pseudophakic eyes implanted with monofocal intraocular lenses. METHODS.: Monocular high-contrast distance (4 m) and near (40 cm) logMAR acuity was determined in 15 subjects (mean ± 1 SD, 57.9 ± 9.0 years) without astigmatism and with 2.5 diopters (D) myopic to 2.0 D hyperopic astigmatic lenses induced in 0.5-D steps at 0-, 45-, 90-, and 135-degree axes. This experiment was repeated for the same range of induced astigmatism with 1.5-, 3-, and 6-mm artificial pupil diameters placed before one eye of 10 subjects dilated with 10% phenylephrine HCl. RESULTS.: Distance acuity deteriorated with astigmatism for all axes tested (p < 0.01). Near acuity deteriorated with hyperopic astigmatism (p < 0.1), whereas it improved with up to 1 D of myopic astigmatism before saturating for all axes tested (p < 0.01). Distance and near acuity improved with a reduction in pupil diameter (p < 0.01). The change in distance and near acuity with induced astigmatism was smaller for 1.5-mm than for 3-mm and 6-mm pupil diameters (p < 0.01). CONCLUSIONS.: Partial restoration of near acuity with uncorrected myopic astigmatism comes with a proportional loss of distance acuity in pseudophakic eyes. Uncorrected myopic astigmatism more than 1 D results in a large loss of distance acuity at no additional benefit to near acuity. Both distance and near acuities with and without astigmatism are benefited with a reduction in pupil diameter. Uncorrected hyperopic astigmatism results in deterioration of both distance and near acuities of pseudophakic eyes.


Decomposing consumer and producer effects on sugar from beverage purchases after a sugar-based tax on beverages in South Africa.
Growing global concern about obesity and diet-related non-communicable diseases has raised interest in fiscal policy as a tool to reduce this disease burden and its social costs, especially excise taxes on sugar-sweetened beverages (SSBs). Of particular interest have been nutrient-based taxes to improve diet quality. These can incentivize producers to reformulate existing products and introduce healthier alternatives into their ranges. In 2018, South Africa adopted a sugar-based tax on SSBs, the Health Promotion Levy (HPL). Early findings suggest that purchases of higher-sugar taxable beverages fell and purchases of no- and lower-sugar beverages increased, alongside significant reductions in the sugar content of overall beverage purchases. However, underlying these changes are consumption shifts as well as product reformulation and changes in producers' product portfolios. Drawing on a household scanner dataset, this study employed a descriptive approach to decompose changes in the sugar content of households' non-alcoholic beverage purchases into producer factors (reformulation and product entry and exit) and consumer factors (product switching and volume changes as a result of price changes, changing preferences, or other factors). We look at these factors as the tax was announced and implemented across a sample of over 3000 South African households, and then by Living Standard Measures (LSM) groups (middle vs. high). The sugar content of beverage purchases fell by 4.9 g/capita/day overall, a 32% decrease. Taken in isolation, consumer switching and volume changes together led to a reduction equivalent to 71% of the total change, while reformulation accounted for a decrease equal to 34% of that change. Middle-LSM households experienced larger reductions than high-LSM households due to larger changes on the consumer side. For both LSM groups, reformulation-led reductions mostly occurred after implementation, and most changes came from taxable beverage purchases. As sugary drink tax designs evolve with broader implementation globally, understanding both supply- and demand-side factors will help to better assess the population and equity potential of these policies.


MicroRNA-200a inhibits cell growth and metastasis by targeting Foxa2 in hepatocellular carcinoma.
Background: MicroRNAs (miRNAs) are a class of endogenous, small non-coding RNAs which function as essential posttranscriptional modulators of gene expression tightly involved in a wide range of diseases, including the hepatocellular carcinoma (HCC). Here, the present study was designed to investigate the expression levels and cellular roles of miR-200a in HCC. Methods: Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was used to detect the expression levels of miR-200a in serums and cell lines. Bioinformation analysis, the luciferase reporter assay, qRT-PCR and western blotting were employed to validate Foxa2 as a direct target gene of miR-200a. Cell proliferation, migration and invasion were assessed to identify whether miR-200a could regulate the biological behaviors of HCC cells by targeting Foxa2. Results: In this study, a low level of miR-200a was observed in patients' serums and HCC cell lines. Overexpression of miR-200a in HCC cell lines reduced cell proliferation, migration and invasion. In addition, transcription factor forkhead box A2 (Foxa2) was identified as a novel target of miR-200a and downregulated at mRNA and protein levels in miR-200a overexpressed cells. Meanwhile, restoration of Foxa2 significantly reversed the tumor suppressive effects of miR-200a. Conclusions: These findings indicate that miR-200a regulates the proliferation, migration and invasion of HCC cells by targeting Foxa2, suggesting that miR-200a may function as a potential therapeutic molecular for the diagnosis and treatment of the liver cancer.


Age-related differences in upper limb proprioceptive acuity.
Although upper limb movements are known to be slower and more variable in elderly persons, the extent to which these changes are associated with deficits in movement-related sensory feedback is poorly understood, despite the importance of proprioception in the control of skilled movement. Age-related changes were examined with 22 participants (10 of M age 27 years and 12 of M age 75 years) in performance of an elbow position-matching task which varied in terms of interhemispheric transfer and/or the need to retrieve memory-based proprioceptive information. Matching errors were significantly greater, and movements more prolonged, and irregular in their time course in the elderly group than in the young group. Impaired performance in conditions requiring interhemispheric transfer and retrieval of memory-based proprioceptive information reflected the importance of cognitive processing during complex sensorimotor tasks. This novel matching paradigm provided a sensitive means of manipulating the demands of the task and may be an effective method for as sessing both cognitive and sensorimotor declines associated with aging.


Osteocytes Exposed to Titanium Particles Inhibit Osteoblastic Cell Differentiation via Connexin 43.
Periprosthetic osteolysis (PPO) induced by wear particles is the most severe complication of total joint replacement; however, the mechanism behind PPO remains elusive. Previous studies have shown that osteocytes play important roles in wear-particle-induced osteolysis. In this study, we investigated the effects of connexin 43 (Cx43) on the regulation of osteocyte-to-osteoblast differentiation. We established an in vivo murine model of calvarial osteolysis induced by titanium (Ti) particles. The osteolysis characteristic and osteogenesis markers in the osteocyte-selective Cx43 (CKO)-deficient and wild-type (WT) mice were observed. The calvarial osteolysis induced by Ti particles was partially attenuated in CKO mice. The expression of β-catenin and osteogenesis markers increased significantly in CKO mice. In vitro, the osteocytic cell line MLO-Y4 was treated with Ti particles. The co-culturing of MLO-Y4 cells with MC3T3-E1 osteoblastic cells was used to observe the effects of Ti-treated osteocytes on osteoblast differentiation. When Cx43 of MLO-Y4 cells was silenced or overexpressed, β-catenin was detected. Additionally, co-immunoprecipitation detection of Cx43 and β-catenin binding in MLO-Y4 cells and MC3T3-E1 cells was performed. Finally, β-catenin expression in MC3T3-E1 cells and osteoblast differentiation were evaluated after 18α-glycyrrhetinic acid (18α-GA) was used to block the intercellular communication of Cx43 between MLO-Y4 and MC3T3-E1 cells. Ti particles increased Cx43 expression and decreased β-catenin expression in MLO-Y4 cells. The silencing of Cx43 increased the β-catenin expression, and the over-expression of Cx43 decreased the β-catenin expression. In the co-culture model, Ti treatment of MLO-Y4 cells inhibited the osteoblastic differentiation of MC3T3-E1 cells and Cx43 silencing in MLO-Y4 cells attenuated the inhibitory effects on osteoblastic differentiation. With Cx43 silencing in the MLO-Y4 cells, the MC3T3-E1 cells, co-cultured alongside MLO-Y4, displayed decreased Cx43 expression, increased β-catenin expression, activation of Runx2, and promotion of osteoblastic differentiation in vitro co-culture. Finally, Cx43 expression was found to be negatively correlated to the activity of the Wnt signaling pathway, mostly through the Cx43 binding of β-catenin from its translocation to the nucleus. The results of our study suggest that Ti particles increased Cx43 expression in osteocytes and that osteocytes may participate in the regulation of osteoblast function via the Cx43 during PPO.


Tutorial on laser speckle rheology: technology, applications, and opportunities.
The onset of several diseases is frequently marked with anomalous mechanical alteration of the affected tissue at the intersection of cells and their microenvironment. Therefore, mapping the micromechanical attributes of the tissues could enhance our understanding of the etiology of human disease, improve the diagnosis, and help stratify therapies that target these mechanical aberrations. We review the tremendous opportunities offered through using optics for imaging the micromechanical properties, at length scales inaccessible to other modalities, in both basic research and clinical medicine. We specifically focus on laser speckle rheology (LSR), a technology that quantifies the mechanical properties of tissues in a rapid, noncontact manner. In LSR, the shear viscoelastic modulus is measured from the time-variant speckle intensity fluctuations reflected off the tissue. The LSR technology is engineered and configured into several embodiments, including bench-top optical systems, endoscopes for minimally invasive procedures, portable point-of-care devices, and microscopes. These technological nuances have primed the LSR for widespread applications in diagnosis and therapeutic monitoring, as demonstrated here, in cardiovascular disease, coagulation disorders, and tumor malignancies. The fast-paced technological advancements, elaborated here, position the LSR as a competent candidate for many more exciting opportunities in basic research and medicine.


β(2 → 1)-β(2 → 6) and β(2 → 1) fructans protect from impairment of intestinal tight junction's gene expression and attenuate human dendritic cell responses in a fructan-dependent fashion.
β(2 → 1)-β(2 → 6) branched graminan-type fructans (GTFs) and β(2 → 1) linear fructans (ITFs) possess immunomodulatory properties and protect human intestinal barrier function, however the mechanisms underlying these effects are not well studied. Herein, GTFs and ITFs effects with different degree of polymerization (DP) values on tight junctions (TJs) genes CLDN-1, -2 and -3, CDH1, OCLN and TJP1 were studied in Caco-2 gut epithelial cells, under homeostatic and inflammatory conditions. Also, cytokine production in dendritic cells (DCs) was studied. Higher DP fructans decreased the expression of the pore forming CLDN-2. Higher DP GTFs enhanced CLDN-3, OCLN, and TJP-1. Fructans prevented mRNA dysregulation of CLDN-1, -2 and -3 induced by the barrier disruptors A23187 and deoxynivalenol in a fructan-type dependent fashion. The production of pro-inflammatory cytokines MCP-1/CCL2, MIP-1α/CCL3 and TNFα by DCs was also attenuated in a fructan-type dependent manner and was strongly attenuated by DCs cultured with medium of Caco-2 cells which were pre-exposed to fructans. Our data show that specific fructans have TJs and DCs modulating effects and contribute to gut homeostasis. This might serve to design effective dietary means to prevent intestinal inflammation.


Erectile dysfunction and treatment of carcinoma of the prostate.
Prostate cancer is the leading malignancy in men in the United States and causes more than 60,000 deaths annually. Treatment of prostate cancer, whether it be with surgery, radiation therapy, cryotherapy, or medical treatment, is associated with significant life-altering morbidity. Incontinence and erectile dysfunction (ED) too often are sequelae of these treatment alternatives. ED can be a significant complication and can alter the life of the patient with prostate cancer and his partner. Newer modifications of the radical prostatectomy with nerve-sparing techniques are the cornerstone of erection preservation. Time following radical prostatectomy has been shown to increase erectile function such that more patients have functional erections at 3 years than 1 year after surgery. With the advent of phosphodiesterase-5 (PDE-5) inhibitors, many men can have improved functional erections and return to active coitus. Prevention of ED also is an important management technique. Evidence is gathering that prophylaxis with regular vasoactive injection or daily PDE-5 agents may be an integral part of preservation of corpus cavernosum smooth muscle function. Combination medical therapy and surgical penile prosthesis implantation also are options for patients who do not respond to oral PDE-5 inhibitors.


[Expression of Snail and E-cadherin in pancreatic carcinoma and clinical significance thereof].
To investigate the expression of Snail, a newly discovered inhibitory transcription factor, and E-cadherin in pancreatic carcinoma (PC) and clinical significance thereof. Immunohistochemistry was used to examine the expression of Snail and E-cadherin in 56 specimens of PC obtained during operation. PC cells of the line of Panc-1 and transfected with pCMV-Tag2B-Snail, a eucaryotic expression vector coding Snail, so as to obtain a stable clone named Panc-1-Snail. RT-PCR was used to detect the mRNA expression of Snail gene in the Panc-1-Snail cells. Immunofluorescence technique and Western blotting were used to detect the expression of E-cadherin in the Pan-1-Snail cells. Transwell cell culture chamber method was used to examine the invasion ability of the Panc-1-and Panc-1-Snail cells. Twenty of the 56 PC specimens (36%) were positive in Snail, mainly located in the nuclei. Seventeen of the 20 Snail-positive PC specimens were with and 3 without lymph node metastasis (P = 0.006); and 7 of the 8 PC specimens with lymph node metastasis were Snail-positive and only 1 was Snail-negative (P = 0.001). Twenty-six PC specimens showed low expression of E-cadherin with remarkable heterogeneity. Of the 20 Snail-positive PC specimens 13 showed low expression of E-cadherin and only 7 showed normal expression of E-cadherin; and 13 of the 36 Snail-negative PC specimens showed low expression of E-cadherin (P = 0.038). RT-PCR showed strong Snail mRNA expression in the Pan-1 cells. Both Western blotting and immunofluorescence technique showed the depression of E-cadherin expression. The Transwell chamber test showed that the number of penetrating Pan-1-Snail cells after 24-hour incubation was (174 +/- 8)/200X field of view, significantly greater than that of the Pan-1 cells [(96 +/- 4)/200X field of view, P < 0.01]. Re-expressed in PC and accelerating the invasion of PC through depressing E-cadherin expression, Snail may present a new marker for predicting the aggressiveness of PC.


Epidemiology and outcomes of dental trauma cases from an urban pediatric emergency department.
The purpose of this retrospective study was to determine the outcomes of traumatized teeth treated in a pediatric emergency department. The records of pediatric patients presenting to the pediatric emergency department of a pediatric hospital over a 56-month period were reviewed and pertinent data were extracted. Treatment outcomes and contributing factors were analyzed for cases with greater than 6 months of follow up. A total of 264 patient records (548 traumatized teeth) were investigated. The mean age of the children was 8.2 years and 62% were boys. The most common ages for dental trauma were between 2-4 years and 8-10 years. Permanent dentition comprised 53% of the traumatized teeth. Extrusive and lateral luxations (29.5%) were the most common injuries encountered. Two hundred and thirty seven teeth (43%) presented for follow-up visits, and the mean duration of follow up was 55.6 days. The number of cases with more than 6 months of follow up decreased to 122 (22%). Of these, 31 (6%) teeth were extracted at the time of injury. Outcomes were ascertained for the remaining 91 (17%) teeth. Emergency dental treatment led to uncomplicated retention of teeth beyond 6 months in 58% of these cases. Luxation injuries had a higher success rate than avulsions (P = 0.046). After receiving emergency dental care in the emergency department, 43% of the teeth presented for follow-up dental care and only 22% were followed up for greater than 6 months. Emergency department treatment translated to successful retention of teeth in 58% of the cases with documented follow up. Severe periodontal injuries resulted in treatment complications.


Decreasing trend in the incidence of stomach cancer in Mumbai, India, during 1988 to 1999.
The time trend in incidence of stomach cancer in males and females in Mumbai, India during 1988 to 1999 was estimated using data collected by the Bombay Population-based Cancer Registry. During the 12-year period, a total of 3657 stomach cancer cases (3.9% of all cancers) were registered by the Bombay Population-based Cancer Registry of which 2467 (5.1% of all male cancers) were in males and 1184 (2.6% of all female cancers) in females. For evaluation of the trend, we applied a linear regression model based on the logarithm of the observed incidence rates. The annual percentage changes were also computed for the incidence rates for evaluating the time trend. A statistically significant decreasing trend in the overall age-adjusted incidence rates of stomach cancer was observed during the period 1988 to 1999, with an yearly decrease of 4.44% in males and 2.56% in females. This decrease was most striking in males in the age groups 40-59 and 60+, and in females only in the age group 40-59. The probability estimates indicated that one out of every 92 men and one out of every 187 women will contract a stomach cancer at some time in their whole life and 95% of the chance is after his or her 40th birthday. The decreasing trend in the age-adjusted incidence rates of stomach cancer in both the sexes indicates that there is a critical change in the etiology of this cancer. The findings may provide clues relating to various life-style and environmental changes impacting on stomach cancer incidence.


Long non-coding RNA TUG1 knockdown repressed the viability, migration and differentiation of osteoblasts by sponging miR-214.
The maxillofacial region in the human body is susceptible to fracture and corresponding soft tissue injury. In the current study, the effect of long non-coding RNA (lncRNA) taurine upregulated gene 1 (TUG1) on maxillofacial fracture development was investigated. In total, 50 patients diagnosed with maxillary fracture and 50 healthy volunteers were enrolled in this study. Participants' TUG1 expression level in serum was measured using reverse transcription-quantitative (RT-q)PCR. After transfection with small interfering (si)-TUG1, microRNA (miR)-214 mimic, miR-214 inhibitor, bone morphogenetic protein 2 (BMP2) mimic or a combination, the biological behavior of osteoblasts was evaluated using MTT, Transwell assays, RT-qPCR, flow cytometry and western blot analysis. Recovery experiments were used to explore the potential mechanism. Results demonstrated that TUG1 expression was decreased in the serum of patients with maxillary fractures. Knockdown of TUG1 repressed viability, migration and differentiation and induced apoptosis of osteoblasts. StarBase v2.0 revealed that TUG1 served as a sponge for miR-214 and BMP2 is a direct target of miR-214. Altogether, it was revealed that TUG1 expression was decreased in patients with maxillary fractures and TUG1 knockdown repressed the biological process of osteoblasts by sponging miR-214.


The first 72 hours of brain tissue oxygenation predicts patient survival with traumatic brain injury.
Utilization of brain tissue oxygenation (pBtO(2)) is an important but controversial variable in the treatment of traumatic brain injury. We hypothesize that pBtO(2) values over the first 72 hours of monitoring are predictive of mortality. Consecutive, adult patients with severe traumatic brain injury and pBtO(2) monitors were retrospectively identified. Time-indexed measurements of pBtO(2), cerebral perfusion pressure (CPP), and intracranial pressure (ICP) were collected, and average values over 4-hour blocks were determined. Patients were stratified according to survival, and repeated measures analysis of variance was used to compare pBtO(2), CPP, and ICP. The pBtO(2) threshold most predictive for survival was determined. There were 8,759 time-indexed data points in 32 patients. The mean age was 39 years ± 16.5 years, injury severity score was 27.7 ± 10.7, and Glasgow Coma Scale score was 6.6 ± 3.4. Survival was 68%. Survivors consistently demonstrated higher pBtO(2) values compared with nonsurvivors including age as a covariate (F = 12.898, p < 0.001). Individual pBtO(2) was higher at the time points 8 hours, 12 hours, 20 hours to 44 hours, 52 hours to 60 hours, and 72 hours of monitoring (p < 0.05). There was no difference in ICP (F = 1.690, p = 0.204) and CPP (F = 0.764, p = 0.389) values between survivors and nonsurvivors including age as a covariate. Classification and regression tree analysis identified 29 mm Hg as the threshold at which pBtO(2) was most predictive for mortality. The first 72 hours of pBtO(2) neurologic monitoring predicts mortality. When the pBtO(2) monitor remains below 29 mm Hg in the first 72 hours of monitoring, mortality is increased. This study challenges the brain oxygenation threshold of 20 mm Hg that has been used conventionally and delineates a time for monitoring pBtO(2) that is predictive of outcome. III, prognostic study.


Fourier law in the alternate-mass hard-core potential chain.
We study energy transport in a one-dimensional model of elastically colliding particles with alternate masses m and M. In order to prevent total momentum conservation, we confine particles with mass M inside a cell of finite size. We provide convincing numerical evidence for the validity of Fourier law of heat conduction in spite of the lack of exponential dynamical instability. Comparison with previous results on similar models shows the relevance of the role played by total momentum conservation.