Chronic glutamate treatment selectively modulates AMPA RNA editing and ADAR expression and activity in primary cortical neurons.
Adenosine-to-inosine RNA editing is a post-transcriptional process, catalyzed by ADAR enzymes, with an important role in diversifying the number of proteins derived from a single gene. In neurons, editing of ionotropic AMPA glutamate receptors has been shown to be altered under several experimental conditions, including severe pathologies, thus highlighting the potential significance of its modulation. In this study, we treated rat primary cortical cell cultures with a sub-lethal dose of glutamate (10 μM), focusing on RNA editing and ADAR activity. We found that chronic glutamate treatment down-regulates RNA editing levels at the R/G site of GluA2-4 subunits of AMPA receptors and at the K/E site of CYFIP2. These changes are site-specific since they were not observed either for the GluA2 Q/R site or for other non-glutamatergic sites. Glutamate treatment also down-regulates the protein expression levels of both ADAR1 and ADAR2 enzymes, through a pathway that is Ca(2+)- and calpain-dependent. Given that AMPA receptors containing unedited subunits show a slower recovery rate from desensitization compared to those containing edited forms, the reduced editing at the R/G site may, at least in part, compensate for glutamate over-stimulation, perhaps through the reduced activation of postsynaptic receptors. In summary, our data provide direct evidence of the involvement of ADAR1 and ADAR2 activity as a possible compensatory mechanism for neuronal protection following glutamate over-stimulation.


MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale.
MET or hepatocyte growth factor (HGF) receptor pathway signaling mediates wound healing and hepatic regeneration, with pivotal roles in embryonic, neuronal, and muscle development. However, dysregulation of MET signaling mediates proliferation, apoptosis, and migration and is implicated in a number of malignancies. In non-small cell lung cancer (NSCLC), aberrant MET signaling can occur through a number of mechanisms that collectively represent a significant proportion of patients. These include MET or HGF protein overexpression, MET gene amplification, MET gene mutation or fusion/rearrangement, or aberrations in downstream signaling or regulatory components. Responses to MET tyrosine kinase inhibitors have been documented in clinical trials in patients with MET-amplified or MET-overexpressing NSCLC, and case studies or case series have shown that MET mutation/deletion is a biomarker that is also predictive of response to these agents. However, other recent clinical data have highlighted an urgent need to elucidate optimal biomarkers based on genetic and/or protein diagnostics to correctly identify patients most likely to benefit in ongoing clinical trials of an array of MET-targeted therapies of differing class. The latest advances in the development of MET biomarkers in NSCLC have been reviewed, toward establishing appropriate MET biomarker selection based on a scientific rationale. Mol Cancer Ther; 16(4); 555-65. ©2017 AACR.


Protonation States of Molecular Groups in the Chromophore-Binding Site Modulate Properties of the Reversibly Switchable Fluorescent Protein rsEGFP2.
The role of protonation states of the chromophore and its neighboring amino acid side chains of the reversibly switching fluorescent protein rsEGFP2 upon photoswitching is characterized by molecular modeling methods. Numerous conformations of the chromophore-binding site in computationally derived model systems are obtained using the quantum chemistry and QM/MM approaches. Excitation energies are computed using the extended multiconfigurational quasidegenerate perturbation theory (XMCQDPT2). The obtained structures and absorption spectra allow us to provide an interpretation of the observed structural and spectral properties of rsEGFP2 in the active ON and inactive OFF states. The results demonstrate that in addition to the dominating anionic and neutral forms of the chromophore, the cationic and zwitterionic forms may participate in the photoswitching of rsEGFP2. Conformations and protonation forms of the Glu223 and His149 side chains in the chromophore-binding site play an essential role in stabilizing specific protonation forms of the chromophore.


A Randomized Controlled Study of a Fully Liquid DTaP-IPV-HB-PRP-T Hexavalent Vaccine for Primary and Booster Vaccinations of Healthy Infants and Toddlers in Latin America.
Hexavalent diphtheria-tetanus-acellular pertussis-inactivated poliovirus-hepatitis B-Haemophilus influenzae type b (DTaP-IPV-HB-PRP-T)-containing vaccines are increasingly the standard of care. This study evaluated the primary series (NCT01177722) and booster (NCT01444781) of a fully liquid DTaP-IPV-HB-PRP-T vaccine in Latin America. Infants (N = 1375) received hepatitis B vaccine at birth and were randomized to one of 3 batches of the investigational DTaP-IPV-HB-PRP-T or licensed control vaccine (DTaP-HB-IPV//PRP-T) at 2-4 to 6 months of age, coadministered with 7-valent pneumococcal conjugate vaccine (PCV7) (2-4-6 months) and rotavirus vaccine (2-4 months). A booster of either DTaP-IPV-HB-PRP-T or control was given at 12-24 months, coadministered with PCV7. Immunogenicity was assessed by validated assays and safety from parental reports. Primary series seroprotection and vaccine response rates were equivalent for DTaP-IPV-HB-PRP-T batches. For pooled batches, noninferiority to the control vaccine was demonstrated for each antigen. There were no descriptive differences in antibody persistence or booster response between DTaP-IPV-HB-PRP-T and the control. The booster responses to either vaccine following DTaP-IPV-HB-PRP-T primary series or to DTaP-IPV-HB-PRP-T following a control vaccine primary series were similar. The anti-aP component (filamentous hemagglutinin [FHA] and pertussis toxin [PT]) vaccine response and anti-Haemophilus influenzae type b (PRP) series seroprotection (≥0.15 µg/mL) rates were ≥73.0% after 2 primary series doses. Antipyretics had no effect on the immune response, and an extra (oral) polio vaccination had no effect on the antipolio booster response. Responses to PCV7 and rotavirus vaccine were similar for each coadministration. There were no safety concerns observed with any vaccine. These results confirm the suitability of the fully liquid DTaP-IPV-HB-PRP-T vaccine for primary and booster vaccination of infants.


The diagnostic value of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) determination in the sera of colorectal adenoma and cancer patients.
Tumor cells, including colorectal cancer (CRC), are able to produce and release matrix metalloproteinase 9 (MMP-9) which is involved in tumor invasion and metastasis. Natural tissue inhibitors of matrix metalloproteinases (TIMPs) regulate activity of MMPs and stimulate tumor growth and malignant transformation. The aim of the present study was to compare the clinical significance of serum MMP-9 with TIMP-1 in the diagnosis of CRC patients and in the differentiation between colorectal adenoma (CA) and cancer. Serum MMP-9 and TIMP-1 were measured in 75 CRC patients, 35 CA, and 70 healthy subjects using enzyme-linked immunosorbent assay. Concentrations of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) were determined by microparticle enzyme immunoassay. Serum levels of all proteins tested were significantly higher in CRC patients than in healthy subjects. Additionally, serum TIMP-1 was significantly higher in patients with CRC than in CA patients. Concentrations of TIMP-1 correlated with tumor stage, nodal involvement, presence of distant metastases, patients' survival, and tumor resectability. Diagnostic sensitivity of TIMP-1 was higher (61%) than those of other biomarkers (MMP-9, 55%; CEA, 39%; CA 19-9, 11%), and increased in combined use with MMP-9 (75%) or CEA (73%). The areas under receiver operating characteristic curves of TIMP-1 were larger than those of MMP-9. Our findings suggest better usefulness of serum TIMP-1 than MMP-9 in the diagnosis of CRC, especially in the assessment of Duke's classification of tumor stage, survival of cancer patients, resectability of tumor, and in the differentiation between CA and cancer.


Better genechip microarray layouts by combining probe placement and embedding.
The microarray layout problem is a generalization of the border length minimization problem, and asks to distribute oligonucleotide probes on a microarray and to determine their embeddings in the deposition sequence in such a way that the overall quality of the resulting synthesized probes is maximized. Because of its inherent computational complexity, it is traditionally attacked in several phases: partitioning, placement, and re-embedding. We present the first algorithm, Greedy+, that combines placement and embedding and that results in improved layouts in terms of border length and conflict index (a more realistic measure of probe quality), both on arrays of random probes and on existing Affymetrix GeneChip arrays. We also present a detailed study on the layouts of the latest GeneChip arrays, and show how Greedy+ can further improve layout quality by as much as 12% in terms of border length and 35% in terms of conflict index.


Microbiological composition associated with interleukin-1 gene polymorphism in subjects undergoing supportive periodontal therapy.
Interleukin-1 gene polymorphism (IL-1 gene) has been associated with periodontitis. The present study examined the subgingival microbiota by IL-1 gene status in subjects undergoing supportive periodontal therapy (SPT). A total of 151 subjects with known IL-1 gene status (IL-1A +4845/IL-1B -3954) (IL-1 gene) were included in this study. Clinical data and subgingival plaque samples (40 taxa) were collected. These taxa were determined by the checkerboard DNA-DNA hybridization method. Gender, smoking habits (n-par tests), age, and clinical periodontal conditions did not differ by IL-1 gene status. IL-1 gene-negative subjects had a higher total bacterial load (mean difference, 480.4 x 10(5); 95% confidence interval [CI], 77 to 884 x 10(5); P <0.02). The levels of Actinobacillus actinomycetemcomitans (mean difference, 30.7 x 10(5); 95% CI, 2.2 to 59.5 x 10(5); P <0.05), Eubacterium nodatum (mean difference, 4.2 x 10(5); 95% CI, 0.6 to 7.8 x 10(5); P <0.02), Porphyromonas gingivalis (mean difference, 17.9 x 10(5); 95% CI, 1.2 to 34.5 x 10(5); P <0.05), and Streptococcus anginosus (mean difference, 4.0 x 10(5); 95% CI, 0.2 to 7.2 x 10(5); P <0.05) were higher in IL-1 gene-negative subjects, an observation specifically found at sites with probing depths <5.0 mm. Bleeding on probing did not differ by IL gene status, reflecting clinical SPT efficacy. IL-1 gene-negative subjects had higher levels of periodontal pathogens. This may suggest that among subjects undergoing SPT, a lower bacterial load is required in IL-1 gene-positive subjects to develop the same level of periodontitis as in IL-1 gene-negative subjects.


[Regulation of the rate of proximal and distal reabsorption after intratubular injection of cobalt ions].
The effect of cobalt on renal tubular electrolyte and water handling was studied in the newt using the method of stationary microperfusion of the proximal and early distal tubules. Na, K, Ca, Mg and Cl concentrations were measured by electron probe analysis in tubule samples. 3H inulin was used to estimate the net fluid reabsorption. 5 X 10(-4) M CoCl2 was applied luminally. Proximal perfusion of cobalt increased significantly electrolytes (Na, Cl, Ca, Mg) and net fluid reabsorption. After cobalt injection in distal tubule sodium relative reabsorption was raised by 32%, chloride by 20%, fluid reabsorption by 27%. There was a reduction of calcium and magnesium transport by 8 and 31% accordingly. Potassium reabsorption did not change significantly. These data indicate that the luminal cobalt application stimulates proximal reabsorption and inhibits calcium reabsorption and activates sodium transport in distal tubule.


Highly specific noninvasive photoacoustic and positron emission tomography of brain plaque with functionalized croconium dye labeled by a radiotracer.
Highly-efficient targeting probes are desirable for disease diagnosis and functional imaging. However, most of the current near-infrared (NIR) probes suffer from low signal conversion, insufficient photostability, poor probe specificity, and limited functions. Herein, an NIR ultrahigh absorbing croconium dye for amyloid (CDA) was designed and synthesized to specifically bind to cerebrovascular amyloid without antibody linkage. This unique CDA is able to strongly bind the hydrophobic channels of amyloid beta (Aβ) fiber with a very strong binding energy of -9.3 kcal mol-1. Our experimental results demonstrate that the amphipathic dye with an intense absorption peak at 800 nm generated a significant local temperature surge under low-power laser irradiation. Compared with representative prominent indocyanine green, Prussian blue, and gold nanorods, this probe can produce the strongest photoacoustic signal based on the same mass concentration. Labeled with radioactive 18F, this multifunctional probe allowed for the ultrasensitive photoacoustic tomography (PAT)/positron emission tomography (PET)/fluorescence imaging of Aβ plaques in the brain cortex. Featured with high spatial resolution and optical specificity, PAT was intrinsically suitable for imaging pathological sites on cortical vessels, whereas PET revealed whole-body anatomy with quantitative biodistribution information. Our study shows that a CDA-based functionalized dye aided with PAT and PET is capable of plaque diagnosis and localization.


Antiviral Drug Ganciclovir Is a Potent Inhibitor of the Proliferation of Müller Glia-Derived Progenitors During Zebrafish Retinal Regeneration.
The purpose of this study was to investigate the effect of the antiviral drug ganciclovir (GCV) on Müller glia dedifferentiation and proliferation and the underlying cellular and molecular mechanisms in adult zebrafish. A Tg(1016tuba1a:GFP) transgenic line was generated to identify injury-induced dedifferentiation of Müller glia. Mechanical retinal damage was induced by a needle-poke injury on the back of the eyes in adult zebrafish. Phosphate-buffered saline or GCV was injected into the vitreous of the eye at the time of injury or through the cornea. The GCV clearance rate from the eye was determined by a reversed-phase HPLC method. Green fluorescent protein (GFP) and bromodeoxyuridine (BrdU) immunofluorescence were used to determine the effect of GCV on retinal regeneration. Cell apoptosis was evaluated by TUNEL staining. Microglia were labeled by vitreous injection of isolectin IB4 conjugates. Quantitative (q)PCR and Western blot analysis were used to determine gene expression in the retina. Ganciclovir treatment significantly reduced the number of BrdU+ Müller glia-derived progenitor cells (MGPCs) at 4 days post injury. Further analysis showed that GCV had no impact on Müller glia dedifferentiation and the initial formation of MGPCs. Our data indicate that GCV irreversibly inhibited MGPC proliferation likely through a p53-p21(cip1)-dependent pathway. Interestingly, unlike control cells, GCV-treated Müller glia cells were "locked" in a prolonged dedifferentiated state. Our study uncovered a novel inhibitory effect of GCV on MGPC proliferation and suggests its potential use as a tool to uncover molecular mechanisms underlying retinal regeneration in zebrafish.


Root Canal Configurations and Morphological Variations in Maxillary and Mandibular Second Molars in a Pakistani Population.
To determine the dental morphology and root canal anatomy of maxillary and mandibular second molars in Pakistani population living in Hyderabad. Retrospective, cross-sectional study. Place and Duration of the Study: Department of Operative Dentistry and Endodontics, Liaquat University of Medical and Health Sciences (LUMHS), Jamshoro, from April to May 2023. This study analysed the number of roots, root canal configurations, and frequency of C-shaped root canals and their configuration assessment. The data was obtained from Cone Beam Computerised Tomography (CBCT) records sourced from the Department of Radiology at Advanced Dental Care Centre of LUMHS. Two-rooted maxillary second molar was present in 10.6% of teeth, while 5.3% were single-rooted. Among mandibular second molars, 6.8% had one root, while 2.3% had three. The maxillary second molar mesiobuccal roots were Type I in 47.7% cases. The maxillary second molars had C1-shaped canals in 3.8% of cases. The study revealed that 10.6% of mandibular second molars had C-shaped canals, 3.0% were C1, 6.8% C3a, and 0.8% C4. A minority of patients had palatal morphology with two roots (MP and DP) and Type 1 canal structure, while a subset had both MP and DP canals. The prevalence of radix in mandibular second molars was found to be relatively infrequent. The prevalent root canal configurations were Type I in the mesiobuccal and palatal roots and Type IV in the mesial root of mandibular second molars. A noteworthy correlation was detected between the molar type characterised by a single root and the existence of a C-shaped canal in the female population. CBCT, Dental anatomy, Gender, Root canal, Morphology, Pakistani population.


Electronic Immunization Alerts and Spillover Effects on Other Preventive Care.
The impact of electronic health record (EHR) immunization clinical alert systems on the delivery of other preventive services remains unknown. We assessed for spillover effects of an EHR immunization alert on delivery of 6 other preventive services, in children 18 to 30 months of age needing immunizations. We conducted a secondary data analysis, with additional primary data collection, of a randomized, historically controlled trial to improve immunization rates with EHR alerts, in an urban, primary care clinic. No significant differences were found in screening for anemia, lead, development, nutrition, and injury prevention counseling in children prompting EHR immunization alerts (n = 129), compared with controls (n = 135). Significant increases in oral health screening in patients prompting EHR alerts (odds ratio = 4.8, 95% CI = 1.8-13.0) were likely due to practice changes over time. An EHR clinical alert system targeting immunizations did not have a spillover effect on the delivery of other preventive services.


Effects of Natural Products on Enzymes Involved in Ferroptosis: Regulation and Implications.
Ferroptosis is a form of regulated cell death that is characterized by the accumulation of iron-dependent lipid peroxides. The regulation of ferroptosis involves both non-enzymatic reactions and enzymatic mechanisms. Natural products have demonstrated potential effects on various enzymes, including GPX4, HO-1, NQO1, NOX4, GCLC, and GCLM, which are mainly involved in glutathione metabolic pathway or oxidative stress regulation, and ACSL3 and ACSL4, which mainly participate in lipid metabolism, thereby influencing the regulation of ferroptosis. In this review, we have provided a comprehensive overview of the existing literature pertaining to the effects of natural products on enzymes involved in ferroptosis and discussed their potential implications for the prevention and treatment of ferroptosis-related diseases. We also highlight the potential challenge that the majority of research has concentrated on investigating the impact of natural products on the expression of enzymes involving ferroptosis while limited attention is given to the regulation of enzyme activity. This observation underscores the considerable potential and scope for exploring the influence of natural products on enzyme activity.


Family care map: Sustaining family-centered care in Polytrauma Rehabilitation Centers.
The study assessed sustainability of the Family Care Map, a family-centered approach to providing care for Veterans with polytrauma-related injuries, in four Department of Veterans Affairs Polytrauma Rehabilitation Centers. We applied a mixed-methods approach. Staff surveys used standardized measures of sustainability, commitment to change, information, and participation during implementation. Qualitative inquiry assessed Family Care Map implementation and facilitators and barriers to sustainability. Staff sustainability perceptions had a significant positive correlation with affective commitment to change, participation, and information received about the change process. Family Care Map integration into standard practices and use of its concepts with patients and families related to staff perceptions about sustainability. The degree of use and integration of the Family Care Map in traumatic brain injury/polytrauma care varied among the Polytrauma Rehabilitation Centers. Some successful sustainability strategies included integration into daily workflow and organizational culture. Examples of sustainability barriers included staff awareness and use and outdated information. Some practices, such as measuring and documenting the use of the Family Care Map in treatment plans, may not routinely occur. The focus on family-centered care will require further evaluation of organization-, staff-, and innovation-level attributes that influence sustainability of changes designed to improve family-centered care.


The potential impact of metabolic syndrome on erectile dysfunction in aging Taiwanese males.
Recently, metabolic syndrome (MtS) has received increasing attention. However, investigations regarding the potential impact of MtS and its components on erectile dysfunction (ED) have not been completely clarified. To determine the potential impact of MtS on ED in aging Taiwanese males. The definition of MtS was according to the modified criteria developed by the Bureau of Health Promotion in Taiwan. The presence and severity of ED were evaluated by International Index of Erectile Function 5 (IIEF-5) scores. A total of 639 subjects with a mean age of 60.2 years (range 40-83) were enrolled during a free health screening. All the men had complete clinical data and questionnaires taken. Clinical variables were compared according to MtS and ED prevalence. Multiple logistic regression analysis was used to determine the independent predictors of ED and MtS. Using age-adjusted multivariate logistic regression analysis, our results showed that subjects with ED had significantly higher prevalence of MtS (P<0.01, OR=2.30, 95% CI: 1.44-3.69). The presence of MtS had significant correlation with lower IIEF-5 scores (P<0.01), which were associated with the increment of MtS components number (P<0.01). Among the MtS components, abnormal fasting blood glucose (FBG) was the most significantly independent factor of MtS for ED (P=0.01, OR=1.60, 95% CI: 1.09-2.35). Testosterone levels were significantly lower in subjects with MtS (P=0.05), while inversely correlated with number of MtS components (P<0.01). In aging Taiwanese males, the presence of MtS is strongly associated with ED and abnormal FBG is the most independent predictor for ED. Low testosterone level might be viewed as another possible common denominator for various pathologies linking MtS to ED.


Tracking of risk factors for coronary heart disease from adolescence to young adulthood with special emphasis on physical activity and fitness. A longitudinal study.
Physical activity (PA), fitness and selected coronary heart disease (CHD) risk factors were studied in 2 Danish adolescent cohorts; changes in PA and fitness from the age of 16-18 years were measured in a subgroup of high school children; changes in lifestyle, fitness level and coronary heart disease risk factors were measured from late adolescence to young adult hood in a random sample of subjects attending school at baseline. Risk factors and physical fitness tracked from adolescence to young adulthood. The proportion of subjects in the upper quintile of risk still being in the upper quintile 8 years later was 2-3 times the expected in most risk factors. No relationship was found between physical activity and coronary heart disease risk factors in the adolescent population, and only a weak, but highly significant, relationship was found between VO2max and blood pressure in the large cohort of 17 year olds. These weak relationships could result from a relatively high fitness level and a small variation in fitness level in the young Danish population. Because of a great statistical power in the group of subjects at the same age from population 2, it was possible to analyze the relationship between blood pressure and fitness further. Lower blood pressure was found with higher fitness level, but only VO2max, and not physical activity, related to blood pressure, and the relationship became weaker with higher fitness level. In the adult male population, the variations in both VO2max and risk factors were much larger and a great number of the men had become sedentary. Inactive lifestyle was associated with low educational level, and the decrease in fitness and increase in coronary heart disease risk factor levels were more distinct in the former trade and vocational students than in the 'gymnasium' students. In the 17-year-old cohort, lower blood pressure was found with higher VO2max until a level of 53 and 45 ml.min-1.kg-1 in boys and girls, respectively, but above these levels no relationship was found between VO2max and blood pressure.


a-Si:H/SiO2 multilayer films fabricated by radio-frequency magnetron sputtering for optical filters.
We examined the optical properties of a-Si:H/SiO2 multilayer films fabricated by radio-frequency magnetron sputtering for optical bandpass filters (BPFs). Because of the high refractive-index contrast between a-Si:H and SiO2, the total number of layers of an a-Si:H/SiO2 multilayer can be relatively small. We obtained an a-Si:H refractive index of 3.6 at lambda = 1550 nm and its extinction coefficient k < 1 x 10(-4) and confirmed by Fourier-transform infrared spectroscopy that such small k is influenced by the Si-H bonding in the film. We fabricated a-Si:H/SiO2 BPFs by using in situ optical monitoring. Thermal tuning of a-Si:H/SiO2 BPF upon a silica substrate was also performed, and a thermal tunability coefficient of 0.07 nm/degree C was obtained.


Cardiac glycosides. 1. A systematic study of digitoxigenin D-glycosides.
A series of digitoxigenin glycosides was studied: five with beta-D-sugars varying stepwise in sugar structure from beta-D-digitoxose to beta-D-galactose, including one beta-D/alpha-D pair. I50 values for these glycosides and digitoxigenin were determined with hog kidney Na+, K+-ATPase. These data suggest a major and unexpected role for 4'-OH conformation in the sugar. All the glycosides with an equatorial 4'-OH were more active than the two with the 4'-OH axial [digitoxigenin beta-D-galactoside (6) I50 = 6.45 X 10(-8) M; digitoxigenin 2'-deoxy-alpha-D-ribo-hexopyranoside (alpha-3a) I50 = 9.33 X 10(-8) M; digitoxigenin I50 = 1.17 X 10(-7) M]. Stereochemistry of the 3'-OH had much less of an activity role than that of the 4'-OH, in contrast to existing models of "sugar-site" binding.


Cohort differences in disease and disability in the young-old: findings from the MRC Cognitive Function and Ageing Study (MRC-CFAS).
Projections of health and social care need are highly sensitive to assumptions about cohort trends in health and disability. We use a repeated population-based cross-sectional study from the Cambridgeshire centre of the UK Medical Research Council Cognitive Function and Ageing Study to investigate trends in the health of the young-old UK population Non-overlapping cohorts of men and women aged 65-69 years in 1991/2 (n = 689) and 1996/7 (n = 687) were compared on: self-reported diseases and conditions; self-rated health; mobility limitation; disability by logistic regression and four-year survival by Cox Proportional Hazards Regression models, with adjustments for differences in socio-economic and lifestyle factors. Survival was similar between cohorts (HR: 0.91, 95% CI: 0.62 to 1.32). There was a significant increase in the number of conditions reported between cohorts, with more participants reporting 3 or more conditions in the new cohort (14.2% vs. 10.1%). When individual conditions were considered, there was a 10% increase in the reporting of arthritis and a significant increase in the reporting of chronic airways obstruction (OR: 1.36, 95% CI: 1.04 to 1.78). This study provides evidence of rising levels of ill-health, as measured by the prevalence of self-reported chronic conditions, in the newer cohorts of the young-old. Though changes in diagnosis or reporting of disease cannot, as yet, be excluded, to better understand whether our findings reflect real increases in ill-health, investment should be made into improved population-based databases, linking self-report and objective measures of health and function, and including those in long-term care.


Chronic Viral Hepatitis: Current Management and Future Directions.
The past decade has seen transformation in the strategies for identifying and managing viral hepatitis, most dramatically the transformation of hepatitis C virus from a mostly chronic affliction to a curable disease that is accessible to wide populations through direct-acting antiviral therapies. More recently, shifting of hepatitis C virus burden to younger patients driven by intravenous drug use has shaped screening recommendations. Future work focusing on effective screening, linkage to care, treatment initiation, and post-cure management will allow countries to work toward meeting goals of eliminating viral hepatitis as a major public health threat. Concurrently, hepatitis B virus has also seen advances in management using oral nucleos(t)ide therapies with high-resistance barriers. However, virologic cure remains elusive in the setting of viral genetic persistence within the hepatocyte nucleus, even with suppressive antiviral therapy. Future directions include a refined definition of "cure," new biomarkers, and development of therapies targeting multiple pathways in the viral pathogenic and replication pathway. Progress is additionally being made on the management of hepatitis D infection. This review summarizes the recent evolution in disease characteristics, associated affected population, and changes in our understanding of management for these infections. We also discuss future directions in the management of viral hepatitis, including discussion on issues related to management before and after antiviral therapy. Conclusion: We summarize recent advances in the identification and management of viral hepatitis, which hold the potential to markedly reduce disease burden and therefore associated liver-related complications. However further work is needed to adequately identify and manage these diseases.


Intermittent luteal phase sertraline treatment of dysphoric premenstrual syndrome.
Dysphoric premenstrual syndrome (PMS) has been associated with serotonergic dysregulation, and serotonergic medications have been reported to alleviate the symptoms of PMS. We investigated the effects of the serotonin reuptake inhibitor sertraline given during only the luteal phase in women with dysphoric PMS. After baseline ratings were obtained during two menstrual cycles, 15 women with dysphoric PMS who also met DSM-IV criteria for premenstrual dysphoric disorder (PMDD) entered single-blind treatment with sertraline 100 mg/day for one full menstrual cycle. Women who responded to this treatment were randomly assigned to a four-cycle double-blind placebo-controlled crossover study in which sertraline 100 mg/day or placebo was each given only during luteal phases of two consecutive menstrual cycles. Eleven (79%) of fourteen women responded to single-blind full-cycle treatment with sertraline and were randomly assigned to the double-blind crossover study. Three patients dropped out of the study while taking placebo owing to nonresponse. For the remaining patients, sertraline given during the luteal phase produced significant improvements in depression, impairment, and global ratings compared with placebo and was equivalent in efficacy to sertraline given during the entire menstrual cycle. Women with dysphoric PMS who responded to continuous sertraline treatment responded equally well to sertraline treatment that was restricted to the luteal phase. Luteal phase treatment may have advantages in side effect burden and costs. Larger controlled trials are warranted to confirm this finding.


Injectable biodegradable hydrogels: progress and challenges.
Over the past decades, injectable hydrogels have emerged as promising biomaterials because of their biocompatibility, excellent permeability, minimal invasion, and easy integration into surgical procedures. These systems provide an effective and convenient way to administer a wide variety of bioactive agents such as proteins, genes, and even living cells. Additionally, they can be designed to be degradable and eventually cleared from the body after completing their missions. Given their unique characteristics, injectable biodegradable hydrogels have been actively explored as drug reservoir systems for sustained release of bioactive agents and temporary extracellular matrices for tissue engineering. This review provides an overview of state-of-the-art strategies towards constructing a rational design of injectable biodegradable hydrogels for protein drug delivery and tissue engineering. We also discuss the use of injectable hydrogels for gene delivery systems and biomedical adhesives.


A murine model system for the study of the human leukemia-associated inhibitory activity.
Mice inoculated with the RFV strain of Friend virus develop an erythroleukemia that spontaneously regresses. Bone marrow cells from leukemic mice produce a factor that inhibits colony formation in agar by normal CFU-Cs. CFU-Cs from leukemic animals are resistant to the factor. Bone marrow cells from some mice whose leukemia has regressed continue to produce the factor, and CFU-Cs from some regressed mice retain resistance to the factor. These observations dupllicate findings reported for patients with acute leukemias and those with leukemia in remission. The RFV system thus serves as an accurate experimental model for the study of hematopoietic cell interactions and the proliferative advantage of neoplastic cells in human leukemias.


Tensor tympani muscle: strange chewing muscle.
This work seeks to alert medical and odontological staff to understanding and using interdisciplinary handling for detecting different pathologies common otic symptoms. It offers better tools for this shared symptomatology during therapy s conservative phase. Tensor tympani muscle physiology and function in the middle ear have been veiled, even when their dysfunction and anatomical relationships may explain a group of confused otic symptoms during conventional clinical evaluation. Middle ear muscles share a common embryological and functional origin with chewing and facial muscles. This article emphasizes that these muscles share a functional neurological and anatomical dimension with the stomatognathic system; these muscles increased tonicity ceases to be a phenomenon having no logical connections. It offers functionality and importance in understanding referred otic symptoms in common with other extra-otical symptom pathologies. Tinnitus, vertigo, otic fullness sensation, hyperacusia, hypoacusia and otalgia are not only primary hearing organ symptoms. They should be redefined and related to the neighboring pathologies which can produce them. There is a need to understand temporomandibular disorders and craniofacial referred symptomatology from neurophysiologic and muscle-skeletal angles contained in the stomatognathic system. Common symptomatology is frequently observed in otic symptoms and temporomandibular disorders during daily practice; this should be understood by each discipline from a broad, anatomical and clinical perspective.


Role of High-Resolution Chest Computed Tomography in a Child with Persistent Tachypnoea and Intercostal Retractions: A Case Report of Neuroendocrine Cell Hyperplasia.
Background: Chronic interstitial lung diseases in children (chILD) are a heterogeneous group of disorders that can represent a clinical challenge for pediatric pneumologists. Among them, neuroendocrine cell hyperplasia of infancy (NEHI) is a diffuse lung disease prevalent in the first years of life that spontaneously improves over time. The clinical presentation of NEHI is indistinguishable from other interstitial lung diseases, so a correct and non-invasive diagnosis by chest computed tomography (CT) without lung biopsy might not be simple. Case presentation: An 8-month-old male infant presented with a history of chronic tachypnoea and dyspnoea since 6 months of age. The patient was born at term, with APGAR scores of 9 and 10 at 1 and 5 min, respectively. Since his second month of life, the patient suffered from abnormal breathing, which was characterized by mild tachypnoea and costal retractions that worsened during breastfeeding, crying, and respiratory infections. Bilateral inspiratory crackles, preferential to the lung bases, without oxygen desaturation were detected. A chest X-ray showed a diffuse over-inflation of the lungs, but laboratory tests did not reveal any abnormalities. High-resolution chest CT documented patchy areas of ground-glass opacity involving the right upper lobe, middle lobe, and lingula, and showed mosaic areas of air-trapping, suggesting a diagnosis of NEHI. The infant was discharged without therapy and gradually improved over time. At 1 year of age, the patient was eupnoeic and chest auscultation had normalized. Conclusions: NEHI is an interstitial disease of infancy characterized by tachypnoea from the first months of life, with a good prognosis and for which a rational diagnostic approach is crucial for making a specific, early diagnosis. Initially, clinical suspicions can be confirmed with reasonable accuracy by a CT scan of the chest. Other more invasive and more expensive investigations should be reserved for selected cases that do not show a spontaneous, favourable clinical evolution.


A novel high-current, high-resolution, low-kinetic-energy electron source for inverse photoemission spectroscopy.
A high-current electron source for inverse photoemission spectroscopy is described. The source comprises a thermal cathode electron emission system, an electrostatic deflector-monochromator, and a lens system for variable kinetic energy (1.6-20 eV) at the target. When scaled to the energy resolution, the electron current is an order of magnitude higher than that of previously described electron sources developed in the context of electron energy loss spectroscopy. Surprisingly, the experimentally measured energy resolution turned out to be significantly better than calculated by standard programs, which include the electron-electron repulsion in the continuum approximation. The achieved currents are also significantly higher than predicted. We attribute this "inverse Boersch-effect" to a mechanism of velocity selection in the forward direction by binary electron-electron collisions.


Analyses of the extent of shared synteny and conserved gene orders between the genome of Fugu rubripes and human 20q.
Cosmid and BAC contig maps have been constructed across two Fugu genomic regions containing the orthologs of human genes mapping to human chromosome 20q. Contig gene contents have been assessed by sample sequencing and comparative database analyses. Contigs are centered around two Fugu topoisomerase1 (top1) genes that were initially identified by sequence similarity to human TOP1 (20q12). Two other genes (SNAI1 and KRML) mapping to human chromosome 20 are also duplicated in Fugu. The two contigs have been mapped to separate Fugu chromosomes. Our data indicate that these linkage groups result from the duplication of an ancestral chromosome segment containing at least 40 genes that now map to the long arm of human chromosome 20. Although there is considerable conservation of synteny, gene orders are not well conserved between Fugu and human, with only very short sections of two to three adjacent genes being maintained in both organisms. Comparative analyses have allowed this duplication event to be dated before the separation of Fugu and zebrafish. Our data (which are best explained by regional duplication, followed by substantial gene loss) support the hypothesis that there have been a large number of gene and regional duplications (and corresponding gene loss) in the fish lineage, possibly resulting from a single whole genome duplication event.


Plasma alpha fetoprotein reference ranges in infancy: effect of prematurity.
The dearth of plasma alpha fetoprotein reference ranges for preterm infants often impairs the clinical interpretation of plasma alpha fetoprotein data collected from ill babies. This study tested our hypothesis that meaningful plasma reference ranges could be established for preterm infants by a simple correction of patient age at sampling date for gestational age deficit at birth. Using a modified radioimmunoassay kit method, determinations of alpha fetoprotein were performed on capillary and venous blood samples collected from 56 babies aged from birth to 5 months with gestational ages ranging from 26 weeks to 43 weeks. Unmodified plasma alpha fetoprotein values were grouped according to patient age and examined statistically using established normal theory methods, but these yielded excessively wide reference intervals and non-Gaussian distribution parameters. Acceptable reference ranges were derived using logarithmic transformation of plasma alpha fetoprotein values and rearrangement against patient age corrected for gestational age deficit. These provisional reference ranges for plasma alpha fetoprotein in preterm (and term) infants are applied to groups of previously meaningless alpha fetoprotein results and used to test the potential usefulness of plasma alpha fetoprotein determination as a diagnostic marker in biliary atresia, hepatitis, and yolk sac derived tumours.


Bottom-up proteomic analysis of human adult cardiac tissue and isolated cardiomyocytes.
The heart is composed of multiple cell types, each with a specific function. Cell-type-specific approaches are necessary for defining the intricate molecular mechanisms underlying cardiac development, homeostasis, and pathology. While single-cell RNA-seq studies are beginning to define the chamber-specific cellular composition of the heart, our views of the proteome are more limited because most proteomics studies have utilized homogenized human cardiac tissue. To promote future cell-type specific analyses of the human heart, we describe the first method for cardiomyocyte isolation from cryopreserved human cardiac tissue followed by flow cytometry for purity assessment. We also describe a facile method for preparing isolated cardiomyocytes and whole cardiac tissue homogenate for bottom-up proteomic analyses. Prior experience in dissociating cardiac tissue or proteomics is not required to execute these methods. We compare different sample preparation workflows and analysis methods to demonstrate how these can impact the depth of proteome coverage achieved. We expect this how-to guide will serve as a starting point for investigators interested in general and cell-type-specific views of the cardiac proteome.


Increase in circulating levels of monocyte chemoattractant protein-1 with aging.
Monocyte chemoattractant protein-1 (MCP-1) is a member of chemokines with chemoattractant activity for monocytes, T cells, mast cells, and basophils. Precursor mRNA or protein was detected at high levels in the lesions of several diseases, such as pulmonary fibrosis, rheumatoid arthritis, atherosclerosis, and some types of tumors. The regulation of MCP-1 production and the role of this chemokine in pathophysiologic states, however, remain largely unknown. In this study, using an enzyme-linked immunosorbent assay (ELISA), we measured the circulating MCP-1 levels in 405 healthy Japanese subjects of various ages, eliciting a profound age-dependent MCP-1 increase. Multivariate regression analysis revealed that significant predictors of MCP-1 value for males were age (p = 0.033) and serum triglyceride (p = 0.039). For females, age was also a significant predictor (p = 0.00002). One possible explanation is that the plasma MCP-1 concentration might reflect the existence of atherosclerosis, although the plasma MCP-1 concentration from patients with coronary artery disease or cerebrovascular accidents appears not to differ from age-matched, disease-free controls. This is the first report linking an increase in a particular chemokine level with aging.


The Influence of Cognitive Impairment on the Fitness-Cognition Relationship in Multiple Sclerosis.
Cognitive processing speed impairment (PSI) is common and debilitating in persons with multiple sclerosis (MS). Exercise training has been proposed as a behavioral approach for possibly managing MS-related processing speed dysfunction, largely based on cross-sectional studies of the relationship of cardiorespiratory fitness and cognitive processing speed. However, there is minimal evidence supporting exercise training as a treatment for MS-related PSI, as the vast majority of the existing studies have examined exercise and cardiorespiratory fitness effects on cognition in samples of noncognitively impaired persons with MS. To that end, the current cross-sectional investigation examined whether cardiorespiratory fitness was differentially associated with processing speed in persons with MS with and without PSI. Sixty-four persons with MS undertook the Symbol Digit Modalities Test for establishing groups with and without MS-related PSI, a modified flanker task for measuring processing speed performance, and an incremental exercise test to exhaustion on a cycle ergometer for measuring cardiorespiratory fitness in a single testing session. Bivariate correlations were performed on cardiorespiratory fitness and processing speed outcomes in PSI group subsamples. In the sample without PSI, cardiorespiratory fitness was not significantly associated with processing speed (P = 0.08). However, in the sample with PSI, cardiorespiratory fitness was significantly associated with processing speed (P = 0.01), such that lower cardiorespiratory fitness was strongly associated with slower processing speed. This study provides preliminary evidence of a significant association between cardiorespiratory fitness and processing speed in persons with MS-related PSI. Such an investigation provides the first direct support for aerobic exercise training as a possible behavioral approach for managing/treating MS-related cognitive impairment, beyond merely improving cognitive performance.


Minimally invasive treatment for anterior pelvic ring injuries with modified pedicle screw-rod fixation: a retrospective study.
Pelvic ring injuries constitute only 2 to 8% of all fractures; however, they occur in 20% of polytrauma patients. High-energy pelvic fractures often result in mechanical instability of the pelvic ring. Successful treatment of unstable pelvic ring fractures remains a challenge for orthopedic surgeons. This study presents a novel internal fixation method for stabilizing unstable anterior pelvic ring fractures using a minimally invasive modified pedicle screw-rod fixation (MPSRF) technique. This retrospective study included six patients with unstable pelvic ring injuries who underwent MPSRF, with or without posterior fixation. Intraoperative parameters such as blood loss, operative time, complications, and quality of reduction (Matta criteria) were recorded and evaluated by a blinded reviewer. In the present clinical series, the mean operative times and mean blood loss for unilateral versus bilateral anterior ring fixations were 176.0 min versus 295.6 min, and 153.3 mL versus 550.0 mL, respectively. No iatrogenic neuropraxia of the lateral femoral cutaneous nerve or femoral nerve palsy occurred. The reduction quality, graded by the Matta criteria, was excellent in five patients and good in one patient. There were no infections, delayed unions, nonunions, or loss of reductions during the follow-up period. Only one patient suffered from a broken rod at 4 months postoperatively. The modified technique represents a novel, minimally invasive procedure for the treatment of anterior pelvic ring fractures and offers a reliable and effective alternative to currently available surgical techniques.


Inpatient allergy/immunology consultations in a tertiary care setting.
Few studies have examined inpatient referral patterns for fellowship training programs and none for allergy/immunology (AI) since 2003. The primary end point was the reason for consultation, and secondary end points included the AI diagnosis made and outcomes. We retrospectively reviewed all inpatient AI consultations from July 1, 2001 through June 30, 2007. These 6 years of data were combined with 14 years of data examining the reason for consult from a previous study. The data were analyzed for trends and changes over the entire 20-year period. A total of 254 AI inpatient consults were reviewed over the 6 years studied. Thirty-six percent (92/254) of inpatient consults were for evaluation of adverse drug reactions (ADRs), 22% (55/254) miscellaneous reasons, 17% (43/254) urticaria/angioedema, 13% (32/254) for possible immunodeficiency, 9% (23/254) for anaphylaxis, and 3% (8/254) for asthma. AI inpatient consults show a significant decline over the recent 6-year period (p = 0.0023) despite stable total hospital admissions since 1998. Over the last 20 years, an 85% decrease (p < 0.00001) in inpatient asthma consults and increases (p < 0.05) in immunodeficiency, rash, and urticaria/angioedema evaluations have been observed. Not following AI recommendations resulted in a 16.6 odds ratio (95% CI, 5.55-49.93) that a patient's clinical status would be worse or unchanged. Inpatient AI consults have declined with associated reduction in asthma inpatient consults. Although ADRs and anaphylaxis consults have been stable, evaluations for immunodeficiency, rash, and urticaria/angioedema have increased. Following inpatient AI recommendations is associated with improved patient outcomes.


A comparison of the effects of silver nanoparticles and silver nitrate on a suite of soil dwelling organisms in two field soils.
Nanomaterials are increasingly used in a wide range of products, leading to growing concern of their environmental fate. In order to understand the fate and effects of silver nanoparticles in the soil environment, a suite of toxicity tests including: plant growth with Elymus lanceolatus (northern wheatgrass) and Trifolium pratense (red clover); collembolan survival and reproduction (Folsomia candida); and earthworm avoidance, survival and reproduction (Eisenia andrei) was conducted. The effect of silver nanoparticles (AgNP) was compared with the effect of ionic silver (as AgNO3) in two agricultural field soils (a sandy loam and a silt loam). Lethal (LC50) or sub lethal (IC50) effect levels are presented for all endpoints and demonstrate that in most cases AgNO3 (i.e. ionic silver) was found to be more toxic than the AgNP across test species. The difference in effects observed between the two forms of silver varied based on test species, endpoint and soil type. In tests that were conducted across different soil types, organisms in the sandier soil had a greater response to the Ag (ionic and nano) than those in soil with a high silt content. Earthworms (avoidance behavior and reproduction) were the most sensitive to both AgNP and AgNO3, while plant emergence was the least sensitive endpoint to both forms of Ag. The use of a test battery approach using natural field soils demonstrates the need to better quantify the dissolution and transformation products of nanomaterials in order to understand the fate and effects of these materials in the soil environment.


E-rosette formation with SRBC and changes in cAMP level of hog lymphocytes--a study of certain affecting factors.
A further study of cAMP change in porcine lymphocytes after E-rosette formation is presented in the present report using peripheral blood lymphocytes of pig mixed with different concentrations of SRBC membrane as well as SRBC treated with different enzymes for modification of the rosette formation. It has been found that cAMP enhancement in lymphocyte follows the increase in the concentration of SRBC membrane used, and that a similar relation appeared between modification of cAMP and enzyme-treated SRBC in the rosette formation. It has also been found that after rosetting with SRBC, cAMP level of lymphocytes began to rise within 1 min, reached its peak at 10 min and then returned to control level in about 8 hr.


Face space representations of movement.
The challenging computational problem of perceiving dynamic faces "in the wild" goes unresolved because most research focuses on easier questions about static photograph perception. This literature conceptualizes face representation as a dissimilarity-based "face space", with axes that describe the dimensions of static images. Some versions express positions in face space relative to a central tendency (norm). Are facial movements represented like this? We tested for representations that accord with an a priori hypothesized motion-based face space by experimentally manipulating faces' motion-based dissimilarity. Because we caricatured movements, we could test for representations of dissimilarity from a motion-based norm. Behaviorally, participants perceived these caricatured expressions as convincing and recognizable. Moreover, as expected, caricature enhanced perceived dissimilarity between facial expressions. Functional magnetic resonance imaging showed that occipitotemporal brain responses, including face-selective and motion-sensitive areas, reflect this face space. This evidence converged across methods including analysis of univariate mean responses (which additionally exhibited norm-based responses), repetition suppression and representational similarity analysis. This accumulated evidence for "representational geometry" shows how perception and visual brain responses to facial dynamics reflect representations of movement-based dissimilarity spaces, including explicit computation of distance from a norm movement.


Incidence and risk factors of delirium in critically ill patients after non-cardiac surgery.
Delirium is a common and deleterious complication in critically ill patients after surgery. The purpose of this study was to determine the incidence and risk factors of delirium in critically ill patients after non-cardiac surgery, and to investigate the relationship between the serum cortisol level and the occurrence of postoperative delirium. In a prospective cohort study, 164 consecutive patients who were admitted to the surgical intensive care unit after non-cardiac surgery were enrolled. Baseline characteristics and perioperative variables were collected. Blood samples were obtained on the first postoperative day and serum cortisol concentrations were measured. Delirium was assessed using the Nursing Delirium Screening Scale until the seventh postoperative day or the disappearance of delirious symptoms. Postoperative delirium occurred in 44.5% of patients (73 of 164). The median time to first onset of delirium is 0 (range 0 to 5 days) and the median duration of delirium is 3 (1 to 13) days. Independent risk factors of postoperative delirium included increasing age (odds ratio (OR) 2.646, 95% confidence interval (CI) 1.431 to 4.890, P = 0.002), a history of previous stroke (OR 4.499, 95%CI 1.228 to 16.481, P = 0.023), high Acute Physiology and Chronic Health Evaluation II score on surgical intensive care unite admission (OR 1.391, 95%CI 1.201 to 1.612, P < 0.001), and high serum cortisol level on the 1st postoperative day (OR 3.381, 95%CI 1.690 to 6.765, P = 0.001). The development of delirium was linked to higher incidence of postoperative complications (28.8% vs. 7.7%, P < 0.001), and longer duration of hospitalization (18 (7 to 74) days vs. 13 (3 to 48) days, P < 0.001). Delirium was a frequent complication in critically ill patients after non-cardiac surgery. High serum cortisol level was associated with increased incidence of postoperative delirium.


Chlamydia psittaci exposure in pet birds.
Chlamydia psittaci is a zoonotic pathogen with a wide range of avian hosts and may be transmitted to humans and cause severe disease. To assess the risk of psittacosis posed by pet birds, the seroprevalence of Chlamydia psittaci antibodies in 360 Eurasian siskins (Carduelis spinus), 289 oriental skylarks (Alauda arvensis) and 36 black-tailed grosbeaks (Coccothraustes migratorius) in Gansu province, north-western China was detected by an indirect haemagglutination assay. Twenty-seven out of 289 (9.34 %) Alauda arvensis, 45 out of 360 (12.50 %) Carduelis spinus and 2 out of 36 (5.56 %) Coccothraustes migratorius were positive for Chlamydia psittaci infection at a cut-off dilution of 1 : 16. The prevalence of Chlamydia psittaci was higher in Carduelis spinus (12.5 %) than in Alauda arvensis (9.34 %) and Coccothraustes migratorius (5.56 %); however, the differences were not statistically significant (P>0.05). Statistical analysis indicated that Chlamydia psittaci seroprevalence in adult pet birds (12.4 %, 67/540) was significantly higher than that in juvenile pet birds (4.83 %, 7/145) (P<0.01). There was no statistical difference in Chlamydia psittaci seroprevalence between male (12.4 %) and female (8.27 %) birds. To our knowledge, this is the first report indicating the seroprevalence of Chlamydia psittaci exposure in pet birds in China. Our results indicate that close contact with pet birds poses the risk of zoonotic transmission of Chlamydia psittaci.


Various mechanisms cause RET-mediated signaling defects in Hirschsprung's disease.
Hirschsprung's disease (HSCR) is a common congenital malformation characterized by the absence of intramural ganglion cells of the hindgut. Recently, mutations of the RET tyrosine kinase receptor have been identified in 50 and 15-20% of familial and sporadic HSCR, respectively. These mutations include deletion, insertion, frameshift, nonsense, and missense mutations dispersed throughout the RET coding sequence. To investigate their effects on RET function, seven HSCR missense mutations were introduced into either a 1114-amino acid wild-type RET isoform (RET51) or a constitutively activated form of RET51 (RET-MEN 2A). Here, we report that one mutation affecting the extracytoplasmic cadherin domain (R231H) and two mutations located in the tyrosine kinase domain (K907E, E921K) impaired the biological activity of RET-MEN 2A when tested in Rat1 fibroblasts and pheochromocytoma PC12 cells. However, the mechanisms resulting in RET inactivation differed since the receptor bearing R231H extracellular mutation resulted in an absent RET protein at the cell surface while the E921K mutation located within the catalytic domain abolished its enzymatic activity. In contrast, three mutations mapping into the intracytoplasmic domain neither modified the transforming capacity of RET-MEN 2A nor stimulated the catalytic activity of RET in our ligand-independent system (S767R, P1039L, M1064T). Finally, the C609W HSCR mutation exerts a dual effect on RET since it leads to a decrease of the receptor at the cell surface and converted RET51 into a constitutively activated kinase due to the formation of disulfide-linked homodimers. Taken together, our data show that allelic heterogeneity at the RET locus in HSCR is associated with various molecular mechanisms responsible for RET dysfunction.


Microparticles and cardiotoxicity secondary to doxorubicin-based chemotherapy in breast cancer patients.
Doxorubicin (DOXO)-cardiotoxicity is a limiting factor for breast cancer chemotherapy. The relationship between microparticles (MPs) and cardiotoxicity remains unclear. MPs can be released under varying pathophysiological conditions. Thereby, this study aimed to assess MPs derived from cardiomyocytes (CardioMPs), platelets (PMPs) and those that expresses tissue factor (TFMPs) in 80 women with breast cancer undergoing DOXO-based chemotherapy, with or without cardiotoxicity in a one-year follow-up. We observed in the cardiotoxicity group higher count of total-MPs at T0 (prior chemotherapy) (p = 0.034), CardioMPs at T0 and T1 (just after chemotherapy) (p = 0.009 and p = 0.0034) and TFMPs at T0 (p = 0.011) compared to non-cardiotoxicity group. The results suggest that MPs could be associated to cardiotoxicity due to DOXO treatment in breast cancer patients.


[Biochemical markers of vitamin supply].
The biochemical indicators to assess the nutritional status of individuals may be divided into 4 categories: methods which measure body stores e.g. plasma vitamin C or urinary excretion of thiamine, methods related to the rate of conversion of vitamins to metabolites e.g. thiamine pyrophosphate content of blood or urinary excretion of pyridoxic acid, methods based on the coenzymatic or hormonal function of vitamin metabolites, e.g., erythrocyte transketolase in the case of vitamin B1 or plasma concentration of 1,25 dihydroxycholecalciferol in the case of vitamin D. Finally, methods derived from true biochemical impairment of the metabolism, e.g., elevated blood pyruvate in borderline vitamin B1 deficiency or prolonged blood clotting time in the case of vitamin K deficiency. The results of all of these methods are for a certain vitamin related to each other and also to the daily intake of the vitamin in question as long as the daily vitamin intake remains stationary and no confounding variables such as disease, smoking or drinking habits interfere. Otherwise the estimation of vitamin intake by measuring biochemical parameters becomes questionable, since biochemical parameters are indicators of nutritional status and not so much of nutrient intake.


Observations on experimental myocardial ischaemia.
Over the past decade major advances have been made in the understanding of myocardial infarction largely through the use of animal models of ischaemia and infarction. Ultrastructural and biochemical aspects of reversible versus irreversible ischaemic injury have helped to clarify the nature of ischaemic cell death. The presence of a border zone of cells which are in the reversible phase of myocardial injury following coronary artery occlusion allows for salvage of ischaemic myocardium by a number of interventions. These interventions include reperfusion, a variety of pharmacological agents, and physical and haemodynamic interventions. Several clinical studies have shown that these interventions may be beneficial in the treatment of patients with acute myocardial infarction.


Myricetin protects pancreatic β-cells from human islet amyloid polypeptide (hIAPP) induced cytotoxicity and restores islet function.
The aberrant misfolding and self-assembly of human islet amyloid polypeptide (hIAPP)-a hormone that is co-secreted with insulin from pancreatic β-cells-into toxic oligomers, protofibrils and fibrils has been observed in type 2 diabetes mellitus (T2DM). The formation of these insoluble aggregates has been linked with the death and dysfunction of β-cells. Therefore, hIAPP aggregation has been identified as a therapeutic target for T2DM management. Several natural products are now being investigated for their potential to inhibit hIAPP aggregation and/or disaggregate preformed aggregates. In this study, we attempt to identify the anti-amyloidogenic potential of Myricetin (MYR)- a polyphenolic flavanoid, commonly found in fruits (like Syzygium cumini). Our results from biophysical studies indicated that MYR supplementation inhibits hIAPP aggregation and disaggregates preformed fibrils into non-toxic species. This protection was accompanied by inhibition of oxidative stress, reduction in lipid peroxidation and the associated membrane damage and restoration of mitochondrial membrane potential in INS-1E cells. MYR supplementation also reversed the loss of functionality in hIAPP exposed pancreatic islets via restoration of glucose-stimulated insulin secretion. Molecular dynamics simulation studies suggested that MYR molecules interact with the hIAPP pentameric fibril model at the amyloidogenic core region and thus prevents aggregation and distort the fibrils.


Reticulum cell sarcoma: an effector cell in antibody-dependent cell-mediated immunity.
A transplantable, murine reticulum cell sarcoma is described which exhibits the cytologic, adherence, and phagocytic properties of macrophages. It forms specific rosettes with erythrocytes in the presence of the corresponding anti-serum. The ascites cells mediate antibody-dependent cellular immunity as assayed by release of radioactivity from 51Cr-labeled erythrocytes. The contribution of contaminating host cells in the cytotoxic reaction was ruled out by growing the tumor in F1 mice and removing the host cells by anti-H2 serum and complement. The tumor cells have receptors for IgG2a and IgG2b immunoglobulins. The availability of a pure population of effector cells in the immune system allows study of the biochemical processes pursuant to lysis of foreign cells.


Association Between Peripheral Neuropathy and Exposure to Oral Fluoroquinolone or Amoxicillin-Clavulanate Therapy.
Peripheral neuropathy has been associated with systemic fluoroquinolone exposure, but risk has been poorly quantified. To calculate relative and absolute risk estimates for the association of fluoroquinolone exposure with peripheral neuropathy and to examine how risk may be affected by timing of fluoroquinolone exposure and by other risk factors. This nested case-control study used anonymized data from all patients routinely registered with general practices in The Health Improvement Network database, a large primary care population database in the United Kingdom, from January 1, 1999, to December 31, 2015. Data analyses were conducted January 8, 2018. The cohort consisted of 1 338 900 adults issued 1 or more prescriptions of fluoroquinolone (34.3%) or amoxicillin-clavulanate (65.7%) antibiotics. Adults with incident peripheral neuropathy were matched (on age, sex, general practice, and calendar time) with up to 4 controls by using incidence density sampling selected from a cohort prescribed oral fluoroquinolone or amoxicillin-clavulanate antibiotics. Incidence rate ratios of peripheral neuropathy were calculated for fluoroquinolone and for amoxicillin-clavulanate exposure and compared with nonexposure among patients without diabetes, with sensitivity analyses testing the consistency of the results. Population mean-adjusted rate differences were then estimated, including the number needed to harm for various durations of fluoroquinolone therapy. Current and cumulative exposure to oral fluoroquinolone or amoxicillin-clavulanate antibiotics. Incident peripheral neuropathy cases recorded in electronic medical records. In total, 5357 patients with incident peripheral neuropathy (mean [SD] age, 65.6 [14.7] years; 2809 women [52.4%]) were matched to 17 285 controls (mean [SD] age, 64.4 [15.2] years; 9485 women [54.9%]) without diabetes. Current oral fluoroquinolone exposure was associated with an increased relative incidence of peripheral neuropathy compared with nonexposure (adjusted incident rate ratio, 1.47; 95% CI, 1.13-1.92). Risk increased by approximately 3% for each additional day of current fluoroquinolone exposure and persisted for up to 180 days following exposure. No significant increased risk was observed with oral amoxicillin-clavulanate exposure. The absolute risk with current oral fluoroquinolone exposure was 2.4 (95% CI, 1.8-3.1) per 10 000 patients per year of current use. The number needed to harm for a 10-day course was 152 083 patients (95% CI, 117 742-202 778) and was greatest among men and among patients older than 60 years. The results of the present study suggested that oral fluoroquinolone therapy was associated with an increased risk of incident peripheral neuropathy that may depend on the timing of the exposure and the cumulative dose. Health care professionals should consider these potential risks when prescribing fluoroquinolone antibiotics.


Contemporary applications of frontal sinus trephination: A systematic review of the literature.
Our objective was to perform a systematic review of the literature on contemporary indications and outcomes for frontal sinus trephination and present an illustrative case of an endoscopically assisted repair of a subcutaneous frontal sinus fistula by trephination technique. PubMed and Ovid databases were used as data sources. A systematic review of the English literature was completed to review reports of frontal trephination from 1980 to 2014. Articles meeting inclusion criteria for inflammatory and noninflammatory indications were reviewed. Articles were systematically reviewed and graded by evidence-based medicine level. An illustrative case from our institution is then presented. The systematic review identified 2,621 published studies. Thirty-eight studies were identified for inclusion. The indications, techniques, outcomes, safety, and complications were reviewed for noninflammatory and inflammatory conditions. There were 32 retrospective case series, reports, or cohort studies (level 4), four systematic reviews (level 3), one prospective analysis (level 3), and one meta-analysis (level 2). Due to the heterogeneity of study cases and inclusion criteria, a meta-analysis was not feasible. We also present a novel closure of an anterior skull base defect resulting in a subcutaneous fistula with use of a frontal trephination approach. The frontal sinus trephination should not be regarded as a procedure of the past, as it useful in the armamentarium of the modern sinus and skull base surgeon. This approach provides access for instrumentation for hard-to-reach frontal sinus disease either purely through a trephination approach or as a supplementation to the transnasal endoscopic approach. Evidence supporting frontal sinus trephination is of levels 2, 3, and 4. Level of evidence: NA.


The effect of heat on the mechanical properties of glass ionomer cements.
The objective of this study was to assess the effect of heat application on the mechanical properties of glass ionomer cements. experimental design. The effect of heat on glass ionomer cements during their setting was evaluated by measuring compressive strength, flexural strength and microhardness. Moroever, temperature changes from one surface of the glass ionomer cement specimens 2, 4, and 6 mm thick to the other surface were measured. A condensable glass ionomer cement (Fuji IX) and a ceramic-reinforced glass ionomer cement (Amalgomer CR) were used as test materials. Heat was applied with soldering iron for 2 minutes at 80±2oC. All mechanical tests were carried out 24 hours after the setting of glass ionomer cements. No significant differences in compressive strength were found between the control groups and the heated groups. There were no statistically significant differences in the flexural strength value for both groups of Fuji IX. On the contrary, when heat was applied to Amalgomer, its mean flexural strength reached a value that was higher than that of Amalgomer control. Significant differences in microhardness were found between the control groups and the heated groups and between Fuji IX and Amalgomer CR. Temperature rising in both glass ionomer cements was also noted. two-way ANOVA was used where appropriate and independent samples t-test was used in case of interaction. It is established that heat application improved the surface mechanical properties of conventional glass ionomer cements.


Arthroplasties (with and without bone cement) for proximal femoral fractures in adults.
Numerous types of arthroplasties may be used in the surgical treatment of a hip fracture (proximal femoral fracture). The main differences between the implants are in the design of the stems, whether the stem is cemented or uncemented, whether a second articulating joint is included within the prosthesis (bipolar prosthesis), or whether a partial (hemiarthroplasty) or total whole hip replacement is used. To review all randomised controlled trials comparing different arthroplasties for the treatment of hip fractures in adults. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (September 2009), CENTRAL (The Cochrane Library 2009, Issue 3), MEDLINE, EMBASE and trial registers (all to September 2009), and reference lists of articles. All randomised and quasi-randomised controlled trials comparing different arthroplasties and their insertion with or without cement, for the treatment of hip fractures. Two review authors independently assessed trial quality, by use of a 10-item checklist, and extracted data. Twenty-three trials involving 2861 older and mainly female patients with proximal femoral fractures are included. Cemented prostheses, when compared with uncemented prostheses (6 trials, 899 participants) were associated with a less pain at a year or later and improved mobility. No significant difference in surgical complications was found. One trial of 220 participants compared a hydroxyapatite coated hemiarthroplasty with a cemented prosthesis and reported no notable differences between the two prosthesis. Comparison of unipolar hemiarthroplasty with bipolar hemiarthroplasty (7 trials, 857 participants, 863 fractures) showed no significant differences between the two types of implant. Seven trials involving 734 participants compared hemiarthroplasty with a total hip replacement (THR). Most studies involved cemented implants. Dislocation of the prosthesis was more common with the THR but there was a general trend within these studies to better functional outcome scores for those treated with the THR. There is good evidence that cementing the prostheses in place will reduce post-operative pain and lead to better mobility. From the trials to date there is no evidence of any difference in outcome between bipolar and unipolar prosthesis. There is some evidence that a total hip replacement leads to better functional outcome than a hemiarthroplasty. Further well-conducted randomised trials are required.


The shape of memory in temporal networks.
How to best define, detect and characterize network memory, i.e. the dependence of a network's structure on its past, is currently a matter of debate. Here we show that the memory of a temporal network is inherently multidimensional, and we introduce a mathematical framework for defining and efficiently estimating the microscopic shape of memory, which characterises how the activity of each link intertwines with the activities of all other links. We validate our methodology on a range of synthetic models, and we then study the memory shape of real-world temporal networks spanning social, technological and biological systems, finding that these networks display heterogeneous memory shapes. In particular, online and offline social networks are markedly different, with the latter showing richer memory and memory scales. Our theory also elucidates the phenomenon of emergent virtual loops and provides a novel methodology for exploring the dynamically rich structure of complex systems.


Clinical and hemodynamic benefit of macitentan and riociguat upfront combination in patients with pulmonary arterial hypertension.
In this open-label study, we evaluated the effect of upfront macitentan and riociguat combination in newly diagnosed pulmonary arterial hypertension (PAH) patients. In 15 consecutive PAH patients, we collected clinical and hemodynamic data at baseline, visit 1 (median 4 months) and visit 2 (median 12 months). Survival and transplantation status were analyzed over 36 months. Statistical analysis included student t-test and 95% confidence interval (CI) ( t-statistic or Clopper-Pearson). Kaplan-Meier was used to estimate survival rate. There were 11/15 women (mean age 56 years), in World Health Organization (WHO) functional class (FC) III ( n = 14) or IV ( n = 1). The 6 min walk distance increased from 281.6 m (baseline) to 315.7 m (visit 1) and visit 2 (313.9 m), representing a 34- and 32-m change ( P < 0.05), respectively, associated with Borg score improvements. Brain natriuretic peptide decreased: 318.2 pg/mL (baseline) to 122.0 pg/mL (visit 1) and 98.6 pg/mL (visit 2) ( P < 0.05). WHO FC improved in eight patients (53%, 95% CI 27%-79%). Pulmonary vascular resistance (9.2 to 5.7 Wood Units) and mean pulmonary artery pressure (47.3 to 38.9 mmHg) decreased; cardiac index increased (2.3 to 3.0 L/min/m2) (baseline to visit 2, all P < 0.05). All patients had intermediate and high risk score (baseline); at 1-year follow-up, dual therapy led to reduction to low risk score in 7/15 (47%) patients. There were no unexpected or serious side effects. Three patients died due to unrelated causes; one patient received a lung transplant. Transplant-free survival rate (36 months) was 85%. Preliminary evidence is provided for effectiveness of initial macitentan and riociguat combination therapy in PAH.


Optimal resources for primary prevention of atherosclerotic diseases. Atherosclerosis Study Group.
This statement is an update of the 1970 Inter-Society Commission for Heart Disease Resources ( ICHD ) report, "Primary Prevention of the Atherosclerotic Diseases." The charge to the Study Group was to assess relevant new data and, where the evidence is less than definitive, to formulate conclusions and recommendations based on best judgment. Current developments are reviewed, and issues raised in response to the earlier recommendations are considered. Recommendations are intended to serve as a guide for individual behavior, physician practice, and the formulation of public health policy.


Phenotypic plasticity of HSP70 and HSP70 gene expression in the Pacific oyster (Crassostrea gigas): implications for thermal limits and induction of thermal tolerance.
Pacific oysters, Crassostrea gigas, living at a range of tidal heights, routinely encounter large seasonal fluctuations in temperature. We demonstrate that the thermal limits of oysters are relatively plastic, and that these limits are correlated with changes in the expression of one family of heat-shock proteins (HSP70). Oysters were cultured in the intertidal zone, at two tidal heights, and monitored for changes in expression of cognate (HSC) and inducible (HSP) heat-shock proteins during the progression from spring through winter. We found that the "control" levels (i.e., prior to laboratory heat shock) of HSC77 and HSC72 are positively correlated with increases in ambient temperature and were significantly higher in August than in January. The elevated level of HSCs during the summer was associated with moderate, 2-3 degrees C, increases in the upper thermal limits for survival. We measured concomitant increases in the threshold temperatures (T(on)) required for induction of HSP70. Total hsp70 mRNA expression reflected the seasonal changes in the expression of inducible but not cognate members of the HSP70 family of proteins. A potential cost of increased T(on) in the summer is that there was no extension of the upper thermal limits for survival (i.e., induction of thermotolerance) after sublethal heat shock at temperatures that were sufficient to induce thermotolerance during the winter months.


Community-Acquired Pneumonia Hospitalization among Children with Neurologic Disorders.
To describe and compare the clinical characteristics, outcomes, and etiology of pneumonia among children hospitalized with community-acquired pneumonia (CAP) with neurologic disorders, non-neurologic underlying conditions, and no underlying conditions. Children <18 years old hospitalized with clinical and radiographic CAP were enrolled at 3 US children's hospitals. Neurologic disorders included cerebral palsy, developmental delay, Down syndrome, epilepsy, non-Down syndrome chromosomal abnormalities, and spinal cord abnormalities. We compared the epidemiology, etiology, and clinical outcomes of CAP in children with neurologic disorders with those with non-neurologic underlying conditions, and those with no underlying conditions using bivariate, age-stratified, and multivariate logistic regression analyses. From January 2010-June 2012, 2358 children with radiographically confirmed CAP were enrolled; 280 (11.9%) had a neurologic disorder (52.1% of these individuals also had non-neurologic underlying conditions), 934 (39.6%) had non-neurologic underlying conditions only, and 1144 (48.5%) had no underlying conditions. Children with neurologic disorders were older and more likely to require intensive care unit (ICU) admission than children with non-neurologic underlying conditions and children with no underlying conditions; similar proportions were mechanically ventilated. In age-stratified analysis, children with neurologic disorders were less likely to have a pathogen detected than children with non-neurologic underlying conditions. In multivariate analysis, having a neurologic disorder was associated with ICU admission for children ≥2 years of age. Children with neurologic disorders hospitalized with CAP were less likely to have a pathogen detected and more likely to be admitted to the ICU than children without neurologic disorders.


[Preterm birth as a risk factor for high blood pressure in children: a systematic review].
Epidemiological studies have suggested that arterial hypertension is a chronic disease that begins in childhood, and that prematurity (birth at less than 37 weeks' gestational age) is potentially associated with the development of hypertension in childhood and adulthood. Our objective was to identify the association between prematurity and high blood pressure in children, using a systematic literature review. Original articles related to the theme and published in English, Portuguese, or Spanish from 1998 to 2009 were selected from the MEDLINE, LILACS, and SciELO databases. We excluded articles without abstracts, review articles, and articles not related to prematurity and hypertension in childhood. Nine articles were located and analyzed: 5 case-control studies, 2 cross-sectional studies, and 2 cohort studies. The majority of the studies failed to show an association between prematurity and arterial hypertension in childhood. However, the influence of prematurity should not be ruled out, given the small number of studies on this theme and the diversity of methodological approaches in the literature.


A novel design of bioartificial kidneys with improved cell performance and haemocompatibility.
Treatment with bioartificial kidneys had beneficial effects in animal experiments and improved survival of critically ill patients with acute kidney injury in a Phase II clinical trial. However, a Phase II b clinical trial failed. This and other results suggested various problems with the current design of bioartificial kidneys. We propose a novel design to improve various properties of device, including haemocompatibility and cell performance. An important feature of the novel design is confinement of the blood to the lumina of the hollow fibre membranes. This avoids exposure of the blood to the non-haemocompatible outer surfaces of hollow fibre membranes, which usually occurs in bioartificial kidneys. We use these outer surfaces as substrate for cell growth. Our results show that commercial hollow fibre membranes can be directly applied in the bioreactor when human primary renal proximal tubular cells are grown in this configuration, and no coatings are required for the formation of robust and functional renal epithelia. Furthermore, we demonstrate that the bioreactor unit produces significant amounts of interleukins. This result helps to understand the immunomodulatory effects of bioartificial kidneys, which have been observed previously. The novel bioartificial kidney design outlined here and the results obtained would be expected to improve the safety and performance of bioartificial kidneys and to contribute to a better understanding of their effects.


Microbial Communities in Sediments of Lagos Lagoon, Nigeria: Elucidation of Community Structure and Potential Impacts of Contamination by Municipal and Industrial Wastes.
Estuarine sediments are significant repositories of anthropogenic contaminants, and thus knowledge of the impacts of pollution upon microbial communities in these environments is important to understand potential effects on estuaries as a whole. The Lagos lagoon (Nigeria) is one of Africa's largest estuarine ecosystems, and is impacted by hydrocarbon pollutants and other industrial and municipal wastes. The goal of this study was to elucidate microbial community structure in Lagos lagoon sediments to identify groups that may be adversely affected by pollution, and those that may serve as degraders of environmental contaminants, especially polycyclic aromatic hydrocarbons (PAHs). Sediment samples were collected from sites that ranged in types and levels of anthropogenic impacts. The sediments were characterized for a range of physicochemical properties, and microbial community structure was determined by Illumina sequencing of the 16S rRNA genes. Microbial diversity (species richness and evenness) in the Apapa and Eledu sediments was reduced compared to that of the Ofin site, and communities of both of the former two were dominated by a single operational taxonomic unit (OTU) assigned to the family Helicobacteraceae (Epsilonproteobacteria). In the Ofin community, Epsilonproteobacteria were minor constituents, while the major groups were Cyanobacteria, Bacteroidetes, and Firmicutes, which were all minor in the Apapa and Eledu sediments. Sediment oxygen demand (SOD), a broad indicator of contamination, was identified by multivariate analyses as strongly correlated with variation in alpha diversity. Environmental variables that explained beta diversity patterns included SOD, as well as levels of naphthalene, acenaphthylene, cobalt, cadmium, total organic matter, or nitrate. Of 582 OTU identified, abundance of 167 was significantly correlated (false discovery rate q≤ 0.05) to environmental variables. The largest group of OTU correlated with PAH levels were PAH/hydrocarbon-degrading genera of the Oceanospirillales order (Gammaproteobacteria), which were most abundant in the hydrocarbon-contaminated Apapa sediment. Similar Oceanospirillales taxa are responsive to marine oil spills and thus may present a unifying theme in marine microbiology as bacteria adapted for degradation of high hydrocarbon loads, and may represent a potential means for intrinsic remediation in the case of the Lagos lagoon sediments.


Operational medicine experience integrated into a military internal medicine residency curriculum.
The optimal training of physicians should prepare them for the environment in which they will practice. During the past several years, the practice of internal medicine has shifted from a focus on the inpatient setting to one that includes an emphasis on the ambulatory clinic. Military internists must be further prepared to practice medicine with forward units, at field hospitals, and in other operational settings. Community-based teaching programs that reflect present and future practice are increasingly recognized as essential, yet details on the structure and implementation of such programs, especially those designed to teach field and operational medicine, are lacking. The Internal Medicine Residency Program at Walter Reed Army Medical Center has developed and implemented an operational medicine curriculum that includes a field medical training exercise. The program is driven by the residents and chief resident and requires little additional funding. Resident research continues to increase, morale remains high, and the first class to complete the 3-year operational curriculum achieved a 100% pass rate on the American Board of Internal Medicine certification examination. We describe our 3-year experience of implementing this program, with an emphasis on curriculum design and execution, qualitative assessment, and initial lessons learned.


LINC02476 Promotes the Malignant Phenotype of Hepatocellular Carcinoma by Sponging miR-497 and Increasing HMGA2 Expression.
Long noncoding RNAs (lncRNAs) can promote hepatocellular carcinoma (HCC) initiation and progression. In this report, we examined the role of lncRNA LINC02476 in HCC. The expression levels of different lncRNAs in HCC were explored using the TCGA database and lncRNA LINC02476 was selected for further study. The expression of LINC02476 in HCC tissues was determined by real-time PCR. The clinicopathological characteristics of HCC patients were analyzed relative to the expression of LINC02476. The expression of LINC02476 was downregulated in HCC cells using a lentiviral vector and different assays were performed to study cell growth, proliferation, invasion, apoptosis and the cell cycle. MiR-497 was selected as a miRNA that could interact with LINC02476 which was further tested by RNA immunoprecipitation. HMGA2 was selected as a possible target of miR-497, and their interaction was examined by a luciferase reporter assay. LINC02476 expression was elevated in HCC cell lines and HCC tissues. When LINC02476 was downregulated, the growth and the invasion of HCC cells decreased in vitro and in vivo. LINC02476 negatively regulated the expression of miR-497 by acting as a ceRNA. HMGA2 was directly targeted and inhibited by miR-497. The results indicate that LINC02476 functions through the miR-497/HMGA2 axis and that it has a role in the growth and metastasis of HCC cells. Therefore, LINC02476 could be an interesting new molecular target in HCC therapies.


Femoral metastatic pathological fractures, impending and actual fractures - A patient survival study.
The skeleton is a common site for metastases. Prostate, breast, lung, renal and thyroid carcinomas account for 80 % of the original cancers, with the femur being the most affected long bone. With improved oncological treatments, prolonged patient survival leads to an increased prevalence of osseous metastases. This study examines the impact of preventive surgery for impending femoral pathological fracture (IFF), versus treatment of pathological femur fracture (PFF) on patient mortality and morbidity. Retrospective cohort of 174 patients undergoing surgery due to femoral metastases (2004-2015). Eighty-two patients were with PFF, and 92 were with IFF based on the Mirels' score. The followed-up period was until 2016. Demographic data, oncological, pathological, radiation, surgical reports, outpatient clinical records, and imaging studies were examined. Exclusion criteria included primary tumours and Multiple Myeloma. The mean age was 64.8 ± 13.3 and 60.2 ± 11.9 years (p = 0.02) in the PFF and the IFF cohorts, with 62.1 % women and 57 % men. The breast was the most common source of femoral metastases. The average Mirels' score was 10 ± 1.2. There was an association between tumour origin and survival. Carcinoma of the lung had the worst survival, while the prostate had the most prolonged survival. Survival rates differed between IFF and PFF (p = 0.03). Postoperative complications occurred in 26 % of the patient, with no difference between IFF & PFF. Breast and lung are the most common tumours to metastasize the femur. Our study revalidates that pathological femoral fractures impede patient survival compared to impending fractures and should undergo preventive surgery. Postoperative complications do not differ between IFF and PFF but remain relatively high. Overall, patients with proximal femoral metastatic disease survive longer than previously published, probably due to improved treatment modalities.


Investigation by 13C-NMR and tricarboxylic acid (TCA) deletion mutant analysis of pathways for succinate formation in Saccharomyces cerevisiae during anaerobic fermentation.
NMR isotopic filiation of 13C-labelled aspartate and glutamate was used to explore the tricarboxylic acid (TCA) pathway in Saccharomyces cerevisiae during anaerobic glucose fermentation. The assimilation of [3-13C]aspartate led to the formation of [2,3-13C]malate and [2,3-13C]succinate, with equal levels of 13C incorporation, whereas site-specific enrichment on C-2 and C-3 of succinate was detected only with [3-13C]glutamate. The non-random distribution of 13C labelling in malate and succinate demonstrates that the TCA pathway operates during yeast fermentation as both an oxidative and a reductive branch. The observed 13C distribution suggests that the succinate dehydrogenase (SDH) complex is not active during glucose fermentation. This hypothesis was tested by deleting the SDH1 gene encoding the flavoprotein subunit of the SDH complex. The growth, fermentation rate and metabolite profile of the sdh1 mutant were similar to those of the parental strain, demonstrating that SDH was indeed not active. Filiation experiments indicated the reductive branch of the TCA pathway was the main pathway for succinate production if aspartate was used as the nitrogen source, and that a surplus of succinate was produced by oxidative decarboxylation of 2-oxoglutarate if glutamate was the sole nitrogen source. Consistent with this finding, a kgd1 mutant displayed lower levels of succinate production on glutamate than on other nitrogen sources, and higher levels of oxoglutarate dehydrogenase activity were observed on glutamate. Thus, the reductive branch generating succinate via fumarate reductase operates independently of the nitrogen source. This pathway is the main source of succinate during fermentation, unless glutamate is the sole nitrogen source, in which case the oxidative decarboxylation of 2-oxoglutarate generates additional succinate.


Osteologic classification of the sphenopalatine foramen.
Textbook descriptions and illustrations of the opening of the sphenopalatine foramen (SPF) into the nasal cavity place it above and behind the posterior end of the middle turbinate (i.e., within the superior meatus). Although true for some skulls, this is not the situation for the majority and may be of importance, because the major blood supply to the nasal cavity enters via this route. Having studied 238 lateral nasal walls, the authors propose a classification of the osteology of the sphenopalatine foramen. In class I (35%) the opening of the SPF is purely into the superior meatus with a notch or foramen in the middle turbinate/ethmoidal crest of the palatine bone. In class II (56%) the SPF spans the ethmoidal crest (i.e., opens into both the superior and middle meati). In class III (9%) there are two separate openings into the superior and middle meati. These findings may explain the route of the artery to the inferior turbinate and indicate the need for care in dealing with the posterior end of the middle turbinate. They may also suggest a potential site for dealing with "difficult" epistaxis via an intranasal route.


[Characteristics of pathogenesis of acute leukemia in children].
The main components of acute leukemia pathogenesis have been considered from the current positions: origination of the leukemic clone, characteristics of leukemia tumor histogenesis, mechanisms of proliferation and differentiation of leukemic cells. The main pathogenetic differences of acute leukemia in children and adults have been traced. The importance of these differences for the clinical picture, prognosis and response to chemotherapy has been analyzed.


Hospital control and decision making: a financial perspective.
A study was conducted to test the hypothesis that there are no significant differences in financial decision making among hospitals in different control categories. Significant differences were found in financial decision making in for-profit hospitals, voluntary hospitals with religious affiliations, and secular voluntary hospitals. Managers of for-profit hospitals base their financial decisions more on the need to achieve operating efficiency and profitability than do managers of voluntary hospitals. Managers of voluntary hospitals with religious affiliations and secular voluntary hospitals give about the same emphasis to efficiency. Surprisingly, however, managers of voluntary hospitals with religious affiliations emphasize profitability and financial leverage more than managers of secular voluntary hospitals do.