Parenteral iron formulations: a comparative toxicologic analysis and mechanisms of cell injury.
Multiple parenteral iron (Fe) formulations exist for administration to patients with end-stage renal disease. Although there are concerns regarding their potential toxicities, no direct in vitro comparisons of these agents exist. Thus, the present study contrasted pro-oxidant and cytotoxic potentials of four available Fe preparations: Fe dextran (Fe dext), Fe sucrose (Fe sucr), Fe gluconate (Fe gluc), and Fe oligosaccharide (Fe OS). Differing dosages (0.06 to 1 mg/mL) of each compound were added to either (1) isolated mouse proximal tubule segments, (2) renal cortical homogenates, or (3) cultured human proximal tubule (HK-2) cells (0.5- to 72-hour incubations). Oxidant injury (malondialdehyde generation) and lethal cell injury (percentage of lactate dehydrogenase release; tetrazolium dye uptake) were assessed. Effects of selected antioxidants (glutathione [GSH], catalase, dimethylthiourea (DMTU), and sodium benzoate also were assessed. Each test agent induced massive and similar degrees of lipid peroxidation. Nevertheless, marked differences in cell death resulted (Fe sucr >> Fe gluc > Fe dext approximately Fe OS). This relative toxicity profile also was observed in cultured aortic endothelial cells. Catalase, DMTU, and sodium benzoate conferred no protection. However, GSH and its constituent amino acid glycine blocked Fe sucr-mediated cell death. The latter was mediated by mitochondrial blockade, causing free radical generation and a severe adenosine triphosphate depletion state. (1) parenteral Fes are highly potent pro-oxidants and capable of inducing tubular and endothelial cell death, (2) markedly different toxicity profiles exist among these agents, and (3) GSH can exert protective effects. However, the latter stems from GSH's glycine content, rather than from a direct antioxidant effect.


Periodontal ligament cells secrete the factor that inhibits osteoclastic differentiation and function: the factor is osteoprotegerin/osteoclastogenesis inhibitory factor.
The periodontal ligament, a highly specialized connective tissue situated between the tooth and the alveolar bone of the tooth socket, has been thought to influence the remodeling of the alveolar bone. The effects of two human periodontal ligament fibroblastic cell populations (HPLFs) on osteoclast-like cell (OCL) formation and the function of authentic osteoclasts were examined. The addition of the conditioned media (CM) from both HPLF cultures (HPLF-CMs) to mouse bone marrow culture inhibited OCL formation in spite of the presence of 10(-8)M 1alpha, 25 dihydroxyvitamin D3 (1alpha,25(OH)2D3). This inhibitory effect was most remarkable when both CMs were added during day 6 to day 9 following bone marrow culture, just at the late stage of OCL differentiation. HPLF-CMs also induced a significant decrease in the pit area and the pit number formed by authentic osteoclasts on ivory slices. The administration of neutralizing monoclonal antibody (OI-1) against human osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF) with HPLF-CMs to mouse bone marrow culture almost completely blocked the inhibitory effect of these CMs on OCL formation. Immunofluorescent examination of HPLF with OI-1 revealed intense positive reactivity in the cytoplasm. Western blot analysis of HPLF-CM using anti-human OPG/OCIF polyclonal antibody resulted in the detection of bands of 60 kDa and 120 kDa which were consistent with those of OPG/OCIF. These results suggest that HPLF cells produce and secrete OPG/OCIF, and that this factor from HPLF prevents the differentiation of the late preosteoclast and the function of the mature osteoclasts.


[Regulatory mechanisms of neural stem cell and strategies for therapy].
Neural stem cells(NSCs) are multipotential progenitor cells that can generate neurons, astrocytes, and oligodendrocytes, the three major cell types in the central nervous system. Due to their self-renewal activities, NSCs can proliferate in an undifferentiated state in vitro, allowing them to be expanded mitotically and harvested in bulk. Recent advances in stem cell biology have led us to investigate methods for the regenerative manipulation of the damaged CNS. However, there is much that is still not known about regulatory mechanisms of the differentiation and self-renewal of NSCs. In this article, we review some of the basic notions regarding the extracellular factors and signal transduction cascades involved in the differentiation and maintenance of NSCs.


Computationally simulated fractional flow reserve from coronary computed tomography angiography based on fractional myocardial mass.
Computed tomography angiography (CCTA)-based calculations of fractional flow reserve (FFR) can improve the diagnostic performance of CCTA for physiologically significant stenosis but the computational resource requirements are high. This study aimed at establishing a simple and efficient algorithm for computing simulated FFR (S-FFR). A total of 107 patients who underwent CCTA and invasive FFR measurements were enrolled in the study. S-FFR was calculated using 145 evaluable coronary arteries with off-the-shelf softwares. FFR ≤ 0.80 was a reference threshold for diagnostic performance of diameter stenosis (DS) ≥ 50%, DS ≥ 70%, or S-FFR ≤ 0.80. FFR ≤ 0.80 was identified in 78 vessels (54%). In per-vessel analysis, S-FFR showed good correlation (r = 0.83) and agreement (mean difference = 0.02 ± 0.08) with FFR. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of S-FFR ≤ 0.80 for FFR ≤ 0.80 were 84%, 92%, 92%, 83%, and 88%, respectively. S-FFR ≤ 0.80 showed much higher predictive performance for FFR ≤ 0.80 compared with DS ≥ 50% or DS ≥ 70% (c-statistics = 0.92 vs. 0.58 or 0.65, p < 0.001, all). The classification agreement between FFR and S-FFR was > 80% when the average of FFR and S-FFR was < 0.76 or > 0.86. Per-patient analysis showed consistent results. In this study, a simple and computationally efficient simulated FFR (S-FFR) algorithm is designed and tested using non-proprietary off-the-shelf software. This algorithm may expand the accessibility of clinical applications for non-invasive coronary physiology study.


Non-prescription sale and dispensing of antibiotics in community pharmacies in Zambia.
In Zambia, antibiotics are categorized as prescription-only medicines. Antibiotics dispensed without a prescription pose a public health threat, which is a concern. Consequently, the aim is to ascertain the extent of non-prescription sales and dispensing of antibiotics in community pharmacies in Zambia. The practice of non-prescription sale and dispensing were assessed in 73 randomly selected community retail pharmacies, using a structured interviewer-administered questionnaire with simulated case scenarios. Majority (97%) stated that clients frequently requested non-prescribed antibiotics. Interviewees usually asked clients' indications (94%), counselled on dosing (96%) and suggested changes to antibiotic choices (97%). All (100%) dispensed non-prescribed antibiotics. Commonly dispensed antibiotics included amoxicillin (52%), cotrimoxazole (25%) and metronidazole (23%). Non-prescription sale and dispensing of antibiotics was significantly associated with interviewees' professional qualification in four out of five simulations. Non-prescription sale and dispensing of antibiotics is widespread in Zambia. Concerted public and professional interventions are needed coupled with stronger regulatory enforcement to reduce this.


Acoustic neuroma diagnosis.
Pure tone audiometry, PTA, has been regarded as an initial step when starting acoustic neuroma, AN, diagnostic service. If observing unilateral/asymmetrical sensorineural hearing loss, electronystagmography, ENG, and registration of auditory brainstem responses, ABRs, are instructed to perform. The measures of the methods are listed appearing particularly effective for AN detecting. Efficacy of ENG and ABR approaches in verification of ANs of even initial stages has been stated to reach the absolute identification score, 100%. In tinnitus and/or vertigo complaints, ENG and ABR examinations are recommended to utilize under normal PTA even. The positive evidence of ANs via ENG and ABR has to validate by contrasting magnetic resonance imaging, MRI, while MRI data are advised to utilize for assessment of concrete strategy of surgical intervention. Under negative ENG and ABR outcomes, on the other hand, MRI is considered as a hardly urgent procedure.


Functional adaptation of the switch-2 nucleotide sensor enables rapid processive translocation by myosin-5.
Active site loops that are conserved across superfamilies of myosins, kinesins, and G proteins play key roles in allosteric coupling of NTP hydrolysis to interaction with track filaments or effector proteins. In this study, we investigated how the class-specific natural variation in the switch-2 active site loop contributes to the motor function of the intracellular transporter myosin-5. We used single-molecule, rapid kinetic and spectroscopic experiments and semiempirical quantum chemical simulations to show that the class-specific switch-2 structure including a tyrosine (Y439) in myosin-5 enables rapid processive translocation along actin filaments by facilitating Mg(2+)-dependent ADP release. Using wild-type control and Y439 point mutant myosin-5 proteins, we demonstrate that the translocation speed precisely correlates with the kinetics of nucleotide exchange. Switch-2 variants can thus be used to fine-tune translocation speed while maintaining high processivity. The class-specific variation of switch-2 in various NTPase superfamilies indicates its general role in the kinetic tuning of Mg(2+)-dependent nucleotide exchange.


Rucaparib: a novel PARP inhibitor for BRCA advanced ovarian cancer.
Rucaparib is a potent small-molecule inhibitor of poly (ADP-ribose) polymerase (PARP) proteins (PARP-1, PARP-2 and PARP-3) that play an important role in repairing DNA damage and maintaining genomic stability. Tumors with mutations in BRCA1/2 or other homologous recombination deficiency (HRD) genes are particularly sensitive to PARP inhibitors because of "synthetic lethality", whereby a therapeutic agent can take advantage of an intrinsic weakness in DNA repair. Rucaparib has been investigated in several preclinical and clinical studies showing promising activity in BRCA-mutant and BRCA-wild-type epithelial ovarian cancers (EOCs). Dose-escalation Phase I studies have established the recommended Phase II dose to be 600 mg twice a day for oral rucaparib. Phase II and III studies have defined its role as treatment for BRCA-mutant recurrent high-grade EOC and as maintenance treatment for platinum-sensitive relapsed EOC following response to platinum-based chemotherapy. Genomic loss of heterozygosity has also been investigated as a potential signature of HRD and as a potential predictive biomarker of response. Treatment-induced adverse events (AEs) have been observed in almost all patients treated with rucaparib, but mainly lower grade; with the most common being nausea, vomiting, asthenia/fatigue, anemia and transient transaminitis. The majority of AEs occurred early in treatment, were transient and have been easily managed with supportive treatment, dose interruption or discontinuation. This review will analyze the results of clinical trials investigating efficacy and safety of rucaparib in patients with ovarian cancer.


Stress recovery during exposure to nature sound and environmental noise.
Research suggests that visual impressions of natural compared with urban environments facilitate recovery after psychological stress. To test whether auditory stimulation has similar effects, 40 subjects were exposed to sounds from nature or noisy environments after a stressful mental arithmetic task. Skin conductance level (SCL) was used to index sympathetic activation, and high frequency heart rate variability (HF HRV) was used to index parasympathetic activation. Although HF HRV showed no effects, SCL recovery tended to be faster during natural sound than noisy environments. These results suggest that nature sounds facilitate recovery from sympathetic activation after a psychological stressor.


The effects of inservice education on the institution of triage protocols.
This correlational study examined the effects of inservice education on the initiation of triage protocols by emergency room nurses for patients experiencing cardiac symptom distress. The study used a pretest/posttest design with a convenience sample of 40 patients who were experiencing cardiac symptom distress. Chart reviews were conducted on 20 patients seen in the emergency room with suspected myocardial infarction. Then emergency room nurses had an inservice program on institution of triage protocols, and 20 more patient charts were reviewed. The study revealed two statistically significant findings. First, the staff nurses incorporated pain and symptom distress measurement tools in physical assessments more frequently after inservice education sessions than before inservice education sessions. Second, the staff nurses documented the use of triage protocols more frequently after the inservice education sessions than before the sessions. These findings suggest that nursing inservice education positively affects nursing care for patients with suspected myocardial infarction.


Impact of sex-specific target dose in chronic heart failure patients with reduced ejection fraction.
A recent study suggested that women with heart failure and heart failure reduced ejection fraction might hypothetically need lower doses of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers ( = renin-angiotensin-system inhibitors) and β-blockers than men to achieve the best outcome. We assessed the current medical treatment of heart failure reduced ejection fraction in men and women in a large contemporary cohort and address the hypothetical impact of changing treatment levels in women. This analysis is part of a large contemporary quality of heart failure care project which includes 5320 (64%) men and 3003 (36%) women with heart failure reduced ejection fraction. Detailed information on heart failure therapy prescription and dosage were collected. Women less often received renin-angiotensin-system inhibitors (79% vs 83%, p < 0.01), but more often β-blockers (82% vs 79%, p < 0.01) than men. Differences in guideline-recommended target doses between sexes were relatively small. Implementing a hypothetical sex-specific dosing schedule (at 50% of the current recommended dose in the European Society of Cardiology guidelines in women only) would lead to significantly higher levels of women receiving appropriate dosing (β-blocker 87% vs 54%, p < 0.01; renin-angiotensin-system inhibitor 96% vs 75%, p < 0.01). Most interestingly, the total number of women with >100% of the new hypothetical target dose would be 24% for β-blockers and 52% for renin-angiotensin-system inhibitors, which can be considered as relatively overdosed. In this large contemporary heart failure registry, there were significant but relatively small differences in drug dose between men and women with heart failure reduced ejection fraction. Implementation of the hypothetical sex-specific target dosing schedule would lead to considerably more women adequately treated. In contrast, we identified a group of women who might have been relatively overdosed with increased risk of side-effects and intolerance.


Alchemy and the history of science. Introduction.
Alchemy is part of the cultural experience of early modern Europe and yet has had to overcome problems of demarcation to be considered relevant to the history of science. This essay considers historiographical and methodological issues that have affected the gradual demarginalization of alchemy among attempts to explain, and find things out about, nature. As an area of historical study, alchemy relates to the history of science as part of an ensemble of practices that explored the natural world through natural philosophy and speculative traditions and by functioning as a nexus of social and intellectual life.


Inhibition of phosphatidylcholine synthesis by vasopressin and angiotensin in rat hepatocytes.
The addition of 1 microM-vasopressin or -angiotensin to isolated rat hepatocytes induced a fast transient inhibition of the rate of incorporation of [Me-3H]choline into phosphatidylcholine. The cationophore A23187 induced a similar inhibition of phosphatidylcholine synthesis. The addition of micromolar Ca2+ to rat liver microsomes inhibited the activity of CDP-choline: 1,2-diacylglycerol cholinephosphotransferase. This inhibition is due a decrease in the Vmax. of the enzyme without affecting the Km for CDP-choline. It is concluded that Ca2+ regulates phosphatidylcholine synthesis in rat liver.


Kinetic and spectral properties of rabbit brain 4-aminobutyrate aminotransferase.
Purification and 4-aminobutyrate-2-oxoglutarate aminotransferase (EC 184.108.40.206) from rabbit brain is described. The method was used as a routine to give between 5 and 10mg of pure enzyme from 750 g of rabbit brain. The enzyme is a dimer made up of subunits each with a mol. wt. of 58000. An absorption spectrum of the freshly prepared enzyme shows peaks at 415 and 330 nm. Treatment of the enzyme with the substrate 4-amino-butyrate or glutamate produces a decrease in the 415 nm and an increase in the 330 nm peak. This conversion, which is attributed to an aldimine into ketimine step in the reaction, is sufficiently slow when 4-aminobutyrate is the substrate to allow it to be followed by stopped-flow spectrophotometry. A first-order rate constant was determined for this step (12s-1) and compared with the turnover number for the enzyme derived by steady-state methods (9.5S-1). The first-order rate constant when glutamate was used as substrate was estimated to be approx. 30s-1.


Literature review of the role of hydroxyl radicals in chemically-induced mutagenicity and carcinogenicity for the risk assessment of a disinfection system utilizing photolysis of hydrogen peroxide.
We have developed a new disinfection system for oral hygiene, proving that hydroxyl radicals generated by the photolysis of 1 M hydrogen peroxide could effectively kill oral pathogenic microorganisms. Prior to any clinical testing, the safety of the system especially in terms of the risk of carcinogenicity is examined by reviewing the literature. Previous studies have investigated indirectly the kinds of reactive oxygen species involved in some sort of chemically-induced mutagenicity in vitro by using reactive oxygen species scavengers, suggesting the possible involvement of hydroxyl radicals. Similarly, possible involvement of hydroxyl radicals in some sort of chemically-induced carcinogenicity has been proposed. Notably, it is suggested that the hydroxyl radical can play a role in heavy metal-induced carcinogenicity that requires chronic exposure to the carcinogen. In these cases, hydroxyl radicals produced by Fenton-like reactions may be involved in the carcinogenicity. Meanwhile, potential advantages have been reported on the use of the hydroxyl radical, being included in host immune defense by polymorphonuclear leukocytes, and medical applications such as for cancer treatment and antibiotics. From these, we conclude that there would seem to be little to no risk in using the hydroxyl radical as a disinfectant for short-term treatment of the oral cavity.


Transmission Dynamics of Bovine Anaplasmosis in a Cattle Herd.
Bovine anaplasmosis is an infectious disease of cattle caused by the obligate intercellular bacterium, Anaplasma marginale, and it primarily occurs in tropical and subtropical regions of the world. In this study, an age-structured deterministic model for the transmission dynamics of bovine anaplasmosis was developed; the model incorporates symptomatic and asymptomatic cattle classes. Sensitivity analysis was carried out to determine the parameters with the highest impact on the reproduction number. The dominant parameters were the bovine natural and disease-induced death rates, disease progression rate in adult cattle, the mechanical devices transmission probability and contact rates, the pathogen contamination, and decay rates on the mechanical devices. The result of the sensitivity analysis suggests that control strategies to effectively prevent/control the spread of bovine anaplasmosis should focus on these parameters according to their positive or negative effect as seen from the sensitivity index. Following the results of the sensitivity analysis, three control strategies were investigated, namely, bovine-culling, safety-control, and universal. In addition to these strategies, three effectiveness levels (low, medium, and high) were considered for each control strategy using the cumulative number of newly infected cases in both juvenile and adult cattle as measure function. The universal strategy (comprising both cattle-culling and safety-control strategies) is only marginally better at reducing the number of infected cattle compare to the safety-control strategy. This result suggests that efforts should be aimed at improving and maintaining good hygiene practices; furthermore, the added benefit of culling infected cows is only minimal and not cost-efficient.


Fabrication and characterization of gefitinib-releasing polyurethane foam as a coating for drug-eluting stent in the treatment of bronchotracheal cancer.
The purpose of the present study was to develop gefitinib-loaded polymeric foams that can be used as coating of drug-eluting stents for palliative treatment of bronchotracheal cancer. Release of such an anticancer drug from such stent coating can retard tumor regrowth into the bronchial lumen. Gefitinib-loaded polyurethane (PU) foams were prepared by embedding either gefitinib micronized crystals or gefitinib-loaded poly(lactic-co-glycolic acid) microspheres in water-blown films, with up to 10% w/w loading for gefitinib microcrystals and 15% w/w for gefitinib microspheres (corresponding to 1.0% w/w drug loading). Drug-release studies showed sustained release of gefitinib over a period of nine months, with higher absolute release rates at higher drug loading content. By the end of the studied nine month release periods, 60-100% of the loaded gefitinib had been released. Foams loaded with gefitinib-PLGA microspheres at 15% w/w showed accelerated drug release after 4 months, coinciding with the degradation of PLGA microparticles in the PU foam as demonstrated by scanning electron microscopy (SEM). When applied on a nitinol braided bronchotrachial stent, PU coatings with gefitinib microspheres showed similar mechanical properties as the drug-free PU coating, which indicated that the loading of microspheres did not affect the mechnical properties of the PU foams. In conclusion, we have fabricated drug-loaded PU foams that are suitable for bronchotracheal stent coating.


Radiation chemistry and the Radiation Research Society: a history from the beginning.
Radiation chemistry studies began in the early 20th century with observations involving the decomposition of various materials by X rays and radium. Hugo Fricke recognized that the chemical effects of radiation should be studied to help understand the response of living systems to radiation, and in 1928 he established a laboratory to conduct such studies. Early radiation chemists were intimately involved in the founding of the Radiation Research Society and contributed substantially to its interdisciplinary culture. In this historical review, the highlights of research in radiation chemistry leading up to the founding of the Radiation Research Society in 1952 are discussed. The status of the field is established at that point, and a sampling of the major accomplishments from then until the present is presented, with emphasis on those scientists who have contributed substantially to the life and culture of the Radiation Research Society.


[Threats as precursors of violent crimes].
Threats are frequent events. For example, in Switzerland in 2002 they accounted for 2.8% of all registered instantaneous crimes and showed a marked increase. Only a small proportion of threats are actually executed. On the other hand, many serious, violent crimes are preceded by threats. Therefore, the question repeatedly arises as to whether the crime could have been prevented by an adequate assessment of the threat. Even if threatening behavior is not a sufficient or necessary precursor to violent crime, it is advisable to take every threat seriously and to carry out a risk assessment. There is far-reaching agreement on the necessity of threat analysis, especially since there is practical evidence that professional risk analysis can prevent criminal acts. Since the baseline rate for grievous violent crime is very low, it is not possible for threat analysis to rely on profile-oriented (static) procedures. Rather, a process-oriented approach is indicated, whereby each threat is assessed in its individual context. Investigations so far have presented findings relating to different aspect of threats that can be helpful in the evaluation of specific, individual cases. In addition to specific analysis of the characteristics of the threat, it is essential to perform a detailed analysis of the relationship between the offender and the victim and of the offender's personality. It is to be expected that more extensive research will make it possible to benefit from an as yet inadequately exploited potential to prevent violent crime.


The Significance of BRAF Mutation in the Epithelioid Glioblastoma Subtype: A Systematic Literature Review and a Case Report with a Unique Intraventricular Topography.
Epithelioid glioblastoma (E-GBM) is an exceedingly rare subtype of isocitrate dehydrogenase (IDH)-wildtype glioblastoma, first included in the WHO 2016 classification and characterized by a dominant population of epithelioid cells. Its histological and molecular defining features remain troublesome. The significance of BRAF mutations to pathological diagnosis and surgical outcome has drawn increasing attention given their promising potential for future adjuvant therapies. Herein, we describe a unique case of an E-GBM in the atrium of the left lateral ventricle and comprehensively analyze the importance of BRAF status in a cohort of 211 E-GBMs from the literature. Our patient was a 40-year-old man with occipital pain. His brain MRI revealed a large intraventricular tumor at the same location as a signal change found 10 years earlier with no additional follow-up. He underwent gross total tumor removal followed by conventional adjuvant treatment. Histopathological diagnosis was consistent with IDH-wildtype E-GBM WHO grade 4 with pleomorphic xanthoastrocytoma-like areas. BRAF p.V600 mutation was demonstrated in the tumoral genetic study. In the cohort analyzed, male patients predominated (63%), the median age was 32 years old, and the 5-year survival rate following diagnosis was 4.2%. BRAF mutations were found in 60.3% of the tumors overall, with this rate increasing to 78.3% in young adults (19-49 years, P < .001). Presence of BRAF mutations associated with tumor progression (P = .001), the event usually leading to death (P < .001). In conclusion, our study supports the importance of genetic BRAF p.V600 mutation analysis because its presence not only points to an E-GBM diagnosis but may also promote tumor progression.


Sustained virologic response after therapy with the HCV protease inhibitor narlaprevir in combination with peginterferon and ribavirin is durable through long-term follow-up.
Achievement of a sustained virologic response (SVR) after peginterferon (PEG-IFN) and ribavirin (RBV) treatment is considered to be a marker for the cure of chronic hepatitis C virus (HCV) infection. Long-term follow-up of patients with SVR after treatment with a direct acting antiviral has not yet been described. We used a randomized placebo-controlled, double-blind, two-period phase 1b trial that was conducted in 40 HCV genotype 1 (treatment-naïve and treatment-experienced)-infected patients. Nineteen patients achieved SVR after treatment with the HCV protease inhibitor narlaprevir followed by PEG-IFN/RBV. In these patients, HCV-RNA tests were scheduled at 3, 6, 12 and 24 months after end of treatment. Patients were followed for a median of 27 months (range 15-32) after end of treatment with a median number of follow-up visits of 4 (range 3-8). All patients remained HCV-RNA negative over time. SVR achieved following narlaprevir and PEG-IFN/RBV-therapy was durable up to 32 months after the end of treatment.


A measure of centrality in cyclic diffusion processes: Walk-betweenness.
Unlike many traditional measures of centrality based on paths that do not allow any repeated nodes or lines, we propose a new measure of centrality based on walks, walk-betweenness, that allows any number of repeated nodes or lines. To illustrate the value of walk-betweenness, we examine the transmission of syphilis in Chicago area and the diffusion of microfinance in 43 rural Indian villages. Walk-betweenness allows us to identify hidden bridging communities in Chicago that were essential in the transmission dynamics. We also find that village leaders with high walk-betweenness are more likely to accelerate the rate of microfinance take-up among their followers, outperforming other traditional centrality measures in regression analyses.


Identification of quinol thioethers in bone marrow of hydroquinone/phenol-treated rats and mice and their potential role in benzene-mediated hematotoxicity.
Metabolism of benzene is required to produce the classical hematological disorders associated with its exposure. After coadministration of hydroquinone (0.9 mmol/kg, ip) and phenol (1.1 mmol/kg, ip) to male Sprague-Dawley rats and DBA/2 mice, 2-(glutathion-S-yl)hydroquinone was identified in the bone marrow of both species. 2,5-Bis(glutathion-S-yl)hydroquinone, 2,6-bis(glutathion-S-yl)hydroquinone, and 2,3,5-tris(glutathion-S-yl)hydroquinone were also observed in the bone marrow of rats but were detected only sporadically in mice. Both species produced 2-(cystein-S-ylglycinyl)hydroquinone, 2-(cystein-S-yl)hydroquinone, and 2-(N-acetylcystein-S-yl)hydroquinone, indicating the presence of a functional mercapturic acid pathway in bone marrow. The ability of bone marrow to acetylate 2-(cystein-S-yl)hydroquinone and deacetylate 2-(N-acetylcystein-S-yl)hydroquinone was confirmed in vitro. Total quinol thioether concentrations were higher in, and eliminated more slowly from, the bone marrow of mice. Intravenous injection of 100 micromol/kg 2-(glutathion-S-yl)hydroquinone to rats gave rise to substantially lower bone marrow C(max) and AUC values compared to values found following coadministration of hydroquinone/phenol, suggesting that the major fraction of the GSH conjugates present in bone marrow are formed in situ. Finally, the erythrotoxicity of several of these conjugates was determined in rats using the erythrocyte 59Fe incorporation assay. Administration of 2,3,5-tris(glutathion-S-yl)hydroquinone (17 micromol/kg, iv), 2,6-bis(glutathion-S-yl)hydroquinone (50 micromol/kg, iv), and benzene (11 mmol/kg, sc) significantly decreased 59Fe incorporation into reticulocytes to 45 +/- 6%, 28 +/- 3%, and 20 +/- 9% of control values, respectively. Although the doses of 2,3,5-tris(glutathion-S-yl)hydroquinone and 2,6-bis(glutathion-S-yl)hydroquinone represented only 0.2% and 0.4% of the dose of benzene, both conjugates reduced 59Fe incorporation to the same degree as benzene. 2-(Glutathion-S-yl)hydroquinone had no effect at the dose tested (200 micromol/kg, iv). In summary, these data suggest that hydroquinone-glutathione conjugates are erythrotoxic and may contribute to benzene-mediated hematotoxicity.


Increased Organizational Stress in Primary Care: Understanding the Impact of the COVID-19 Pandemic, Medicaid Expansion, and Practice Ownership.
Primary care is the foundation of health care, resulting in longer lives and improved equity. Primary care was the frontline of the COVID-19 pandemic public response and essential for access to care. Yet primary care faces substantial structural and systemic challenges. As part of a longitudinal analysis to track the capacity and health of primary care, we surveyed every primary care practice in Virginia in 2018 and again in 2022. Surveys were emailed or mailed up to 6 times and nonresponders received a phone call. Questions assessed organizational characteristics, scope of care, capacity, and organizational stress in the prior year. From respondents, 39 clinicians, nurses, staff, administrators, and practice managers were interviewed. 526 out of 2296 primary care practices (23% response rate) completed the survey, with broad representation across geography, ownership, and payer mix. Compared with 2018, in 2022 there were increases in practices owned by health systems (25% vs 43%, P < .0001) and average percent of patients with Medicaid per practice (12% vs 22%, P < .0001). The percent of practices reporting any major stressor increased from 34% to 53% (P < .0001). The main increased stress was losing a clinician, with 13% of practices in 2018 versus 42% in 2022 reporting losing a clinician (P < .0001). Primary care practices are resilient and continue to serve their communities, including a broad scope of services and care for underserved people. However, the COVID-19 pandemic caused significant stress. With an increase in clinicians leaving clinical practice, we anticipate worsening access to primary care.


Modulation of the P1 plasmid partition protein ParA by ATP, ADP, and P1 ParB.
ParA is an essential P1 plasmid partition protein. It represses transcription of the par genes (parA and parB) and is also required for a second, as yet undefined step in partition. ParA is a ParB-stimulated ATPase that binds to a specific DNA site in the par promoter region. ATP binding and hydrolysis by ParA affect ParA activities in vitro. ATP and ADP binding stimulate ParA DNA binding and dimerization; however, ATP hydrolysis has a negative effect on DNA binding. Our current experiments reveal that ATP binding and hydrolysis affect ParA conformation and ParA sensitivity to ParB. Nucleotide binding assays show that ParA binds ATP better than ADP (Kd values of 33 and 50 microM, respectively). Interaction with these nucleotides as well as ATP hydrolysis by ParA alter ParA conformation as established by CD and ParA sensitivity to heat denaturation. Finally, we show that ParB stimulates ParA DNA binding. This stimulation requires ATP hydrolysis in vitro, suggesting that one role for ATP hydrolysis in vivo is to make ParA repressor sensitive to ParB. Our observations lead to the suggestion that ATP binding and hydrolysis have separable roles in ParA repressor function and perhaps in ParA partition functions as well.


Age-dependence of relative telomere length profiles during spermatogenesis in man.
Telomeres, the protective structures at the outmost ends of chromosomes, shorten in all somatic cells with each cell-division and by cumulative oxidative damage. To counteract that these shortened telomeres are passed on to offspring, the telomeres are elongated by the enzyme, telomerase, during human spermatogenesis. A few groups have tried to elucidate this process by measuring telomerase activity in the various cell-types during spermatogenesis, but until now, no one has ever measured telomere length (TL) during these different stages in humans. Some groups have measured TL in spermatozoa and surprisingly found that telomeres of older men are longer, than those from younger men. To elucidate this phenomenon we investigated if the distribution of TL over the various precursor germ cells in old males differed from young males, perhaps indicating a more ubiquitous telomere elongation in testes from older men. We therefore obtained testicular biopsies from 6 older and 6 younger men undergoing vasectomy. The cells were suspended as single cells and smeared onto slides, followed by characterization of cell stages by phase contrast microscopy. Mean TL in individual cells was subsequently measured by telomere QFISH. Our data revealed no difference in the TL profile during spermatogenesis between younger and older men. All men had a similar profile which strongly resembled the telomerase expression profile found by others. This indicates that the longer telomeres in older men are not caused by a wider window of telomere elongation, stretching over more cell-types of spermatogenesis.


Association of polymorphisms of the xeroderma pigmentosum complementation group F gene with increased glioma risk.
We aimed to investigate the role of 4 single nucleotide polymorphisms of the xeroderma pigmentosum complementation group F (XPF) gene (rs3136038, rs1799798, rs1800067, and rs2276466) in glioma, and the roles of gene-gene interactions in the risk of developing this type of cancer. We collected samples from 225 glioma cases and 262 controls and genotyped the rs3136038, rs1799798, rs1800067, and rs2276466 polymorphisms using a 384-well plate format with the Sequenom MassARRAY platform. Individuals carrying the rs1800067 GG genotype were more likely to have an increased risk of glioma when compared with carriers of the A/A genotype in a co-dominant model, with an odds ratio (OR) [95% confidence interval (CI)] of 2.85 (1.14-7.76). However, we did not find an association with increased risk of glioma for the polymorphisms rs3136038, rs1799798, and rs2276466 in XPF. The combination genotype of the rs1800067 G allele and the rs2276466 G allele was associated with a moderate risk of glioma (OR = 1.71, 95%CI = 1.02-2.87). Our study suggests that the rs1800067 genetic variant of XPF functions in the development of glioma.


The Pathogenic Mutation T182A Converts the Prion Protein into a Molten Globule-like Conformation Whose Misfolding to Oligomers but Not to Fibrils Is Drastically Accelerated.
Delineation of the effects of pathogenic mutations linked with familial prion diseases on the structure and misfolding of prion protein (PrP) will be useful in understanding the molecular mechanism of PrP misfolding. Here, it has been shown that the pathogenic mutation T182A causes a drastic reduction in the apparent cooperativity and enthalpy of unfolding of the mouse prion protein (moPrP) under misfolding-prone conditions by converting the protein into a molten globule (MG)-like conformation. Hydrogen-deuterium exchange studies in conjunction with mass spectrometry indicate that the T182A mutation disrupts the core of the protein, thereby increasing overall structural dynamics. T182A moPrP is shown to misfold to oligomers very much faster than does wild-type (wt) moPrP but to misfold to fibrils at a rate similar to that of wt moPrP. This observation suggests that oligomers are unlikely to play a productive role in the direct pathway of aggregation from monomer to fibrils. The observation that fully folded T182A moPrP has a MG-like structure, and that it misfolds to oligomers much faster than does wt moPrP, suggests that a MG-like intermediate, whose structure resembles that of fully folded T182A moPrP, might be populated early on the pathway of misfolding of wt moPrP to oligomers.


The importance of impulsivity and attention switching deficits in perpetrators convicted for intimate partner violence.
It has been stated that Attention deficit hyperactivity disorder (ADHD) increases the likelihood of risky behavior such as intimate partner violence (IPV), but the cognitive mechanisms that facilitate or underlie these types of behavior remain unexplained. In this regard, several authors have established that impulsivity and inattentive symptoms might affect basic processes such as emotional decoding and set-shifting abilities, which are important processes for emotional and behavioral regulation. Hence, these symptoms entail a reduction in sensitivity to key contextual stimuli. Accordingly, the main aim of this study was to examine the involvement of impulsivity (assessed by self-reports) and attention switching impairments (assessed with the Attention Switching Task; AST), as well as the associations between these cognitive processes in facial emotion decoding (assessed by the eyes test) and cognitive flexibility impairments (measured by the Wisconsin Card Sorting Test, WCST) in a sample of IPV perpetrators (n = 89; mean age = 40) and a control group matched on socio-demographic characteristics (n = 39; mean age = 41). IPV perpetrators had higher trait impulsivity and greater attention switching costs than controls. Moreover, differences were also found between groups in facial expression decoding and WCST performance, with IPV perpetrators showing lower Eyes Test and WCST scores. Mainly, we observed that the ability to recognize facial expressions was poorer when individuals showed high impulsivity in both groups, but this association was only explained by deficits in attention switching in IPV perpetrators. Our research reinforces the importance of impulsivity and inattentive symptoms as targets for specific cognitive rehabilitation interventions designed to prevent the long-term IPV risk of recidivism.


Tissue confirmation of disease recurrence in breast cancer patients: pooled analysis of multi-centre, multi-disciplinary prospective studies.
Treatment decisions in recurrent breast cancer are usually based on the estrogen (ER), progesterone (PgR) and HER2 receptor status of the primary tumour. Retrospective studies suggest that discordance between receptor expression of primary and recurrent breast cancer exists. A pooled analysis of individual patient data from two large prospective studies comprising biopsy of recurrent lesions obtained from consenting patients was undertaken. Tissue was analyzed for ER, PgR by immunohistochemistry and HER2 by FISH. Receptor status of recurrent disease was compared with that of the primary tumour. Recruiting clinicians assessed whether or not receptor discordance affected subsequent systemic treatment. Two hundred and eighty-nine patients underwent biopsy. Recurrent biopsy specimens were obtained from locoregional recurrence in 48.1% and from distant metastases in 51.9%. Distant sites included skin/soft tissue (25.0%), bone/bone marrow (19.2%) and liver (15.8%). Benign disease or second primary cancer was observed in 7.6% of biopsies. Discordance in ER, PgR or HER2 between confirmed primary and recurrent breast cancer was 12.6%, 31.2% and 5.5%, respectively (all p<0.001). Biopsy results altered management in 14.2% of patients undergoing biopsy (95% confidence intervals 10.4-18.8%, p≤0.0001). The duration between primary and recurrent disease, the site of recurrence and the receptor profile of the primary tumour did not affect discordance rates. There is substantial discordance in receptor status between primary and recurrent breast cancer. The number needed to biopsy in order to alter treatment was 7.1. Patients with recurrent breast cancer should have tissue confirmation of receptor status of recurrent disease.


15N and 13C{14N} NMR investigation of the major nitrogen-containing segment in an aquatic fulvic acid: evidence for a hydantoin derivative.
A nitrogen-rich segment in a fulvic acid (FA) from Pony Lake, a coastal pond in Antarctica, was investigated by (15)N and (13)C{(14)N} solid-state NMR techniques. As reported previously, the (13)C{(14)N} spectrum of C bonded to N exhibits a peak at 157 ppm that is assigned to an sp(2)-hybridized carbon bonded to at least two nitrogen atoms. This segment contains 48% of all N in the sample. (15)N NMR shows distinct signals, 20 ppm upfield and downfield from the typical peptide resonance; dipolar dephasing confirmed that they are due to protonated N. The well-resolved downfield peak, which accounts for 1/4 of the spectral area, cannot be assigned to aromatic heterocycles, such as purines, because the fraction of aromatic C bonded to N in this sample is very small. Analysis of (15)N chemical-shift trends and (15)N NMR of model compounds, such as arginine and its derivatives, excludes assignment to a guanidinium ion or to substituted guanidino groups. Similarly, ureido groups, -NH-CO-NH-, that are not bonded to a second C = O do not match the observed (15)N peaks in the FA, since both N resonate upfield from the peptide resonance. On the other hand, all chemical shifts are matched within the observed range by the -C(alkyl)-NH-CO-NH-CO-C structure found in two nonaromatic heterocycles, hydantoin and dihydrouracil. The five-membered hydantoin ring, which is found in the purine metabolite allantoin, provides a better match than the six-membered dihydrouracil ring. Regular uracil or thymine fails to produce adequate agreement with observed chemical shifts.


Binocular summation revisited: Beyond √2.
Our ability to detect faint images is better with two eyes than with one, but how great is this improvement? A meta-analysis of 65 studies published across more than 5 decades shows definitively that psychophysical binocular summation (the ratio of binocular to monocular contrast sensitivity) is significantly greater than the canonical value of √2. Several methodological factors were also found to affect summation estimates. Binocular summation was significantly affected by both the spatial and temporal frequency of the stimulus, and stimulus speed (the ratio of temporal to spatial frequency) systematically predicts summation levels, with slow speeds (high spatial and low temporal frequencies) producing the strongest summation. We furthermore show that empirical summation estimates are affected by the ratio of monocular sensitivities, which varies across individuals, and is abnormal in visual disorders such as amblyopia. A simple modeling framework is presented to interpret the results of summation experiments. In combination with the empirical results, this model suggests that there is no single value for binocular summation, but instead that summation ratios depend on methodological factors that influence the strength of a nonlinearity occurring early in the visual pathway, before binocular combination of signals. Best practice methodological guidelines are proposed for obtaining accurate estimates of neural summation in future studies, including those involving patient groups with impaired binocular vision. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Interactions of bacterial cell division protein FtsZ with C8-substituted guanine nucleotide inhibitors. A combined NMR, biochemical and molecular modeling perspective.
FtsZ is the key protein of bacterial cell-division and target for new antibiotics. Selective inhibition of FtsZ polymerization without impairing the assembly of the eukaryotic homologue tubulin was demonstrated with C8-substituted guanine nucleotides. By combining NMR techniques with biochemical and molecular modeling procedures, we have investigated the molecular recognition of C8-substituted-nucleotides by FtsZ from Methanococcus jannaschii (Mj-FtsZ) and Bacillus subtilis (Bs-FtsZ). STD epitope mapping and trNOESY bioactive conformation analysis of each nucleotide were employed to deduce differences in their recognition mode by each FtsZ species. GMP binds in the same anti conformation as GTP, whereas 8-pyrrolidino-GMP binds in the syn conformation. However, the anti conformation of 8-morpholino-GMP is selected by Bs-FtsZ, while Mj-FtsZ binds both anti- and syn-geometries. The inhibitory potencies of the C8-modified-nucleotides on the assembly of Bs-FtsZ, but not of Mj-FtsZ, correlate with their binding affinities. Thus, MorphGTP behaves as a nonhydrolyzable analog whose binding induces formation of Mj-FtsZ curved filaments, resembling polymers formed by the inactive forms of this protein. NMR data, combined with molecular modeling protocols, permit explanation of the mechanism of FtsZ assembly impairment by C8-substituted GTP analogs. The presence of the C8-substituent induces electrostatic remodeling and small structural displacements at the association interface between FtsZ monomers to form filaments, leading to complete assembly inhibition or to formation of abnormal FtsZ polymers. The inhibition of bacterial Bs-FtsZ assembly may be simply explained by steric clashes of the C8-GTP-analogs with the incoming FtsZ monomer. This information may facilitate the design of antibacterial FtsZ inhibitors replacing GTP.


Critical pathways in heart function: bis(2-chloroethoxy)methane-induced heart gene transcript change in F344 rats.
Gene transcript changes after exposure to the heart toxin, bis(2-chloroethoxy)methane (CEM), were analyzed to elucidate mechanisms in cardiotoxicity and recovery. CEM was administered to 5-week-old male F344/N rats at 0, 200, 400, or 600 mg/kg by dermal exposure, 5 days per week, for a total of 12 doses by study day 16. Heart toxicity occurred after 2 days of dosing in all 3 regions of the heart (atrium, ventricle, interventricular septum) and was characterized by myofiber vacuolation, necrosis, mononuclear-cell infiltration, and atrial thrombosis. Ultrastructural analysis revealed that the primary site of damage was the mitochondrion. By day 5, even though dosing was continued, the toxic lesions in the heart began to resolve, and by study day 16, the heart appeared histologically normal. RNA was extracted from whole hearts after 2 or 5 days of CEM dosing. After a screen for transcript change by microarray analysis, dose-response trends for selected transcripts were analyzed by qRT-PCR. The selected transcripts code for proteins involved in energy production, control of calcium levels, and maintenance of heart function. The down-regulation of ATP subunit transcripts (Atp5j, ATP5k), which reside in the mitochondrial membranes, indicated a decrease in energy supply at day 2 and day 5. This was accompanied by down-regulation of transcripts involved in high-energy consumption processes such as membrane transport and ion channel transcripts (e.g., abc1a, kcnj12). The up-regulation of transcripts encoding for temperature regulation and calcium binding proteins (ucp1 and calb3) only at the 2 low exposure levels, suggest that these adaptive processes cannot occur in association with severe cardiotoxicity as seen in hearts at the high exposure level. Transcript expression changes occurred within 2 days of CEM exposure, and were dose-and time-dependent. The heart transcript changes suggest that CEM cardiotoxicity activates protective processes associated energy conservation and maintenance of heart function.


Plasma Levels of Matrix Metalloproteinase-9 in Children With Chronic Spontaneous Urticaria.
Chronic spontaneous urticaria (CSU) is a disease that is primarily seen in adults and is comparatively rare in children. Consequently, only a few studies have focused on the pathogenesis of the disease in children. This study investigated the possible role of metalloproteinase-9 (MMP-9) in the pathogenesis of CSU in children. The study group was composed of 54 children with CSU; 34 healthy children comprised the control group. The demographic and clinical features of the study group were extensively evaluated, and laboratory assessments were also performed. An enzyme-linked immunosorbent assay was used to evaluate levels of plasma MMP-9. Disease activity was quantified using the urticaria activity score (UAS). The median value of plasma MMP-9 was 108.9 ng/mL (interquartile range, 93.3-124.1) in the CSU group and 87.8 ng/mL (69.4-103.0) in the control group. The difference between the 2 groups was statistically significant (P<0.001). Also, MMP-9 levels showed a significant positive correlation with UAS (rho=0.57, P<0.001). Twenty-six percent of patients had positive autologous serum skin test (ASST) results. Neither UAS nor plasma MMP-9 levels were significantly different between ASST-positive and -negative patients (P>0.05). Plasma MMP-9 levels were elevated in children with CSU and were positively correlated with disease activity. MMP-9 may be both a good biomarker of disease activity and a potential therapeutic target in CSU.


Using Wavelet Packet Transform for Surface Roughness Evaluation and Texture Extraction.
Surface characterization plays a significant role in evaluating surface functional performance. In this paper, we introduce wavelet packet transform for surface roughness characterization and surface texture extraction. Surface topography is acquired by a confocal laser scanning microscope. Smooth border padding and de-noise process are implemented to generate a roughness surface precisely. By analyzing the high frequency components of a simulated profile, surface textures are separated by using wavelet packet transform, and the reconstructed roughness and waviness coincide well with the original ones. Wavelet packet transform is then used as a smooth filter for texture extraction. A roughness specimen and three real engineering surfaces are also analyzed in detail. Profile and areal roughness parameters are calculated to quantify the characterization results and compared with those measured by a profile meter. Most obtained roughness parameters agree well with the measurement results, and the largest deviation occurs in the skewness. The relations between the roughness parameters and noise are analyzed by simulation for explaining the relatively large deviations. The extracted textures reflect the surface structure and indicate the manufacturing conditions well, which is helpful for further feature recognition and matching. By using wavelet packet transform, engineering surfaces are comprehensively characterized including evaluating surface roughness and extracting surface texture.


Families affected by deafness: hospital services uptake in a multiethnic population.
To examine the uptake of relevant hospital services by families with deaf children and to compare use of these services between Pakistani and white families. A total of 214 deaf children with amplification aids who attended their paediatric outpatient and school medical appointments from October 2000 to March 2003 were studied in an observational cohort study. The demographic profile of both the Pakistani and white families was similar. Pakistani children had a statistically significant excess of the following risk factors: consanguineous marriages (86.4% Pakistani, 1.5% white), family history of deafness (66.4% Pakistani, 38.8% white), and family size (birth order >5: 12.8% Pakistani: 4.5% white). White children were more likely to have had post-meningitis deafness (1.4% Pakistani, 13.4% white) and congenital infections, or have dysmorphic features (5.0% Pakistani, 13.4% white). Overall the uptake of relevant hospital services by Pakistani and white families was very similar irrespective of an early or late diagnosis. There was an increased likelihood of white families declining cochlear implantation (17.6% Pakistani, 75.0% white). This study did not show significant differences in hospital service uptake despite different risk profiles for childhood deafness for both Pakistani and white families in Bradford. Among specialist services offered, cochlear implantation was more likely to be accessed by Pakistani families.


Cytogenetic aberrations and their prognostic value in a series of 330 splenic marginal zone B-cell lymphomas: a multicenter study of the Splenic B-Cell Lymphoma Group.
We conducted a retrospective collaborative study to cytogenetically characterize splenic marginal zone lymphoma (SMZL) and ascertain the prognostic value of chromosomal aberrations. Of 330 cases, 72% displayed an aberrant karyotype, 53% were complex, and 29% had a single aberration. The predominant aberrations were gains of 3/3q and 12q, deletions of 7q and 6q and translocations involving 8q/1q/14q. CD5 expression was detected in 39 of 158 cases (25%). The cytogenetic makeup of the CD5(+) group differed significantly from that of the CD5(-) group. Cases with unmutated IGHV were significantly associated with deletions of 7q and TP53. A strong association was noted between usage of the IGVH1-2 and deletion 7q, 14q alterations, and abnormal karyotype. On univariate analysis, patients with more than or equal to 2 aberrations, 14q alterations, and TP53 deletions had the shortest survival; 7q deletion did not affect survival. On multivariate analysis, cytogenetic aberrations did not retain prognostic significance; the parameters negatively affecting survival were hemoglobin and age. In conclusion, the cytogenetic profile of SMZL is distinct from other B-cell lymphomas. Complexity of the karyotype, 14q aberrations, and TP53 deletions are poor prognostic indicators and may be considered together with other clinicobiologic parameters to ascertain the prognosis of SMZL.


Peripheral protein organization and its influence on lipid diffusion in biomimetic membranes.
Protein organization on biomembranes and their dynamics are essential for cellular function. It is not clear, however, how protein binding may influence the assembly of underlying lipids or how the membrane structure leads to functional protein organization. Toward this goal, we investigated the effects of annexin a5 binding to biomimetic membranes using fluorescence imaging and correlation spectroscopy. Annexin a5 (anx a5), a peripheral intracellular protein that plays a membrane remodeling role in addition to other functions, binds specifically and tightly to anionic (e.g., phosphatidylserine)-containing membranes in the presence of calcium ion. Our fluorescence microscopy reveals that annexin likely forms assemblies, along with a more dispersed population, upon binding to anionic biomembranes in the presence of calcium ion, which is reflected in its two-component Brownian motion. To investigate the effects of annexin binding on the underlying lipids, we used specific acyl chain labeled phospholipid analogues, NBD-phosphatidylcholine (NBD-PC) and NBD-phosphatidylserine (NBD-PS). We find that both NBD-labeled lipids cluster under anx a5 assemblies, as compared with when they are found under the dispersed annexin population, and NBD-PS exhibits two-component lateral diffusion under the annexin assemblies. In contrast, NBD-PC diffusion is slower by an order of magnitude under the annexin assemblies in contrast to its diffusion when not localized under anx a5 assemblies. Our results indicate that, upon binding to membranes, the peripheral protein annexin organizes the underlying lipids into domains, which may have functional implications in vivo.


The aging digestive tract: what should anesthesiologists know about it?
At present, elderly individuals represent approximately 18.5% of the European population and account for about 23% of surgical procedures performed. This patient population is at a higher risk for perioperative complications and adverse postoperative outcome. This narrative review highlights our current knowledge about physiological changes in the aging gut and the implications for anesthesiologists. The reduced response to stimuli in the pharynx, and reduction of the cough reflex that occurs in many older individuals, probably explains the increased incidence of aspiration pneumonia that occurs in the elderly. These changes also increase the risk for aspiration during anesthesia. Aging affects the clearance of fluids and solids in the esophagus, associated with a higher incidence of gastro-esophageal reflux disease. Healthy aging appears to be associated with modest slowing of gastric emptying, but this does not demand prolonged preoperative fasting. The physiological changes associated with polypharmacy also make elderly patients a risk group for pulmonary aspiration during anesthesia. Further research is needed to determine the effects of commonly used anesthetic agents on the pharyngo-gastrointestinal tract in elderly patients.


Micromonospora orduensis sp. nov., isolated from deep marine sediment.
A novel actinobacterial strain, designated S2509T, was isolated from marine sediment collected by a dredge at a depth of 45 m along Melet River offshore of the southern Black Sea coast, Ordu, Turkey. The cell wall peptidoglycan of strain was found to contain meso-diaminopimelic acid and 3-OH-diaminopimelic acid. The whole cell sugars detected were arabinose, glucose, rhamnose, ribose and xylose. The diagnostic phospholipids of strain S2509T were found to be diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, a glycolipid and two unidentified phospholipids. The predominant menaquinones were identified as MK-9(H8), MK-9(H6), MK-10(H8), MK-9(H4), MK-10(H4) and MK-10(H6). The major cellular fatty acids were found to be iso-C16:0, iso-C15:0 and 10-methyl C17:0. The taxonomic position of the strain was established using a polyphasic approach, showing that S2509T strain belongs to the genus Micromonospora. Phylogenetic analysis based on the 16S rRNA gene sequence of strain S2509T showed that it is closely related to the type strain of Micromonospora chokoriensis DSM 45160T (99.37% sequence similarity), and phylogenetically clustered with Micromonospora inaquosa LB39T (99.37%), Micromonospora lupini Lupac 14NT (99.16%), Micromonospora violae NEAU-zh8T (99.23%) and Micromonospora taraxaci NEAU-P5T (99.03%). The phylogenetic analysis based on the gyrB gene sequence of strain S2509T confirmed its close relationship with M. chokoriensis JCM 13247T (96.5% sequence similarity). Whole genome sequences confirmed by digital DNA-DNA hybridization analysis that the strain S2509T represents a novel species in the genus Micromonospora, for which the name Micromonospora orduensis sp. nov. is proposed. The type strain is S2509T (=DSM 45926T = KCTC 29201T).


(-)-Epicatechin Reduces Blood Pressure and Improves Left Ventricular Function and Compliance in Deoxycorticosterone Acetate-Salt Hypertensive Rats.
(−)-Epicatechin (E) is a flavanol found in green tea and cocoa and has been shown to attenuate tumour necrosis factor alpha (TNF-α)-mediated inflammation, improve nitric oxide levels, promote endothelial nitric oxide synthase (eNOS) activation and inhibit NADPH oxidase. This study investigated the effect of 28 days of low epicatechin dosing (1 mg/kg/day) on the cardiovascular function of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Wistar rats (n = 120, 8 weeks of age) underwent uninephrectomy and were randomised into four groups (uninephrectomy (UNX), UNX + E, DOCA, DOCA + E). DOCA and DOCA + E rats received 1% NaCl drinking water along with subcutaneous injections of 25 mg deoxycorticosterone-acetate (in 0.4 mL of dimethylformamide) every fourth day. UNX + E and DOCA + E rats received 1 mg/kg/day of epicatechin by oral gavage. Single-cell micro-electrode electrophysiology, Langendorff isolated-heart assessment and isolated aorta and mesenteric organ baths were used to assess cardiovascular parameters. Serum malondialdehyde concentration was used as a marker of oxidative stress. Myocardial stiffness was increased and left ventricular compliance significantly diminished in the DOCA control group, and these changes were attenuated by epicatechin treatment (p < 0.05). Additionally, the DOCA + E rats showed significantly reduced blood pressure and malondialdehyde concentrations; however, there was no improvement in left ventricular hypertrophy, electrophysiology or vascular function. This study demonstrates the ability of epicatechin to reduce blood pressure, prevent myocardial stiffening and preserve cardiac compliance in hypertrophied DOCA-salt rat hearts.


The enhancer of human papillomavirus type 16: binding sites for the ubiquitous transcription factors oct-1, NFA, TEF-2, NF1, and AP-1 participate in epithelial cell-specific transcription.
The enhancer of human papillomavirus type 16 (HPV-16) is considered to be specific for epithelial cells, in particular for cervical carcinoma-derived cell lines. We reexamined this hypothesis with the complete enhancer as well as nonoverlapping subclones and found all clones to be active in epithelial cell lines derived from the epidermis and from carcinomas of the cervix, mammary gland, and colon, but inactive in fibroblast, lymphoma, and embryonal carcinoma cells. Although the virus infects only human mucosal epithelia, enhancer activity was independent of the exact type or of the species of origin of the transfected epithelial cell. In spite of epithelial cell specificity, we found that the activity of the HPV-16 enhancer varied strongly from a cytomegalovirus enhancer and the simian virus 40 enhancer in a cell line-dependent manner. This suggests varying quantitative contributions of enhancer elements rather than regulation by an all-or-none switch. Cell type specificity was maintained by a 91-bp subclone of the 400-bp enhancer. Most of the enhancer activity of this fragment was eliminated by alternative mutations in binding sites for the ubiquitous factors AP-1, nuclear factor 1 (NF1), or TEF-2. These three types of factors bind this 91-bp enhancer without cooperation, although activation appears to be synergistic. Outside the 91-bp fragment, a motif typical for papillomavirus enhancers, namely an octamerlike sequence flanked by an NF1-binding site, contributes to enhancer function, as the activity was strongly reduced upon its deletion. In HPV-16, this motif is bound by the oct-1 factor as well as by a probably novel factor, NFA, whereas a related motif of HPV-11 is recognized only by NFA. On examination, none of the five types of transcription factors involved in HPV enhancer activation was restricted to epithelial cells, but NF1, AP-1, and oct-1 were present in higher concentration in HeLa cells than in fibroblasts. Only NF1 showed some qualitative cell type-specific differences. We propose that the epithelial specificity of the HPV-16 enhancer is brought about via binding sites for supposed ubiquitous transcription factors. The mechanism of this activation apparently involves synergism between factors that vary in concentration and may include cell-specific functional differences residing outside the DNA-binding domain of these factors.


Targeted therapies in head and neck cancer: past, present and future.
Head and neck cancers remain a significant health problem globally. The addition of chemotherapy to radiotherapy for locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) has led to improvements in locoregional disease control and in survival, but is associated with substantial acute and late toxicities. In recurrent and/or metastatic SCCHN, there have been no improvements in survival, despite the manipulation of standard therapeutic regimens and the introduction of newer cytotoxic agents. Over the last decade, targeted therapies have been increasingly used in a range of solid tumor types. This article discusses the clinical evidence for the use of a number of targeted agents in the treatment of locoregionally advanced and recurrent and/or metastatic SCCHN. The article focuses on the epidermal growth factor receptor (EGFR) inhibitors, for which the majority of clinical information is available. These include the monoclonal antibody (MAb) cetuximab and the tyrosine kinase inhibitors, erlotinib and gefitinib. Clinical data for the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, are also presented.


Controlling the conformational stability of coiled-coil peptides with a single stereogenic center of a peripheral β-amino acid residue.
The key issue in the research on foldamers remains the understanding of the relationship between the monomers structure and conformational properties at the oligomer level. In peptidomimetic foldamers, the main goal of which is to mimic the structure of proteins, a main challenge is still better understanding of the folding of peptides and the factors that influence their conformational stability. We probed the impact of the modification of the peptide periphery with trans- and cis-2-aminocyclopentanecarboxylic acid (ACPC) on the structure and stability of the model coiled-coil using circular dichroism (CD), analytical ultracentrifugation (AUC) and two-dimensional nuclear magnetic resonance spectroscopy (2D NMR). Although, trans-ACPC and cis-ACPC-containing mutants differ by only one peripheral stereogenic center, their conformational stability is strikingly different.


Isolation of two differentially glycosylated forms of peptidyl-dipeptidase A (angiotensin converting enzyme) from pig brain: a re-evaluation of their role in neuropeptide metabolism.
Peptidyl-dipeptidase A (angiotensin converting enzyme; ACE, EC 220.127.116.11), has been purified from pig kidney and striatum by affinity chromatography employing the selective inhibitor lisinopril as ligand. The inclusion of a 2.8 nm spacer arm improved the yield of the enzyme compared with the 1.4 nm spacer arm described in previous work. Two forms of striatal ACE (Mr 180,000 and 170,000), but only a single form of kidney ACE (Mr 180,000), were isolated by this procedure. Both forms of striatal ACE were recognized by a polyclonal antibody to kidney ACE. No significant differences in substrate specificity or inhibitor sensitivity between kidney and striatal ACE could be detected. In particular, the amidated neuropeptide, substance P, was hydrolysed identically by both preparations and no significant hydrolysis of the related tachykinin peptides neurokinin A and neurokinin B could be detected. After chemical or enzymic deglycosylation, kidney and both forms of striatal ACE migrated identically on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis with an apparent Mr of 150,000. We suggest that the two detectable forms of ACE in pig brain are not isoenzymes but are the result of differential glycosylation in different cell types in the brain. It appears that ACE, unlike endopeptidase-24.11, does not have the general capacity to hydrolyse and inactivate the tachykinin peptides at a significant rate in brain.


ADP binding to myosin cross-bridges and its effect on the cross-bridge detachment rate constants.
We have studied the binding of adenosine diphosphate (ADP) to attached cross-bridges in chemically skinned rabbit psoas muscle fibers and the effect of that binding on the cross-bridge detachment rate constants. Cross-bridges with ADP bound to the active site behave very similarly to cross-bridges without any nucleotide at the active site. First, fiber stiffness is the same as in rigor, which presumably implies that, as in rigor, all the cross-bridges are attached. Second, the cross-bridge detachment rate constants in the presence of ADP, measured from the rate of decay of the force induced by a small stretch, are, over a time scale of minutes, similar to those seen in rigor. Because ADP binding to the active site does not cause an increase in the cross-bridge detachment rate constants, whereas binding of nucleotide analogues such as adenyl-5'-yl imidodiphosphate (AMP-PNP) and pyrophosphate (PPi) do, it was possible, by using ADP as a competitive inhibitor of PPi or AMP-PNP, to measure the competitive inhibition constant and thereby the dissociation constant for ADP binding to attached cross-bridges. We found that adding 175 microM ADP to 4 mM PPi or 4 mM AMP-PNP produces as much of a decrease in the apparent cross-bridge detachment rate constants as reducing the analogue concentration from 4 to 1 mM. This suggests that ADP is binding to attached cross-bridges with a dissociation constant of approximately 60 microM. This value is quite similar to that reported for ADP binding to actomyosin subfragment-1 (acto-S1) in solution, which provides further support for the idea that nucleotides and nucleotide analogues seem to bind about as strongly to attached cross-bridges in fibers as to acto-S1 in solution (Johnson, R.E., and P. H. Adams. 1984. FEBS Letters. 174:11-14; Schoenberg, M., and E. Eisenberg. 1985. Biophysical Journal. 48:863-871; Biosca, J.A., L.E. Greene, and E. Eisenberg. 1986. Journal of Biological Chemistry. 261:9793-9800).


Antimuscarinic intoxication resulting from the ingestion of moonflower seeds.
To report a case in which ingestion of moonflower seeds resulted in antimuscarinic intoxication. An 18-year-old man was found at a local convenience store hallucinating and incoherent. Upon presentation to the emergency department, his signs and symptoms included tachycardia, confusion, dilated pupils, and dry, flushed, hot skin. He was admitted to the intensive care unit. Hallucinations and symptoms resolved within 36-48 hours after hospitalization. The patient then reported that he had ingested moonflower seeds. He recovered and was released 4 days after admission. Based on the patient's description and clinical presentation, the moonflower seeds were believed to be Datura inoxia. This species of plant is similar to jimson weed, or Datura stramonium. These plants are known to contain high concentrations of anticholinergic substances; ingestion can result in anticholinergic intoxication. Signs and symptoms that commonly occur include hallucinations, tachycardia, dilated pupils, and disorientation. In our patient, use of the Naranjo probability scale indicated a possible relationship between the moonflower seed ingestion and the patient's signs and symptoms. Ingestion of the Datura species can result in severe toxicity. Each plant varies in the concentrations of alkaloid substances. For this reason, it is very important for individuals to become educated on the toxicities and potential risks associated with recreational use of these plants.


Carotid Plaque Inflammation Imaged by 18F-Fluorodeoxyglucose Positron Emission Tomography and Risk of Early Recurrent Stroke.
Background and Purpose- Plaque inflammation contributes to stroke and coronary events. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) identifies plaque inflammation-related metabolism. Almost no prospective data exist on the relationship of carotid 18F-FDG uptake and early recurrent stroke. Methods- We did a multicenter prospective cohort study BIOVASC (Biomarkers/Imaging Vulnerable Atherosclerosis in Symptomatic Carotid disease) of patients with carotid stenosis and recent stroke/transient ischemic attack with 90-day follow-up. On coregistered carotid 18F-FDG PET/computed tomography angiography, 18F-FDG uptake was expressed as maximum standardized uptake value (SUVmax) in the axial single hottest slice. We then conducted a systematic review of similar studies and pooled unpublished individual-patient data with 2 highly similar independent studies (Dublin and Barcelona). We analyzed the association of SUVmax with all recurrent nonprocedural stroke (before and after PET) and with recurrent stroke after PET only. Results- In BIOVASC (n=109, 14 recurrent strokes), after adjustment (for age, sex, stenosis severity, antiplatelets, statins, diabetes mellitus, hypertension, and smoking), the hazard ratio for recurrent stroke per 1 g/mL SUVmax was 2.2 (CI, 1.1-4.5; P=0.025). Findings were consistent in the independent Dublin (n=52, hazard ratio, 2.2; CI, 1.1-4.3) and Barcelona studies (n=35, hazard ratio, 2.8; CI, 0.98-5.5). In the pooled cohort (n=196), 37 recurrent strokes occurred (29 before and 8 after PET). Plaque SUVmax was higher in patients with all recurrence ( P<0.0001) and post-PET recurrence ( P=0.009). The fully adjusted hazard ratio of any recurrent stroke was 2.19 (CI, 1.41-3.39; P<0.001) and for post-PET recurrent stroke was 4.57 (CI, 1.5-13.96; P=0.008). Recurrent stroke risk increased across SUVmax quartiles (log-rank P=0.003). The area under receiver operating curve for all recurrence was 0.70 (CI, 0.59-0.78) and for post-PET recurrence was 0.80 (CI, 0.64-0.96). Conclusions- Plaque inflammation-related 18F-FDG uptake independently predicted future recurrent stroke post-PET. Although further studies are needed, 18F-FDG PET may improve patient selection for carotid revascularization and suggest that anti-inflammatory agents may have benefit for poststroke vascular prevention.


Three membrane-conductance mechanisms activated by noradrenaline in vascular smooth muscle.
Membrane mechanisms activated by noradrenaline in vascular smooth muscle have been studied with the perforated patch technique. From ion substitution experiments it was evident that the application of noradrenaline increased the membrane permeability to potassium, chloride and cations (non-selective) through three distinct ion channels. The K and Cl currents were activated when the intracellular calcium concentration (Cai) was increased and are therefore calcium-activated mechanisms (IK(Ca) and ICl(Ca)). In contrast, the non-selective cation current (Icat) was not activated directly by an increase in Cai, but calcium appeared to possess a permissive role in the generation of Icat. The non-selective cation conductance was highly permeable to divalent cations, but was not inhibited by calcium-antagonists. IK(Ca), ICl(Ca) and Icat were blocked by the alpha 1-adrenoceptor selective antagonist prazosin (10(-8) M), but were unaffected by yohimbine (10(-6) M) and, thus, all three membrane mechanisms are linked to the alpha 1-adrenoceptor.


Utilising a collective case study system theory mixed methods approach: a rural health example.
Insight into local health service provision in rural communities is limited in the literature. The dominant workforce focus in the rural health literature, while revealing issues of shortage of maldistribution, does not describe service provision in rural towns. Similarly aggregation of data tends to render local health service provision virtually invisible. This paper describes a methodology to explore specific aspects of rural health service provision with an initial focus on understanding rurality as it pertains to rural physiotherapy service provision. A system theory-case study heuristic combined with a sequential mixed methods approach to provide a framework for both quantitative and qualitative exploration across sites. Stakeholder perspectives were obtained through surveys and in depth interviews. The investigation site was a large area of one Australian state with a mix of rural, regional and remote communities. 39 surveys were received from 11 locations within the investigation site and 19 in depth interviews were conducted. Stakeholder perspectives of rurality and workforce numbers informed the development of six case types relevant to the exploration of rural physiotherapy service provision. Participant perspective of rurality often differed with the geographical classification of their location. The numbers of onsite colleagues and local access to health services contributed to participant perceptions of rurality. The complexity of understanding the concept of rurality was revealed by interview participants when providing their perspectives about rural physiotherapy service provision. Dual measures, such as rurality and workforce numbers, provide more relevant differentiation of sites to explore specific services, such rural physiotherapy service provision, than single measure of rurality as defined by geographic classification. The system theory-case study heuristic supports both qualitative and quantitative exploration in rural health services research.


Bioactivity of antioxidants in extruded products prepared from purple potato and dry pea flours.
Measuring antioxidant activity using a biologically relevant assay adds important evidence to aid in understanding the role of phytochemicals based on data from in vivo and chemical assays of extrusion processed purple potato and pea flours. A cellular antioxidant activity assay could provide biologically relevant information on bioactive compounds in raw as well as processed food products. The objective of this study was to investigate the complete phytochemical profiles, antioxidant activity, cellular antioxidant activity, and their contribution to bioactivity in purple potato flour, dry pea flour, raw formulations, and extrusion cooked products prepared with the above ingredients. The free fraction of extracts contributed 68, 64, and 88% to total phenolics, total antioxidant activity (ORAC value), and total flavonoids, respectively, in purple potato flour (PPF). Similarly, extracts in the free fraction contributed 87, 86, and 64% to total phenolics, total antioxidant activity (ORAC value), and total flavonoids, respectively, in dry pea flour (DPF). The amount of total phenolics and total flavonoids in purple potato flour and the antioxidant activity of PPF and DPF were comparable to published data. However, a higher amount in the total flavonoids and lower in the total phenolics of DPF were observed. Caffeic, p-coumaric, and ferulic acids were mostly observed in the bound extracts of raw formulations as in the extrudates, whereas chlorogenic acid was predominant in the free extracts. The extruded products had significantly higher (p < 0.05) content of total phenolics, ORAC antioxidant activity, and flavonoids, compared to the raw formulations. Extrusion processing increased the cellular antioxidant activity of the extrudates prepared from 35:65 and 50:50 PPF/DPF (w/w) of ingredients compared with control raw formulations in a dose-dependent manner. Increase of PPF significantly increased (p < 0.05) the cellular antioxidant activity of 35-50% PPF formulations.


A human immunodeficiency virus prime-boost immunization regimen in humans induces antibodies that show interclade cross-reactivity and neutralize several X4-, R5-, and dualtropic clade B and C primary isolates.
A human immunodeficiency virus (HIV) vaccine that will be useful in diverse geographic regions will need to induce a broad immune response characterized by cross-clade immunity. To test whether a clade B-based HIV candidate vaccine could induce interclade humoral responses, including neutralizing activity against primary HIV-1 isolates, sera were tested from recipients of a vaccine consisting of recombinant canarypox virus vCP205 and recombinant gp120(SF2). Serum antibodies exhibited strong immunochemical cross-reactivity with V3 peptides from clades B, C, and F, with weaker activity for several V3 peptides from clades A, D, G, and H; essentially no reactivity could be demonstrated with V3 peptides from clades E and O. Extensive cross-clade reactivity was also documented by enzyme-linked immunosorbent assay with all nine recombinant HIV envelope glycoproteins tested from clades B, D, and E. In addition, vaccinees' sera displayed significant neutralizing activity against 5 of 14 primary isolates tested, including one X4 virus and two dualtropic viruses (from clade B) and two R5 viruses (from clades B and C). This is the first demonstration of the induction by a candidate HIV vaccine constructed from clade B laboratory strains of HIV of neutralizing activity against R5 and clade C primary isolates. The data suggest that, by virtue of their ability to induce cross-clade immune responses, appropriately formulated HIV vaccines based on a finite number of HIV isolates may ultimately be able to protect against the wide range of HIV isolates affecting the populations of many geographic regions.


Studies on protein kinase C and colon carcinogenesis.
To further understand the molecular mechanisms of bile acid-mediated colon tumor promotion, we have examined the possible role of protein kinase C (PKC) in this process. Protein kinase C has been implicated in tumor promotion because it is the receptor for the tumor promoter 12-0-tetradecanoyl-phorbol-13-acetate (TPA) and mediates the action of this compound as well as that of other tumor promoters and growth factors. Our studies show that, in a manner analogous to 12-0-tetradecanoyl-phorbol-13-acetate, deoxycholic acid (DOA) can induce a time-dependent cellular redistribution of PKC as well as a concentration-dependent overexpression of the ornithine decarboxylase gene. These results taken together with our previous findings demonstrating decreased levels of PKC in human colon carcinomas compared with adjacent normal mucosa provide evidence that PKC has a role in colon carcinogenesis.


Characterization and biological activities of humic substances from mumie.
Mumie, a semihard black resin formed by long-term humification, is believed to have therapeutic properties. Although mumie has been used in folk medicine since ancient times, there is little information available concerning the physicochemical properties of its constituents and the mechanisms of its therapeutic efficacy. For this study crude mumie was fractionated into fulvic acid (FA), humic acid (HA), humin, hymatomelanic acid, and two low molecular weight fractions (LMW1 and LMW2). The FA fraction was divided into five subfractions, FA1-FA5. The mumie fractions were characterized by IR, UV-vis, and fluorescence spectroscopy. Total carbohydrate content in the fractions was analyzed using the phenol reaction method. The relative content of polar groups and nonpolar hydrocarbon fragments in the mumie fractions correlated well with solubility in an aqueous medium. Biological characterization was performed using only the FA fractions. FA1 and FA2 enhanced the production of reactive oxygen species (ROS) and nitric oxide in murine peritoneal macrophages, as determined with the use of 2',7'-dichlorofluorescin diacetate and Griess reagent, respectively. The enchancement of ROS and nitric oxide production correlated with the level of total carbohydrates in the fractions. Murine splenic lymphocytes treated with FA1 showed a dose-dependent increase in [(3)H]thymidine uptake. These findings suggest that FA derived from mumie has immunomodulatory activity.


Nonspecific factors in monkey tissues and serum causing inhibition of plaque formation and hemagglutination by dengue viruses.
Normal monkey serum and the supernatant fluid from different triturated monkey tissues have been studied for the presence of nonspecific arbovirus hemagglutination and plaque forming inhibitors of dengue viruses types 1, 2, 3, and 4. Hemagglutination inhibition (HI) activity was present in most tissue specimens and demonstrated a significant gradient of effectiveness starting with, respectively, serum, spleen, adrenal, and lung having a high degree of activity, whereas skin, heart, muscle, brain, and liver demonstrated low HI titers. A slightly reversed gradient of effectiveness was obtained for the case of dengue virus inhibition of plaque formation with bile, liver, thymus, spleen, and adrenal giving high 50% plaque reduction titers and heart, muscle, serum, skin, and fat demonstrating little or no activity. Analysis by Sephadex G-200 chromatography and sucrose density gradient centrifugation suggests that HI and plaque formation inhibition are independent activities of normal serum or tissue constituents or both. Also, in addition to the physical methods of characterization, chemical treatment by absorption with kaolin or acetone extraction indicate both phenomena to be the result of the action of lipids or lipoproteins.


Impact of postoperative morbidity on outcomes in patients with advanced epithelial ovarian cancer undergoing intestinal surgery at the time of primary or interval cytoreductive surgery: A Memorial Sloan Kettering Cancer Center Team Ovary study.
To assess the impact of short-term postoperative complications on oncologic outcomes for patients with epithelial ovarian cancer undergoing primary cytoreductive surgery (PCS) or interval cytoreductive surgery (ICS) with intestinal resection. A retrospective chart review was performed for patients with ovarian cancer who underwent PCS or ICS with at least one intestinal resection at our institution from 1/1/2015 to 12/31/2020. Progression-free survival (PFS) and overall survival (OS) were analyzed for the PCS and ICS cohorts separately. Short-term complications within 30 days of surgery (surgical secondary events [SSEs]) were graded by a validated institutional SSE system. Among 437 patients who underwent intestinal resections during PCS (n = 289) or ICS (n = 148), 183 (42%) had one, 180 (41%) had two, and 74 (17%) had three intestinal resections. Six (1.4%) of 437 patients experienced an anastomotic leak postoperatively. There were no perioperative deaths. There was no difference in PFS and OS for patients who underwent PCS with any SSE vs. no SSE within 30 days of surgery (HR, 1.05; 95% CI: 0.76-1.47; p = 0.75 and HR, 0.79; 95% CI: 0.49-1.26; p = 0.32, respectively). There was no difference in PFS and OS for patients who underwent ICS with any SSE vs. no SSE within 30 days of surgery (HR, 1.43; 95% CI: 0.99-2.07; p = 0.055 and HR. 1.18; 95% CI: 0.72-1.93; p = 0.52, respectively. Short-term postoperative morbidity for patients who underwent intestinal surgery during primary surgical management for advanced ovarian cancer did not impact oncologic outcomes.


Is atopy in early childhood a risk factor for ADHD and ASD? a longitudinal study.
Previous studies have found a temporal concordance in the increased prevalence of atopic diathesis/atopic diseases, attention-deficit hyperactivity disorder (ADHD), and autistic spectrum disorder (ASD) worldwide. But, the temporal association among these 3 distinct diseases is unknown. 14,812 atopic subjects diagnosed with any atopic disease (asthma, atopic dermatitis, allergic rhinitis, or allergic conjunctivitis) before the age of 3 (atopic cohort) and 6944 non-atopic subjects with no lifetime atopic disease (non-atopic cohort), born between 1997 and 2000, were enrolled and followed to December 31, 2010 to identify the development of ADHD and ASD. The presence of any atopic disease in early childhood increased the risk of developing ADHD (hazard ratio [HR]: 1.97) and ASD (HR: 3.40) in later life. Greater numbers of atopic comorbidities (4 comorbidities: ADHD: HR: 2.53; ASD: HR: 4.29) were significantly related to a greater risk of developing ADHD and ASD. Atopic diathesis in early childhood elevated the risk of developing ADHD and ASD in later life, with the dose-dependent relationship of more atopic comorbidities with a greater likelihood of ADHD and ASD.


Vibrational spectra and physico-chemical properties of astrophysical analogs.
We undertake in this paper a theoretical study based on DFT methodology of amorphous solids formed by methane, water and nitrogen in a ratio of 1 : 3 : 3. By varying the size of the cell containing this mixture of molecules, we study the effect of the corresponding cell volume and density on the predicted IR spectra, in particular on the hydrogen bond modes. Also the relative stability of the structures as a function of the density is studied. We have enclosed a large density range, from a very low value that simulates a gas-phase mixture, to values corresponding to solids under fairly high internal stress, with an intermediate range that could be expected to cover the values of mixtures at astronomical conditions. The variation of the energy at constant temperature with the volume of the unit cell fits well to a Morse function, which allows finding an equation of state for the material in the range of volumes studied here.


Regulatory role for nucleosome assembly protein-1 in the proliferative and vasculogenic phenotype of pulmonary endothelium.
Pulmonary microvascular endothelial cells (PMVECs) are enriched with progenitor cells that underlie their rapid proliferation and vasculogenic capacity. However, the molecular basis for such an enhanced growth potential is unknown. Nucleosome assembly protein-1 (NAP1), and its related family of proteins, have been incriminated in control of cell growth in a range of species. We therefore sought to determine whether NAP1 contributes to the rapid proliferation and vasculogenesis that is observed in PMVECs. NAP1 was expressed at a high level in two fast-growing cell types, including PMVECs and resident microvascular endothelial progenitor cells that were selected from PMVECs, whereas it was expressed at a low level in slow-growing pulmonary artery endothelial cells (PAECs). Heterologous NAP1 expression increased the growth potential of PAECs, whereas inhibiting NAP1 expression reduced the growth potential of PMVECs. Despite its impact on endothelial cell growth, NAP1 did not influence the expression of endothelial cell-selective markers (PECAM-1, VE-cadherin, von Willebrand factor), and it did not influence cell type-specific lectin binding criterion; PMVECs interact with Griffonia simplicifolia lectin, whereas PAECs interact with Helix pomatia lectin. PMVECs possess a higher basal transelectrical resistance than do PAECs, indicative of their more restrictive barrier property. Changing NAP1 expression did not normalize this basal barrier function between PMVECs and PAECs. To examine whether the growth-promoting actions of NAP1 influence blood vessel formation, endothelial cells were mixed into Matrigel and subcutaneously implanted. PMVECs generated eightfold more blood vessels than did PAECs over a 10-day time course. Heterologous NAP1 expression in PAECs increased the number of blood vessels formed by this cell type, where blood vessel growth approached that seen with PMVECs. Thus, our findings indicate that NAP1 functions as an important regulator of the proliferative and vasculogenic endothelial cell phenotype without globally impacting endothelial cell phenotype specification.


Use of Telehealth to Improve Access to Care at the United States Department of Veterans Affairs During the 2017 Atlantic Hurricane Season.
This brief report examines the shift from in-person care to US Department of Veterans Affairs (VA) telehealth services during 3 devastating hurricanes in 2017 (Harvey, Irma, and Maria). VA administrative data were used to analyze the number and percentage of telehealth services 30 d pre- and 30 d post- the 2017 hurricanes for 3 hurricane-impacted VA medical centers (VAMCs): Houston (Texas), Orlando (Florida), and San Juan (Puerto Rico). All 3 VAMCs remained open during the hurricanes. For the Houston VAMC, during the first week post-Harvey, in-person patient visits decreased while telehealth visits increased substantially. Similarly, for the Orlando VAMC, during the 1-wk post-Irma, telehealth use increased substantially. For the San Juan VAMC, there were many interruptions in the use of telehealth due to many power outages, resulting in a modest increase in the use of telehealth post-Irma/Maria. The most commonly used telehealth services at Houston and Orlando VAMCs during the hurricanes were: primary care, triage, mental health, and home health. Telehealth has the potential to improve post-disaster access to and coordination of care. However, more information is needed to better understand how telehealth services can be used as a post-disaster health-care delivery tool, particularly for patients receiving care outside of systems such as VA.


Grammatical and nongrammatical contributions to closed-class word selection.
Closed-class word selection was investigated by focusing on determiner production. Native speakers from three different languages named pictures of objects using determiner plus noun phrases (e.g., in French "la table" [the-sub(feminineA) table], while ignoring distractor determiners printed on the pictures (e.g., "le" [the-sub(masculine)]. The target and distractor expressed either shared or different grammatical and nongrammatical features (gender, number, and definiteness). A gender-facilitation effect was observed and attributed to noun processing. Crucially, across five experiments, distractors that shared a feature with the target determiner never resulted in longer naming latencies than distractors that were more different. These results indicate that activating related candidates is not detrimental for determiner retrieval, suggesting a noncompetitive mechanism of closed-class word selection.


Molecular epidemiology of Cryptococcus neoformans in Brazil and the United States: evidence for both local genetic differences and a global clonal population structure.
Little is known about the global molecular epidemiology of the human pathogenic fungus Cryptococcus neoformans. We studied 51 clinical and environmental (pigeon excreta) isolates from two cities in Brazil (Belo Horizonte and Rio de Janeiro) by analyzing their carbon assimilation patterns, electrophoretic karyotypes, restriction fragment length polymorphisms (RFLPs) with the C. neoformans repetitive element-1 (CNRE-1), and URA5 sequences. Results were compared to those previously obtained for isolates from New York City by the same DNA typing methods. Computer-assisted analysis of RFLPs and contour-clamped homogeneous electrophoresis (CHEF) patterns and URA5 sequences was performed to generate dendrograms. Some environmental and clinical isolates were found to be indistinguishable by CHEF, CNRE-1 RFLP, and URA5 sequence analyses. Similarly, some isolates from Rio de Janeiro and Belo Horizonte were indistinguishable by the three DNA typing techniques. Overall, Brazilian isolates appeared to be less heterogeneous by DNA analysis than isolates from other regions. Several Brazilian isolates were highly related to New York City isolates. Phylogenetic analysis of the sequences obtained for the Brazilian isolates and those obtained for New York City isolates was congruent with the dendrogram generated from the CNRE-1 RFLP data. In summary our results indicate (i) that the discriminatory power of the DNA typing method differs for Brazilian and New York City strains, with the order being CNRE-1 RFLP analysis > URA5 sequence analysis > CHEF analysis and CHEF analysis > URA5 sequence analysis > CNRE-1 RFLP analysis, respectively; (ii) that there are differences in local genetic diversity for Brazilian and New York City isolates; (iii) that there is additional evidence linking clinical isolates to those in pigeon excreta; and (iv) that some isolates from Brazil and New York City are closely related, consistent with the global dispersal of certain pathogenic strains.


Purpura with ulcerative skin lesions and mixed cryoglobulinemia in a quiescent hepatitis B virus carrier.
Mixed cryoglobulinemia is occasionally seen in patients with hepatitis B virus (HBV) infection. This report presents the case of a quiescent HBV carrier who had type II mixed cryoglobulinemia, protracted purpura, ulcerative skin lesions and advanced chronic kidney disease. The cutaneous manifestations of the patient improved along with a decrease in the serum cryoglobulin and HBV-deoxyribonucleic acid levels following the initiation of oral entecavir in combination with plasmapheresis. However, the patient ultimately required prednisolone due to the limited benefits of these treatments. We also discuss various concerns regarding steroid treatment in patients with mixed cryoglobulinemia complicated by HBV infection.