Thyroid Disruption by Bisphenol S Analogues via Thyroid Hormone Receptor β: in Vitro, in Vivo, and Molecular Dynamics Simulation Study.
Bisphenol S (4-hydroxyphenyl sulfone, BPS) is increasingly used as a bisphenol A (BPA) alternative. The global usage of BPS and its analogues (BPSs) resulted in the frequent detection of their residues in multiple environmental media. We investigated their potential endocrine-disrupting effects toward thyroid hormone receptor (TR) β. The molecular interaction of BPSs toward TRβ ligand binding domain (LBD) was probed by fluorescence spectroscopy and molecular dynamics (MD) simulations. BPSs caused the static fluorescence quenching of TRβ LBD. The 100 ns MD simulations revealed that the binding of BPSs caused significant changes in the distance between residue His435 at helix 11(H11) and residue Phe459 at H12 in comparison to no ligand-bound TRβ LBD, indicating relative repositioning of H12. The recombinant two-hybrid yeast assay showed that tetrabromobisphenol S (TBBPS) and tetrabromobisphenol A (TBBPA) have potent antagonistic activity toward TRβ, with an IC10 of 10.1 and 21.1 nM, respectively. BPS and BPA have the antagonistic activity with IC10 of 312 and 884 nM, respectively. BPSs significantly altered the expression level of mRNA of TRβ gene in zebrafish embryos. BPS and TBBPS at environmentally relevant concentrations have antagonistic activity toward TRβ, implying that BPSs are not safe BPA alternatives in many BPA-free products. Future health risk assessments for TR disruption and other adverse effects should focus more on the structure-activity relationship in the design of environmentally benign BPA alternatives.


Vulnerability of individual fish to capture by trawling is influenced by capacity for anaerobic metabolism.
The harvest of animals by humans may constitute one of the strongest evolutionary forces affecting wild populations. Vulnerability to harvest varies among individuals within species according to behavioural phenotypes, but we lack fundamental information regarding the physiological mechanisms underlying harvest-induced selection. It is unknown, for example, what physiological traits make some individual fish more susceptible to capture by commercial fisheries. Active fishing methods such as trawling pursue fish during harvest attempts, causing fish to use both aerobic steady-state swimming and anaerobic burst-type swimming to evade capture. Using simulated trawling procedures with schools of wild minnows Phoxinus phoxinus, we investigate two key questions to the study of fisheries-induced evolution that have been impossible to address using large-scale trawls: (i) are some individuals within a fish shoal consistently more susceptible to capture by trawling than others?; and (ii) if so, is this related to individual differences in swimming performance and metabolism? Results provide the first evidence of repeatable variation in susceptibility to trawling that is strongly related to anaerobic capacity and swimming ability. Maximum aerobic swim speed was also negatively correlated with vulnerability to trawling. Standard metabolic rate was highest among fish that were least vulnerable to trawling, but this relationship probably arose through correlations with anaerobic capacity. These results indicate that vulnerability to trawling is linked to anaerobic swimming performance and metabolic demand, drawing parallels with factors influencing susceptibility to natural predators. Selection on these traits by fisheries could induce shifts in the fundamental physiological makeup and function of descendent populations.


Soluble epoxide hydrolase deficiency attenuates neointima formation in the femoral cuff model of hyperlipidemic mice.
Epoxyeicosatrienoic acids (EETs) have antiinflammatory effects and are required for normal endothelial function. The soluble epoxide hydrolase (sEH) metabolizes EETs to their less active diols. We hypothesized that knockout and inhibition of sEH prevents neointima formation in hyperlipidemic ApoE(-/-) mice. Inhibition of sEH by 12-(3-adamantan-1-yl-ureido) dodecanoic acid or knockout of the enzyme significantly increased plasma EET levels. sEH activity was detectable in femoral and carotid arteries. sEH knockout or inhibition resulted in a significant reduction of neointima formation in the femoral artery cuff model but not following carotid artery ligation. Although macrophage infiltration occurred abundantly at the site of cuff placement in both sEH(+/+) and sEH(-/-), the expression of proinflammatory genes was significantly reduced in femoral arteries from sEH(-/-) mice. Moreover, an in vivo 5-bromo-2'-deoxyuridine assay revealed that smooth muscle cell proliferation at the site of cuff placement was attenuated in sEH knockout and sEH inhibitor-treated animals. These observations suggest that inhibition of sEH prevents vascular remodeling in an inflammatory model but not in a blood flow-dependent model of neointima formation.


Radioimmunoassay of human platelet thrombospondin: different patterns of thrombospondin and beta-thromboglobulin antigen secretion and clearance from the circulation.
A method for radioimmunoassay of human thrombospondin was developed. Monospecific precipitating anti-human thrombospondin antibody was raised in rabbits after injection of thrombospondin purified by fibrinogen-agarose chromatography and preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The linear portion of the thrombospondin radioimmunoassay standard curve was 0.5 to 20 ng/ml. Normal platelets and platelet-poor plasma contained 28,900 +/- 14,500 ng thrombospondin per 10(9) platelets and 60.6 +/- 10.7 ng/ml (mean +/- SD), respectively. Using radioimmunoassays for beta-thromboglobulin and thrombospondin antigens, we compared platelet location and secretion of these proteins. Both antigens shared similar distributions in platelet subcellular fractions with the largest amount localized to platelet alpha-granules. With thrombin (0.25 U/ml) as a platelet agonist, 62.4% and 19.5% of total beta-thromboglobulin and thrombospondin, respectively, were secreted from suspensions of washed human platelets. Because only 20% of the total platelet thrombospondin was secreted, further studies were initiated to determine whether the remaining thrombospondin became localized on the activated platelets membrane. 125I-Fab antithrombospondin specifically bound to activated platelets but not to unstimulated platelets. In contrast, 125I-Fab anti-beta-thromboglobulin did not bind to activated platelets. Plasma clearance of human beta-thromboglobulin (half-life fast 7.6 minutes, slow 56.6 minutes) and of human thrombospondin (half-life fast 29.9 minutes, slow 190 minutes) followed a biphasic exponential curve. In conclusion, both beta-thromboglobulin and thrombospondin are located in platelet alpha-granules, but they show a different pattern of secretion and expression on the platelet membrane and plasma clearance.


[Impact of a rescue program on the operability of patients with bronchogenic carcinoma and chronic obstructive pulmonary disease].
Bronchogenic carcinoma and chronic obstructive pulmonary disease (COPD) are strongly associated in our setting, occurring together in around 70% of cases. Approximately 60% of COPD patients who require resection for bronchogenic carcinoma are considered unfit for surgery because of seriously impaired lung function. The purpose of this study was to evaluate the extent to which a rescue program could improve lung function in COPD patients who had previously been considered unfit for surgery because of poor lung function. The study enrolled COPD patients who had not been considered for surgical resection because they had a predicted postoperative forced expiratory volume in 1 second (FEV1) of less than 1 L. All of the patients participated in a 2-week rescue program that involved optimization of drug treatment (inhaled bronchodilators and/or corticosteroids) and intensive respiratory physiotherapy. Lung function was analyzed before and after the program. We evaluated 30 patients (26 men and 4 women) with a mean (SD) age of 66.7 (8.15) years and an initial FEV1 of 1.497 (0.27) mL (FEV1% of 55.7% [20.14%]). None of the patients had respiratory failure (PaO2 of 77.0 [9.4] mm Hg and PaCO2 of 41.6 [2.4] mm Hg). Twenty-four patients (80%) showed significant improvement in lung function (P< .001) after the program and were admitted for resection. Two wedge resections, 18 lobectomies, 2 pneumonectomies, and 2 exploratory thoracotomies were performed (based on oncologic indications). Nineteen of the 24 patients who underwent surgery had no complications. Two patients had prolonged air leaks, 1 empyema, and 1 hemothorax. One patient died from sepsis. A large number (80%) of COPD patients previously considered unfit for surgical resection because of seriously impaired lung function can be admitted for surgery following an intensive drug and respiratory physiotherapy rescue program.


Learning to Quantify Emphysema Extent: What Labels Do We Need?
Accurate assessment of pulmonary emphysema is crucial to assess disease severity and subtype, to monitor disease progression, and to predict lung cancer risk. However, visual assessment is time-consuming and subject to substantial inter-rater variability while standard densitometry approaches to quantify emphysema remain inferior to visual scoring. We explore if machine learning methods that learn from a large dataset of visually assessed CT scans can provide accurate estimates of emphysema extent and if methods that learn from emphysema extent scoring can outperform algorithms that learn only from emphysema presence scoring. Four Multiple Instance Learning classifiers, trained on emphysema presence labels, and five Learning with Label Proportions classifiers, trained on emphysema extent labels, are compared. Performance is evaluated on 600 low-dose CT scans from the Danish Lung Cancer Screening Trial and we find that learning from emphysema presence labels, which are much easier to obtain, gives equally good performance to learning from emphysema extent labels. The best performing Multiple Instance Learning and Learning with Label Proportions classifiers, achieve intra-class correlation coefficients around 0.90 and average overall agreement with raters of 78% and 79% compared to an inter-rater agreement of 83%.


First Report of Potato spindle tuber viroid Naturally Infecting Field Tomatoes in the Dominican Republic.
In recent years, viroid disease outbreaks have resulted in serious economic losses to a number of tomato growers in North America (1,2,3). At least three pospiviroids have been identified as the causal agents of tomato disease, including Potato spindle tuber viroid (PSTVd), Tomato chlorotic dwarf viroid (TCDVd), and Mexican papita viroid (MPVd). In the spring of 2013, a severe disease outbreak with virus-like symptoms (chlorosis and plant stunting) was observed in a tomato field located in the Dominican Republic, whose tomato production is generally exported to the United States in the winter months. The transplants were produced in house. The disease has reached an epidemic level with many diseased plants pulled and disposed of accordingly. Three samples collected in May of 2013 were screened by ELISA against 16 common tomato viruses (Alfalfa mosaic virus, Cucumber mosaic virus, Impatiens necrotic spot virus, Pepino mosaic virus, Potato virus X, Potato virus Y, Tobacco etch virus, Tobacco mosaic virus, Tobacco ringspot virus, Tomato aspermy virus, Tomato bushy stunt virus, Tomato mosaic virus, Tomato ringspot virus, Tomato spotted wilt virus, Groundnut ringspot virus, and Tomato chlorotic spot virus), a virus group (Potyvirus group), three bacteria (Clavibacter michiganensis subsp. michiganensis, Pectobacterium atrosepticum, and Xanthomonas spp.), and Phytophthora spp. No positive result was observed, despite the presence of symptoms typical of a viral-like disease. Further analysis by RT-PCR using Agdia's proprietary pospiviroid group-specific primer resulted in positive reactions in all three samples. To determine which species of pospiviroid was present in these tomato samples, full-genomic products of the expected size (~360 bp) were amplified by RT-PCR using specific primers for PSTVd (4) and cloned using TOPO-TA cloning kit (Invitrogen, CA). A total of 8 to 10 clones from each isolate were selected for sequencing. Sequences from each clone were nearly identical and the predominant sequence DR13-01 was deposited in GenBank (Accession No. KF683200). BLASTn searches into the NCBI database demonstrated that isolate DR13-01 shared 97% sequence identity to PSTVd isolates identified in wild Solanum (U51895), cape gooseberry (EU862231), or pepper (AY532803), and 96% identity to the tomato-infecting PSTVd isolate from the United States (JX280944). The relatively lower genome sequence identity (96%) to the tomato-infecting PSTVd isolate in the United States (JX280944) suggests that PSTVd from the Dominican Republic was likely introduced from a different source, although the exact source that resulted in the current disease outbreak remains unknown. It may be the result of an inadvertent introduction of contaminated tomato seed lots or simply from local wild plants. Further investigation is necessary to determine the likely source and route of introduction of PSTVd identified in the current epidemic. Thus, proper control measures could be recommended for disease management. The detection of this viroid disease outbreak in the Dominican Republic represents further geographic expansion of the viroid disease in tomatoes beyond North America. References: (1). K.-S. Ling and M. Bledsoe. Plant Dis. 93:839, 2009. (2) K.-S. Ling and W. Zhang. Plant Dis. 93:1216, 2009. (3) K.-S. Ling et al. Plant Dis. 93:1075, 2009. (4) A. M. Shamloul et al. Can. J. Plant Pathol. 19:89, 1997.


How do women at increased, but unexplained, familial risk of breast cancer perceive and manage their risk? A qualitative interview study.
The perception of breast cancer risk held by women who have not had breast cancer, and who are at increased, but unexplained, familial risk of breast cancer is poorly described. This study aims to describe risk perception and how it is related to screening behaviour for these women. Participants were recruited from a population-based sample (the Australian Breast Cancer Family Study - ABCFS). The ABCFS includes women diagnosed with breast cancer and their relatives. For this study, women without breast cancer with at least one first- or second-degree relative diagnosed with breast cancer before age 50 were eligible unless a BRCA1 or BRCA2 mutation had been identified in their family. Data collection consisted of an audio recorded, semi-structured interview on the topic of breast cancer risk and screening decision-making. Data was analysed thematically. A total of 24 interviews were conducted, and saturation of the main themes was achieved. Women were classified into one of five groups: don't worry about cancer risk, but do screening; concerned about cancer risk, so do something; concerned about cancer risk, so why don't I do anything?; cancer inevitable; cancer unlikely. The language and framework women use to describe their risk of breast cancer must be the starting point in attempts to enhance women's understanding of risk and their prevention behaviour.


[Effect of a 17 beta estradiol gel preparation on hormone levels in menopausal women].
Different delivery forms of supplemental estrogens may differ in their hormonal effects. The aim of this study was to assess the effects of a daily dose of 2.5 g of 17 beta estradiol transdermal gel, given during four weeks, on hormone levels of six postmenopausal women. At the fourth week we observed a significant increase in estradiol and a decrease in FSH levels. Estrone levels also increased but the estradiol/estrone ratio was maintained in values over 1. No changes in SHBG or IGF1 levels were observed. Two patients that used the gel in the abdominal skin achieved lower estradiol levels (below 60 pg/ml). We conclude that the gel increased serum estradiol levels over 60 pg/ml in four of six women, that there is a big individual variability and the application zone could influence the serum estradiol levels achieved.


Report of the First International Consensus on Standardized Nomenclature of Antinuclear Antibody HEp-2 Cell Patterns 2014-2015.
During the 12th International Workshop on Autoantibodies and Autoimmunity held in Sao Paulo, Brazil, on August 28, 2014, a full day session was devoted to establishing a consensus on the nomenclature of staining patterns observed in the antinuclear antibody (ANA) indirect immunofluorescence test on HEp-2 cells. The current report summarizes the collective agreements with input from the host Brazilian and international communities that represented research, clinical, and diagnostic service laboratories. Patterns are categorized in three major groups (nuclear, cytoplasmic, and mitotic patterns) and each pattern has been defined and described in detail. The consensus nomenclature and representative patterns are made available online at the international consensus on antinuclear antibody pattern (ICAP) website (www.ANApatterns.org). To facilitate continuous improvement and input, specific comments on ICAP are encouraged and these will be discussed in subsequent ICAP meetings. The ultimate goal with the establishment of the ICAP is to promote harmonization and understanding of autoantibody test nomenclature, as well as interpretation guidelines for ANA testing, thereby optimizing usage in patient care.


Ferroptosis: A Trusted Ally in Combating Drug Resistance in Cancer.
Ferroptosis, which is an iron-dependent, non-apoptotic cell death mechanism, has recently been proposed as a novel approach in cancer treatment. Bearing distinctive features and its exclusive mechanism have put forward the potential therapeutic benefit of triggering this newly discovered form of cell death. Numerous studies have indicated that apoptotic pathways are often deactivated in resistant cells, leading to a failure in therapy. Hence, alternative strategies to promote cell death are required. Mounting evidence suggests that drug-resistant cancer cells are particularly sensitive to ferroptosis. Given that cancer cells consume a higher amount of iron than healthy ones, ferroptosis not only stands as an excellent alternative to trigger cell death and reverse drug-resistance, but also provides selectivity in therapy. This review focuses specifically on overcoming drugresistance in cancer through activating ferroptotic pathways and brings together the relevant chemotherapeutics-based and nanotherapeutics-based studies to offer a perspective for researchers regarding the potential use of this mechanism in developing novel therapeutic strategies.


Migration of a foreign body to the rectum: A case report and literature review.
Rectal foreign bodies are not an uncommon finding in outpatient departments globally. Most such objects are inserted through the anus. Occasionally, a foreign body may be ingested and may successfully pass through the entire gastrointestinal tract and be held up in the rectum. In extremely rare cases, foreign bodies in adjacent tissues or organs can penetrate the rectal wall and enter the rectal lumen. We report a rare case that the IUCD had migrated and was embedded in the rectal wall. A part of the IUCD was loosened and deformed into a metallic wire that protruded through the anus. A 45-year-old woman presented with complaints of a metallic wire protruding through her anus when she used the washroom. The wire would become longer when she manually pulled it; however, this process was associated with pain in the lower abdomen, and she therefore stopped manipulating it. A rectal foreign body secondary to intrauterine contraceptive device (IUCD) migration and rectal perforation, as well as a pelvic cyst. Under general anesthesia, she underwent laparoscopic removal of the rectal foreign body, pelvic adhesiolysis, pelvic cyst resection, and ileostomy combined with colonoscopy. Her postoperative recovery was uneventful. Foreign bodies in adjacent tissues or organs can penetrate the rectal wall and enter the rectal lumen. Regular follow-up after IUCD insertion is very important. We report this rare case that would increase awareness among clinicians regarding the differential diagnosis and treatment in such cases.


Conceptualizing the impacts of dual practice on the retention of public sector specialists - evidence from South Africa.
'Dual practice', or multiple job holding, generally involves public sector-based health workers taking additional work in the private sector. This form of the practice is purported to help retain public health care workers in low and middle-income countries' public sectors through additional wage incentives. There has been little conceptual or empirical development of the relationship between dual practice and retention. This article helps begin to fill this gap, drawing on empirical evidence from a qualitative study focusing on South African specialists. Fifty-one repeat, in-depth interviews were carried out with 28 doctors (predominantly specialists) with more than one job, in one public and one private urban hospital. Findings suggest dual practice can impact both positively and negatively on specialists' intention to stay in the public sector. This is through multiple conceptual channels including those previously identified in the literature such as dual practice acting as a 'stepping stone' to private practice by reducing migration costs. Dual practice can also lead specialists to re-evaluate how they compare public and private jobs, and to overworking which can expedite decisions on whether to stay in the public sector or leave. Numerous respondents undertook dual practice without official permission. The idea that dual practice helps retain public specialists in South Africa may be overstated. Yet banning the practice may be ineffective, given many undertake it without permission in any case. Regulation should be better enforced to ensure dual practice is not abused. The conceptual framework developed in this article could form a basis for further qualitative and quantitative inquiry.


Nutritional Requirements for Mycelial Growth of Milk-White Toothed Mushroom, Irpex lacteus (Agaricomycetes), in Submerged Culture.
Irpex lacteus, a medicinal fungus, is used in traditional Chinese medicine to treat chronic glomerulonephritis. In this work, a strain of I. lacteus was isolated from the fruiting body of a wild specimen and identified by ITS-5.8S ribosomal DNA sequencing analysis. Then the nutritional requirements and culture conditions for mycelial growth of I. lacteus in semisynthetic liquid media were investigated using the one-factor-at-a-time and orthogonal matrix methods. Optimum growth occurred at 30°C and 35°C. I. lacteus mycelia grew well at pH values between 3 and 9, suggesting that this strain is not sensitive to pH. The nutritional components, including 9 carbohydrates, 9 nitrogen compounds, 11 vitamins, and 10 mineral elements, were studied for their effects on mycelial growth in submerged cultures of I. lacteus. Among these variables, soluble starch, peptone, yeast extract, and calcium chloride were identified as required for optimum mycelial growth. The concentrations of each component were optimized using an orthogonal design, and the effects of medium composition on mycelial growth were found in the order soluble starch > yeast extract > peptone > calcium chloride. The optimal concentrations of these components for mycelial growth were determined to be 60 g/L soluble starch, 35 g/L peptone, 15 g/L yeast extract, and 0.6 g/L calcium chloride. Under the optimum medium and culture conditions, the maximum biomass reached 13.73 g/L after 3 days in submerged culture, a value over twice that reached using the basal medium. These results provide a basis for further physiological study and industrial fermentation of I. lacteus.


[Prevalence of metabolic syndrome in a population of transport workers--prospective study].
The metabolic syndrome is a problem which regards public health this phenomenon being explined by the world -wide obesity epidemy.The metabolic syndromes prevalence varies with the studied populations.The unhealthy lifestyle which is defined by peoples sedentary character and unhealthy diets is being significantlly asociated with the metabolic syndromes prevalence growth. The study was performed on 836 individuals with ages between 25 and 65 years, who have a questionnare based interview.Their blood pressure was measured, some anthropometric measures were taken and several laboratory test were made. The diagnosis of metabolic syndrome was established according to the consensual deffinition that was published in October 2009. The metabolic syndrome is a compilation of clinical and biological elements which cause the individ to have a higher cardiovascular risk. The metabolic syndrome increased prevalance in the study is significantlly asociated with the growth of the obesitys and hypertensions prevalance. The lifestyle of the individuals from the study is based on unhealthy diets and sedentarism.


Exploring Differences in Dogs' and Wolves' Preference for Risk in a Foraging Task.
Both human and non-humans species face decisions in their daily lives which may entail taking risks. At the individual level, a propensity for risk-taking has been shown to be positively correlated with explorative tendencies, whereas, at the species level a more variable and less stable feeding ecology has been associated with a greater preference for risky choices. In the current study we compared two closely related species; wolves and dogs, which differ significantly in their feeding ecology and their explorative tendencies. Wolves depend on hunting for survival with a success rate of between 15 and 50%, whereas free-ranging dogs (which make up 80% of the world dog population), are largely scavengers specialized on human produce (i.e., a more geographically and temporally stable resource). Here, we used a foraging paradigm, which allowed subjects to choose between a guaranteed less preferred food vs. a more preferred food, which was however, delivered only 50% of the time (a stone being delivered the rest of time). We compared identically raised adult wolves and dogs and found that in line with the differing feeding ecologies of the two species and their explorative tendencies, wolves were more risk prone than dogs.


Fetal growth restriction and pulmonary hypertension in premature infants with bronchopulmonary dysplasia.
To identify the association between birth weight (BW)-for-gestational age (GA) and pulmonary hypertension (PHTN) at 36 weeks in infants with moderate-severe bronchopulmonary dysplasia (BPD). In this retrospective cohort study, we followed 138 premature infants (≤ 28 weeks) with moderate and severe BPD (National Institutes of Health consensus definition) born at Prentice Women's Hospital between 2005 and 2009. BW percentiles were calculated using the Fenton growth curve for premature infants. PHTN was determined using a standardized algorithm of echocardiogram review at 36 weeks. Logistic regression was used to evaluate the associations between BW percentile subgroups and PHTN, taking into account antenatal and neonatal factors that were related to PHTN. PHTN was associated with small BW-for-GA, ranging from thresholds of <10th to <25th percentile (P<0.001). These associations remained significant when comparing BW <25th percentile to the reference group (50 to 89 th percentile); after adjustment for GA, gender, multiple gestation, race/ethnicity (odds ratio (OR)=4.2; 95% confidence interval (CI)=1.5, 12.1); and after further adjustment for maternal vascular disease, intrauterine infection, oligohydramnios and relevant postnatal factors (OR=5.7; 95% CI=1.5, 21.2). Longitudinal follow-up of this cohort showed a trend toward higher morbidity and death among PHTN infants with BW <25th percentile. BW-for-GA is an important predictor of PHTN in premature infants with moderate-severe BPD. Our findings contribute to the growing evidence supporting fetal mechanisms of later onset pulmonary vascular disease.


[Clinical studies on chronic prostatitis and prostatitis-like syndrome (4). The kampo treatment for intractable prostatitis].
Kampo treatment was attempted in cases of chronic nonbacterial prostatitis and prostatitis-like syndrome which was intractable or recurred when treated with western medicine. The clinical effects of Kampo treatment were excellent in 21.3% with an efficacy rate of 67.2% for the cases with chronic non-bacterial prostatitis, and excellent in 19.5% with an efficacy rate of 52.4% in the cases with prostatitis-like syndrome. When the clinical effects were compared with those of western therapy performed in the cases which had recurrence, Kampo treatment showed more excellent effects (p less than 0.1) for both types of disease, and the treatment with Chinese medicine was suggested useful. In a comparison of the effects between the cases given only Kampo treatment and those given both Kampo treatment and western treatment using anti-inflammatory agents, no difference was seen in the cases with the prostatitis-like syndrome, but in the cases with chronic non-bacterial prostatitis, the effects were better in the concomitant treatment group than in the group given only Kampo treatment (p less than 0.1). The response to the Kampo treatment differed depending on the type of disease. Among the antibacterial agents used concomitantly in the cases of chronic non-bacterial prostatitis, new-quinolones showed better results than ST compounds or tetracyclines, but no statistically significant differences were seen among the drugs. Of the Kampo drugs used, Keisibukuryogan and Simotuto showed high clinical usefulness in both types of disease and there was no statistically significant difference among the other drugs. The incidence rate of side effects (Goji) due to Kampo treatment was 6.3% and was higher in patients administered Keisibukuryogan.


Minor fetal sonographic findings in autism spectrum disorder.
Autism spectrum disorder (ASD) is more prevalent in the population than ever before. It is debatable whether this is a real increase in incidence, a change in the diagnostic criteria, or both. The diagnosis is usually made by age 3 years; therefore, obstetricians and fetal-maternal specialists generally display limited awareness of the disorder. Unlike fetuses with chromosomal diseases, which have distinctive physical anomalies, some fetuses that eventually will develop ASD have minor physical anomalies. This is even truer in pregnant women who already have a child with ASD. Those fetuses have a 20 times higher risk of developing ASD than the general population. The more frequent minor physical changes that may be potentially detected by ultrasound are as follows: changes in head circumference (that become more noticeable after 6 months of age), the ratio between the second and the fourth digits, left handedness, and palatal changes. Obstetricians, Maternal - Fetal Medicine specialists, Pediatricians, Sonographers After completing this CME activity, physicians should better able to classify the increasing prevalence of this disorder, and to assess the minor physical changes in fetuses that some may be seen on ultrasound during pregnancy.


Activation of contraction in cat ventricular myocytes: effects of low Cd(2+) concentration and temperature.
The effects of Cd(2+) (20 microM) and different bath temperatures were used to study the contributions of two separate triggering mechanisms, L-type Ca(2+) current (I(Ca)) and reverse mode Na(+)/Ca(2+) exchange, to excitation-contraction (E-C) coupling in cat ventricular myocytes. Ionic currents and cell shortening were studied with patch pipettes filled with K(+)-containing internal solution and discontinuous ("switch") voltage clamp. Superfusion with Cd(2+) blocked cell shortening that closely mirrored the block of I(Ca); the voltage dependence of Cd(2+)-induced reduction in contraction was bell-shaped, displaying minima at test potentials below -10 mV and above +50 mV and a maximum at about +20 mV. Cd(2+)-insensitive cell shortening was blocked by ryanodine (10 microM) and Ni(2+) (4-5 mM). When an action potential was used as the command waveform for the voltage clamp (action potential clamp), Cd(2+) reduced contraction to approximately 60 +/- 7% of control cell shortening (n = 7). The remaining contraction was blocked by ryanodine and Ni(2+). Superfusion with nifedipine (10 microM) caused nearly identical effects to Cd(2+). The voltage dependence of contraction was sigmoidal at temperatures above 34 degrees C but bell-shaped below 30 degrees C. When Cd(2+) was added to superfusate, contraction was abolished at 25 degrees C (to 6 +/- 3% of control) but reduced only modestly at 34 degrees C (to 65 +/- 13% of control, test potential +10 mV, n = 4, P < 0.01). These results indicate that 1) there is a component of contraction that is sensitive to I(Ca) antagonists, and the block is equivalent with either organic or inorganic antagonists; 2) the contribution of Na(+)/Ca(2+) exchange to triggering of contraction under our experimental conditions is fairly linear throughout the entire voltage range tested; 3) the contribution of I(Ca) is superimposed on this background component contributed by the Na(+)/Ca(2+) exchanger; and 4) triggering via the exchanger is temperature-dependent, providing a major contribution at physiological temperatures but failing at temperatures below 30 degrees C in a nearly all-or-none fashion.


Barriers, facilitators and attitudes influencing health promotion activities in general practice: an explorative pilot study.
The number of chronically ill patients increases every year. This is partly due to an unhealthy lifestyle. However, the frequency and quality of (evidence-based) health promotion activities conducted by Dutch general practitioners (GPs) and practice nurses (PNs) are limited. The aim of this pilot study was to explore which lifestyle interventions Dutch GPs and PNs carry out in primary care, which barriers and facilitators can be identified and what main topics are with respect to attitudes towards health promoting activities. These topic areas will be identified for a future, larger scale study. This qualitative study consisted of 25 semi-structured interviews with sixteen GPs and nine PNs. ATLAS.ti was used to analyse the transcripts of the interviews. All GPs and PNs said they discuss lifestyle with their patients. Next to this, GPs and PNs counsel patients, and/or refer them to other disciplines. Only few said they refer patients to specific lifestyle programs or interventions in their own practice or in the neighbourhood. Several barriers and facilitators were identified. The main topics as barriers are: a lack of patients' motivation to make lifestyle changes, insufficient reimbursement, a lack of proven effectiveness of interventions and a lack of overview of health promoting programs in their neighbourhood. The most cited facilitators are availability of a PN, collaboration with other disciplines and availability of interventions in their own practice. With respect to attitudes, six different types of GPs were identified reflecting the main topics that relate to attitudes, varying from 'ignorer' to 'nurturer'. The topics relating to PNs attitudes towards health promotion activities, were almost unanimously positive. GPs and PNs all say they discuss lifestyle issues with their patients, but the health promotion activities that are organized in their practice vary. Main topics that hinder or facilitate implementation are identified, including those that relate to attitudes of GPs and PNs.


Superoxide production by digitonin-stimulated guinea pig granulocytes. The effects of N-ethyl maleimide, divalent cations; and glycolytic and mitochondrial inhibitors on the activation of the superoxide generating system.
N-ethylmaleimide, divalent cations, ethylene glycol bis (beta aminoethyl ether) N,N,N',N',-tetraacetate, 2-deoxyglucose, cyanide, and dinitrophenol were examined for their effect on the ability of guinea pig granulocytes to generate superoxide (O(2) (-)) when stimulated by digitonin. N-ethylmaleimide (1 mM) inhibits only when added before complete activation of the O(2) (-) generating system, and at lower concentrations (0.05-0.2 mM) slows the activation process. Ca(++) is required for maximum O(2) (-) generation, and Mg(++) decreases the amount of Ca(++) required. Ethylene glycol bis (beta aminoethyl ether) N,N,N',N',-tetraacetate (10 mM) inhibits only if added before complete activation. Incubation of cells in 2-DOG causes a time- and concentration-dependent inhibition of O(2) (-) generation. It also increases the time required for activation of this system. Cyanide and dinitrophenol increase the rate of O(2) (-) production. However, when these compounds are added to cells whose O(2) (-) production is partially inhibited by incubation in 2-deoxyglucose, complete inhibition results. If cyanide or dinitrophenol is added after activation of 2-deoxyglucose-treated cells, no further inhibition occurs. On the basis of the above results, we conclude that the activation of the O(2) (-) generating system is N-ethylmaleimide sensitive, Ca(++) dependent, and energy requiring, but that the activity of the enzyme system in the cell is not.


[Paralytic ileus in pheochromocytoma. Possible correlation with an attempt at adrenal phlebography].
Following adrenal phlebography, obstruction of the large bowel associated with adrenergic crisis was observed in a 60 year old patient with pheochromocytoma. As in other published cases of ileus associated with pheochromocytoma, high urinary catecholamine concentrations were found in our patient and the tumor resected at surgery was large. As phlebography immediately preceded the onset of ileus and hypertensive crisis, it is postulated that angiography led to massive secretion of catecholamines, which caused the hypertensive crisis as well as the ileus. The possible mechanisms by which phlebography may lead to adrenergic crisis are discussed. It is concluded that in suspected pheochromocytoma all angiographic examinations should be carried out under simultaneous treatment with alpha-blocking agents.


Identification of novel leishmanicidal molecules by virtual and biochemical screenings targeting Leishmania eukaryotic translation initiation factor 4A.
Leishmaniases are neglected parasitic diseases in spite of the major burden they inflict on public health. The identification of novel drugs and targets constitutes a research priority. For that purpose we used Leishmania infantum initiation factor 4A (LieIF), an essential translation initiation factor that belongs to the DEAD-box proteins family, as a potential drug target. We modeled its structure and identified two potential binding sites. A virtual screening of a diverse chemical library was performed for both sites. The results were analyzed with an in-house version of the Self-Organizing Maps algorithm combined with multiple filters, which led to the selection of 305 molecules. Effects of these molecules on the ATPase activity of LieIF permitted the identification of a promising hit (208) having a half maximal inhibitory concentration (IC50) of 150 ± 15 μM for 1 μM of protein. Ten chemical analogues of compound 208 were identified and two additional inhibitors were selected (20 and 48). These compounds inhibited the mammalian eIF4I with IC50 values within the same range. All three hits affected the viability of the extra-cellular form of L. infantum parasites with IC50 values at low micromolar concentrations. These molecules showed non-significant toxicity toward THP-1 macrophages. Furthermore, their anti-leishmanial activity was validated with experimental assays on L. infantum intramacrophage amastigotes showing IC50 values lower than 4.2 μM. Selected compounds exhibited selectivity indexes between 19 to 38, which reflects their potential as promising anti-Leishmania molecules.


[Motor responses in transcranial magnetic stimulation and somatosensory evoked potentials in patients with pain syndromes].
The main goal was to evaluate the motor and somatosensory systems by recording evoked motor responses (EMRs) during transcranial magnetic stimulation (TMS) and somatosensory evoked potentials (SEPs) in patients with neurogenic pain syndromes before and after implantation of the systems for chronic antipain epidural stimulation. Fifteen patients with neurogenic pain syndromes and a control group of 15 apparently healthy examinees were examined. The patients were found to have a significant reduction in the motor thresholds of EMRs during TMS and an increase in the amplitude of EMRs after implantations of the systems. There were no significant changes in the amplitude-time characteristics of short SEPs as compared to the healthy examinees and after implantation of the systems. Analysis of the amplitude-time characteristics of long SEPs in these patients revealed a significant increase in the amplitude of the component P250 as compared to the normal values and its decrease after implantation of the systems.


Rat Pancreatic Beta-Cell Culture.
In this chapter, we describe the methods used to culture mainly rat pancreatic beta cells. We consider necessary to use this approach to get more information about physiological, biophysical, and molecular biology characteristics of primary beta cells. Most of the literature published has been developed in murine and human beta-cell lines. However, there are many differences between tumoral cell lines and native cells because, in contrast to cell lines, primary cells do not divide. Moreover, cell lines can be in various stages of the cell cycle and thus have a different sensitivity to glucose, compared to primary cells. Finally, for these reasons, cell lines can be heterogeneous, as the primary cells are. The main problem in using primary beta cells is that despite that they are a majority within a culture they appear mixed with other kinds of pancreatic islet cells. If one needs to identify single cells or has an only beta-cell composition, it is necessary to process the sample further. For example, one may obtain an enriched population of beta cells using fluorescence-activated cell sorting or identify single cells with the reverse hemolytic plaque assay. The other problem is that cells change with time in culture, becoming old and losing some characteristics, and so must be used preferentially during the first week. The development of human beta-cell cultures is of importance in medicine because we hope one day to be able to transplant viable beta cells to patients with diabetes mellitus type 1.


CR3 (Mac-1, alpha M beta 2, CD11b/CD18) and Fc gamma RIII cooperate in generation of a neutrophil respiratory burst: requirement for Fc gamma RIII and tyrosine phosphorylation.
Cooperation among plasma membrane receptors in activating signal transduction cascades is not well understood. For almost 20 years, it has been clear that when a particulate foreign body is opsonized with complement as well as IgG, the efficiency of IgG effector functions is markedly enhanced. However, the molecular mechanisms involved in cooperation between IgG Fc receptors and complement receptors have not been elucidated. In this work, we show that when human neutrophils (PMN) are plated on a surface coated with both anti-CR3 and anti-Fc gamma RIII antibodies, the respiratory burst which occurs is equivalent to that stimulated by anti-Fc gamma RII. The CR3 ligand iC3b is as effective as anti-CR3 for cooperating with anti-Fc gamma RIII in generation of a respiratory burst. The synergy between CR3 and Fc gamma RIII for activating the NADPH oxidase is abolished by Fab of anti-Fc gamma RII. Nonetheless, the observed synergy is not an artifact of unintended Fc gamma RII ligation, since (a) only this combination of antibodies works to generate H2O2; (b) coating plates with either of the antibodies alone cannot activate the respiratory burst at any dose; (c) LAD (CR3 deficient) cells, which are perfectly competent to mount a respiratory burst when Fc gamma RII is engaged, are incapable of activating the respiratory burst when adherent to wells coated with anti-Fc gamma RIII and anti-CR3; (d) direct engagement of Fc gamma RII activates the respiratory burst by a pathway pharmacologically distinguishable from the synergistic respiratory burst. Fc gamma RIII/CR3 synergy is abolished by cytochalasin B and herbimicin, suggesting that both the actin cytoskeleton and tyrosine phosphorylation are necessary for activation of the synergistic respiratory burst. Further analysis shows that CR3 and Fc gamma RIII have distinct roles in activation of this Fc gamma RII-dependent assembly of the NADPH oxidase. Ligation of CR3 is sufficient to lead to Fc gamma RII association with the actin cytoskeleton on the adherent PMN surface. Coligation of Fc gamma RIII is required for tyrosine phosphorylation of Fc gamma RII. These data are consistent with a model in which phosphorylation of Fc gamma RII or a closely associated substrate initiates activation of a signal transduction pathway leading to oxidase assembly. These are the first data to demonstrate a molecular mechanism for synergy between IgG Fc and complement receptors in activation of phagocyte effector functions.


Initial system design method for non-rotationally symmetric systems based on Gaussian brackets and Nodal aberration theory.
Freeform surfaces play important roles in improving the imaging performance of off-axis optical systems. However, for some systems with high requirements in specifications, the structure of the freeform surfaces could be very complicated and the number of freeform surfaces could be large. That brings challenges in fabrication and increases the cost. Therefore, to achieve a good initial system with minimum aberrations and reasonable structure before implementing freeform surfaces is essential for optical designers. The already existing initial system design methods are limited to certain types of systems. A universal tool or method to achieve a good initial system efficiently is very important. In this paper, based on the Nodal aberration theory and the system design method using Gaussian Brackets, the initial system design method is extended from rotationally symmetric systems to general non-rotationally symmetric systems. The design steps are introduced and on this basis, two off-axis three-mirror systems are pre-designed using spherical shape surfaces. The primary aberrations are minimized using the nonlinear least-squares solver. This work provides insight and guidance for initial system design of off-axis mirror systems.


The relationship between yeast cell size and cell division in Candida albicans.
The mean size and percentage of budded and unbudded cells of Candida albicans grown in batch culture over a wide range of doubling times have been measured. Cell volume decreased with increased doubling time and a nonlinear approach to an asymptotic minimum was observed. When cells were separated by age according to bud scars, each age showed a similar decrease. During each cell division cycle, size increased slowly during both budded and unbudded periods so that each generation was significantly larger than the preceding. There was no difference in size between the parent portion of budded cells and unbudded cells of the same age. Time-lapse photomicroscopy of cells growing on solid medium showed that cells divide asymmetrically with larger parents having a shorter subsequent cycle time than the smaller daughter, although the time utilized for bud formation was similar. When cells were shifted from a medium supporting a low growth rate and small size to a medium supporting a faster growth rate and larger size, both budded and unbudded cells increased significantly in size. As the doubling time increased, both the budded and unbudded portions of parental and daughter cycles increased.


Leveraging Genomics for Head and Neck Cancer Treatment.
The genomic landscape of head and neck squamous cell carcinoma (HNSCC) has been recently elucidated. Key epigenetic and genetic characteristics of this cancer have been reported and substantiated in multiple data sets, including those distinctive to the growing subset of human papilloma virus (HPV)-associated tumors. This increased understanding of the molecular underpinnings of HNSCC has not resulted in new approaches to treatment. Three Food and Drug Administration-approved molecular targeting agents are currently available to treat recurrent/metastatic disease, but these have exhibited efficacy only in subsets of HNSCC patients, and thus surgery, chemotherapy, and/or radiation remain as standard approaches. The lack of predictive biomarkers to any therapy represents an obstacle to achieving the promise of precision medicine. This review aims to familiarize the reader with current insights into the HNSCC genomic landscape, discuss the currently approved and promising molecular targeting agents under exploration in laboratories and clinics, and consider precision medicine approaches to HNSCC.


Reciprocal tripartite interactions between the Aedes aegypti midgut microbiota, innate immune system and dengue virus influences vector competence.
Dengue virus is one of the most important arboviral pathogens and the causative agent of dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. It is transmitted between humans by the mosquitoes Aedes aegypti and Aedes albopictus, and at least 2.5 billion people are at daily risk of infection. During their lifecycle, mosquitoes are exposed to a variety of microbes, some of which are needed for their successful development into adulthood. However, recent studies have suggested that the adult mosquito's midgut microflora is critical in influencing the transmission of human pathogens. In this study we assessed the reciprocal interactions between the mosquito's midgut microbiota and dengue virus infection that are, to a large extent, mediated by the mosquito's innate immune system. We observed a marked decrease in susceptibility to dengue virus infection when mosquitoes harbored certain field-derived bacterial isolates in their midgut. Transcript abundance analysis of selected antimicrobial peptide genes suggested that the mosquito's microbiota elicits a basal immune activity that appears to act against dengue virus infection. Conversely, the elicitation of the mosquito immune response by dengue virus infection itself influences the microbial load of the mosquito midgut. In sum, we show that the mosquito's microbiota influences dengue virus infection of the mosquito, which in turn activates its antibacterial responses.


Ontogenetic shifts in morphology and resource use of cisco Coregonus artedi.
Two previously described lacustrine cisco Coregonus spp. morphs [i.e. a small (<300 mm fork length, L(F)), low-gillraker (≤44) morph and a large (≥300 mm L(F) ), high-gillraker (≥45) morph] from Great Slave Lake, NT, Canada, were found to be synonymous with cisco Coregonus artedi. Geometric body shape did not differ between the two size classes nor could they be differentiated by 24 size-corrected linear measurements, indicating that the two groups had similar phenotypes. Strong, positive correlations between all linear characters and geometric centroid size (a composite variable of fish body length, mass and age) suggested that body morphology changed with age as fish grew. Total gillraker number (N(GR)) increased with L(F) according to: N(GR) = 36.3 + 0.034L(F). Differences in gillraker number and phenotype with age and size were explained by shifts in habitat and trophic resource use. Relative abundance within 0-30, 30-60, 60-90 and >90 m depth strata differed between size classes suggesting that morphology changed when fish shifted their habitat as they grew older. Large C. artedi had lower δ(13)C and slightly higher δ(15)N, indicating greater reliance on pelagic prey resources (i.e. more or larger zooplankton, such as Mysis spp.), compared to small C. artedi, which relied slightly more on benthic prey. Gillraker shape and number have always been used as key diagnostic characters in coregonine taxonomy; based on the findings presented here, ontogenetic shifts should be accounted for in resulting classifications.


Evolution of microtubule organizing centers across the tree of eukaryotes.
The architecture of eukaryotic cells is underpinned by complex arrrays of microtubules that stem from an organizing center, referred to as the MTOC. With few exceptions, MTOCs consist of two basal bodies that anchor flagellar axonemes and different configurations of microtubular roots. Variations in the structure of this cytoskeletal system, also referred to as the 'flagellar apparatus', reflect phylogenetic relationships and provide compelling evidence for inferring the overall tree of eukaryotes. However, reconstructions and subsequent comparisons of the flagellar apparatus are challenging, because these studies require sophisticated microscopy, spatial reasoning and detailed terminology. In an attempt to understand the unifying features of MTOCs and broad patterns of cytoskeletal homology across the tree of eukaryotes, we present a comprehensive overview of the eukaryotic flagellar apparatus within a modern molecular phylogenetic context. Specifically, we used the known cytoskeletal diversity within major groups of eukaryotes to infer the unifying features (ancestral states) for the flagellar apparatus in the Plantae, Opisthokonta, Amoebozoa, Stramenopiles, Alveolata, Rhizaria, Excavata, Cryptophyta, Haptophyta, Apusozoa, Breviata and Collodictyonidae. We then mapped these data onto the tree of eukaryotes in order to trace broad patterns of trait changes during the evolutionary history of the flagellar apparatus. This synthesis suggests that: (i) the most recent ancestor of all eukaryotes already had a complex flagellar apparatus, (ii) homologous traits associated with the flagellar apparatus have a punctate distribution across the tree of eukaryotes, and (iii) streamlining (trait losses) of the ancestral flagellar apparatus occurred several times independently in eukaryotes.


Interaction and destabilization of a monoclonal antibody and albumin to surfaces of varying functionality and hydrophobicity.
Protein products come into contact with many surfaces of differing wettability during bioprocessing, formulation and delivery, but corresponding data for the adsorbed conformations and the associated force of adhesion (F(ad)) is sparse. Here we have generated a series of hydrophilic and hydrophobic surfaces through silanization of silica with various terminal groups, characterizing the surface energies and droplet contact angles. F(ad) measured by atomic force microscopy for oriented monolayers of a human monoclonal antibody (mAb-1) clearly distinguished hydrophobic surfaces (low F(ad) values) from hydrophilic surfaces (high F(ad) values). High F(ad) for a methoxy capped polyethylene glycol (1000 MW) surface supports the interaction of mAb-1 with buried ethylene oxide groups, consistent with mAb-1 compression into a distorted brush border. Solid state circular dichroism showed that mAb-1 (β-sheet) or albumin (α-helical) adsorbed to bare silica beads largely retained their secondary structures. However, the extent of structural loss upon protein adsorption to functionalized silica beads could not be simply correlated to hydrophilic/hydrophobic surface interaction as seen for the F(ad) measurements. For example, of the hydrophilic surfaces mAb-1 unfolded notably more when adsorbed to the aminopropyl surface, and of the hydrophobic surfaces both mAb-1 and albumin retained most secondary structure when adsorbed to the perfluorooctyl surface (consistent with the lipophobic perfluorinated moiety limiting exposure of the protein hydrophobic core). The data show that F(ad) values are not necessarily predictive of the subsequent extent of structural relaxation, and that significant structural loss is evident for proteins adsorbed to both hydrophilic and hydrophobic surfaces.


Topological spin-orbit interaction of light in anisotropic inhomogeneous subwavelength structures.
Spin-orbit interaction resulting from spatial polarization state manipulation is demonstrated. Polarization-state manipulation is achieved by utilizing the effective birefringent nature of subwavelength structures acting as an anisotropic inhomogeneous medium. Experimental verification is obtained by measuring the effect of the unavoidable spin-dependent Pancharatnam-Berry phase modulation on the far-field diffraction pattern of the beam. Unlike the usual dynamic spin-orbit interaction that splits spin states in the temporal frequency (energy) domain, this topological spin-orbit interaction results in the splitting of spin states degenerated by their spatial frequencies (momentum).


"I have failed to separate my HIV from this pain": the challenge of managing chronic pain among people with HIV.
Pain is a highly prevalent and burdensome symptom among people with HIV (PWH). This study aims to identify how the experience of living with HIV and chronic pain influences pain beliefs, health-seeking and pain management. Thirty-nine purposively sampled PWH with chronic pain (sample characteristics = 61% women, 79% Black, Asian and minority ethnic groups, 18% men who have sex with men, 45-54 median age category) participated in focus groups in London. Focus groups were co-facilitated with community members. Transcripts wereanalysed using a thematic approach. Findings revealed that HIV stigma, fractured care pathways, and general practitioners' lack of HIV training are barriers to supported pain management. Unaddressed pain results in poorer mental health and reduced quality of life, which has important clinical implications for HIV treatment adherence. Creating HIV-specific pain resources, activating social networks, and pain self-management techniques are potential solutions. Person-centred assessment and HIV training is needed to help clinicians identify PWH with chronic pain. Clear guidelines need to be developed to identify which health service providers are responsible for chronic pain management in PWH. This study generated a refined version of the Fear Avoidance Model that introduces a dimension of HIV-specific behaviours that impact PWHs seeking chronic pain management.


Cell-type-specific cytotoxicity of anti-CD4 and anti-CD8 ricin immunotoxins against human alloreactive T-cell clones.
Potent T-cell subset-directed immunotoxins (ITs) were generated by conjugating the anti-CD4 monoclonal antibody (MoAb) G17-2 and the anti-CD8 MoAb G10.1 to the ribosome-inhibitory protein, ricin. The cell-type-specific cytotoxicities of the generated ITs were evaluated at the clonal level using human alloreactive T-cell clones. The kinetics of anti-CD4 ricin-induced inactivation of protein synthesis in target CD4+ cloned T-cells was first order with no detectable lag period and a maximum rate of 0.07 logs per hour (t10 = 13.6 hours; first-order rate constant/K = 0.17 hr-1). The alloantigen specific lytic function of the CD4+ cytolytic T-cell clone JMAC28 was acutely sensitive to anti-CD4 ricin, and no residual lytic activity against allogeneic targets was detectable 24 hours after treatment with as little as 0.5 mmol/L anti-CD4 ricin. Notably, both anti-CD4 ricin and anti-CD8 ricin elicited a selective and dose-dependent inhibition of clonal proliferation of target T-cell clones with a maximum kill of greater than 3 logs at 5 nmol/L. No significant "bystander effects" were observed for non-target cells. Bone marrow progenitor cells CFU-GM, BFU-E, and CFU-GEMM were only minimally affected by either IT. We conclude that these ITs show considerable potential for effective depletion of T-cell subpopulations from allogeneic donor marrow grafts for clinical graft-versus-host disease (GVHD) prophylaxis.


Animal models of serotonergic psychedelics.
The serotonin 5-HT(2A) receptor is the major target of psychedelic drugs such as lysergic acid diethylamide (LSD), mescaline, and psilocybin. Serotonergic psychedelics induce profound effects on cognition, emotion, and sensory processing that often seem uniquely human. This raises questions about the validity of animal models of psychedelic drug action. Nonetheless, recent findings suggest behavioral abnormalities elicited by psychedelics in rodents that predict such effects in humans. Here we review the behavioral effects induced by psychedelic drugs in rodent models, discuss the translational potential of these findings, and define areas where further research is needed to better understand the molecular mechanisms and neuronal circuits underlying their neuropsychological effects.


CHEMICAL PACEMAKERS : PART I. CATALYTIC BRAIN IRON. PART II. ACTIVATION ENERGIES OF CHEMICAL PACEMAKERS.
1. Iron spicules found in the brains of general paretic patients are formed from endogenous brain iron normally present in another form. This supports our earlier view that the micro value of 16,000 obtained in advanced paretics for alpha brain wave frequencies as a measure of cortical respiration comes about from the slowing of an iron catalyzed link in cortical respiration such as would result from the reduction of available cytochrome and its oxidase, thus making this step a chemical pacemaker. 2. To test the basic theory of chemical pacemakers, a study was made of the succinate-fumarate enzyme system containing succino-dehydrogenase and cytochrome-cytochrome oxidase acting sequentially. 3. The micro value for the unpoisoned system is 11,200 +/- 200 calories. 4. According to theory, the addition of a critical amount of cyanide known to be a specific poison of the cytochrome-cytochrome oxidase system (and not of the dehydrogenase) should shift the micro cleanly to 16,000 calories, and it does. 5. According to theory, selenite, a specific poison for the dehydrogenase, should stop all respiration without shifting the micro. This also is found to be the case. 6. The theory also predicts that if the micro is shifted from 11,000 +/- to 16,000 +/- by cyanide, the subsequent addition of a critical amount of selenite should shift the micro back again to 11,000 +/- calories, and this is found to occur. 7. It is concluded that approximately 11,000 calories is the energy of activation of the succino-dehydrogenase-catalyzed step and 16,000 calories is that for the cytochrome-cytochrome oxidase-catalyzed step. These two values are encountered more frequently than any others in physiological systems. It is to be recalled that a shift of micro for alpha brain wave frequencies from 11,000 to 16,000 calories occurs in the course of advancing syphilitic brain infection and is accompanied by a change in form of brain iron.


Highest permanent human habitation.
The aim of this analysis was to determine the altitude of the highest permanent human habitation in the hope that this will throw some light on what determines the highest altitude that a community can tolerate indefinitely. A number of places where people have lived at very high altitudes for long periods of time are reviewed. Individuals have lived for as long as 2 yr at an altitude of 5950 m, and there was a miner's camp at 5300 m for several years. The highest permanently inhabited town in the world at the present time appears to be La Rinconada, a mining village of over 7000 people in southern Peru at an altitude of up to 5100 m, which has been in existence for over 40 yr. The altitude of the highest permanent human habitation is determined partly by economic factors, rather than solely by human tolerance to hypoxia.


Surgical treatment of spinal intradural arachnoid cysts using endoscopy.
Spinal intradural arachnoid cysts are a rare cause of spinal cord compression. Since 2000, the authors have treated patients using 2- or 3-level hemilaminectomy or laminectomy followed by partial cyst wall resection as well as endoscopic inspection and fenestration of the cyst wall. They evaluated the usefulness and reliability of endoscopic treatment for this clinical entity based on long-term follow-up results. Between 1997 and 2003, 11 patients (3 males and 8 females) with spinal intradural arachnoid cysts were treated, and the authors conducted a retrospective review of these cases. Before 2000, 5 patients were surgically treated without the use of endoscopic techniques. During that time, more than 4 levels of hemilaminectomy were performed to expose and remove cyst walls that extended longitudinally over the spinal axis. Beginning in 2000, endoscopy was used in all 6 cases. Up to 3 levels of hemilaminectomy or 2 levels of laminectomy were performed, and the cyst wall was resected through the bone window. An endoscope was inserted into the cyst cavity and moved in the cranial and caudal direction to fenestrate the cyst wall, resulting in communication of the cyst cavity with the subarachnoid space. Postoperatively, the neurological symptoms of all patients improved. During long-term follow-up (mean 114.8 months), none of the patients treated with or without endoscopy experienced recurrent cyst formation. Endoscopic techniques allow neurosurgeons to treat spinal intradural arachnoid cysts less invasively than with standard surgical approaches. Although the number of cases reviewed in this report is small, the data suggest that the use of endoscopy can be an important option in the surgical treatment of spinal arachnoid cysts.


A metabolic unit for studies on human nutrition.
In clinical nutrition we are used to dealing with the clinical management of patients, but of equal or greater importance is the study of how nutrition affects the development of diseases or modifies its manifestations. This field is complex and links physiological studies of nutrition to the epidemiological analyses which form the basis of thinking in public health in Mexico today. Thus a number of studies have investigated the nutritional risk factors leading to the development of diseases such as heart disease and cancer (1-10). This epidemiological research requires the difficult task of accurately assessing the food consumption of individuals: with poor methodologies the chances of erroneous results are very high. This has implications for both group and individual comparison. Physiological studies on the effects of highly controlled changes in food intake on risk factors then allows the epidemiology to be interpreted in metabolic terms. In this paper we illustrate some of the benefits of metabolic studies and some of the requirements for this successful conduct.


Organoid modeling of lung-resident immune responses to SARS-CoV-2 infection.
Tissue-resident immunity underlies essential host defenses against pathogens, but analysis in humans has lacked in vitro model systems where epithelial infection and accompanying resident immune cell responses can be observed en bloc. Indeed, human primary epithelial organoid cultures typically omit immune cells, and human tissue resident-memory lymphocytes are conventionally assayed without an epithelial infection component, for instance from peripheral blood, or after extraction from organs. Further, the study of resident immunity in animals can be complicated by interchange between tissue and peripheral immune compartments. To study human tissue-resident infectious immune responses in isolation from secondary lymphoid organs, we generated adult human lung three-dimensional air-liquid interface (ALI) lung organoids from intact tissue fragments that co-preserve epithelial and stromal architecture alongside endogenous lung-resident immune subsets. These included T, B, NK and myeloid cells, with CD69+CD103+ tissue-resident and CCR7- and/or CD45RA- TRM and conservation of T cell receptor repertoires, all corresponding to matched fresh tissue. SARS-CoV-2 vigorously infected organoid lung epithelium, alongside secondary induction of innate cytokine production that was inhibited by antiviral agents. Notably, SARS-CoV-2-infected organoids manifested adaptive virus-specific T cell activation that was specific for seropositive and/or previously infected donor individuals. This holistic non-reconstitutive organoid system demonstrates the sufficiency of lung to autonomously mount adaptive T cell memory responses without a peripheral lymphoid component, and represents an enabling method for the study of human tissue-resident immunity.


Dependent personality features in a complex case of borderline personality disorder.
Borderline personality disorder is a complex disease model as it encompasses a diversity of pathological personality traits and psychopathological symptoms. It is not surprising, therefore, that it is often manifested by personality disorders across all three clusters and accompanied by other mental (Axis I) disorders. This melange makes both psychological treatment and pharmacotherapy especially challenging, and this paper describes the case of a particularly complex case of a 33-year-old Romanian patient, who has a history of severe deprivation in childhood, mood and substance use disorder in association with borderline pathology. In the course of treatment from many sources and interventions, it has become clear that dependence is a key component of the pathology and has been rewarded with a degree of success in management. Copyright © 2016 John Wiley & Sons, Ltd.


Provider-initiated HIV testing and counseling among tuberculosis patients in Kassala, Eastern Sudan.
Because of the overlapping global incidence of tuberculosis (TB) and human immunodeficiency virus (HIV) infections, collaborative efforts are required for successful TB and HIV control programs. The current study was conducted at Kassala Hospital in Eastern Sudan and investigated the implementation of provider-initiated HIV testing and counseling (PITC) for patients infected with TB. Using a cross-sectional study design, patients who had been recently diagnosed with TB between January and December 2010 were consecutively enrolled. A total of 858 newly infected TB patients were enrolled in the study. Of these patients, 152 patients (17.7%) were given counseling, and 109 patients (12.7%) underwent HIV testing. The overall HIV infection rate among those tested was 18.3%. From a multivariate analysis, female sex (OR=17.0, 95% CI=8.7-33.1; P<0.001), education level below secondary education (OR=2.6, 95% CI=1.6-4.1; P<0.001), rural residency (OR=1.7, 95% CI=1.3-2.9; P=0.001), and non-governmental employee status (OR=10.4, 95% CI=6.7-16.3; P<0.001) were each associated with lower rates of PITC. Thus, in this setting, the frequency of PITC is low among TB-infected patients and is especially low for females, those of low educational status, and non-governmental employees.


Quality of indoor residential air and health.
About 90% of our time is spent indoors where we are exposed to chemical and biological contaminants and possibly to carcinogens. These agents may influence the risk of developing nonspecific respiratory and neurologic symptoms, allergies, asthma and lung cancer. We review the sources, health effects and control strategies for several of these agents. There are conflicting data about indoor allergens. Early exposure may increase or may decrease the risk of future sensitization. Reports of indoor moulds or dampness or both are consistently associated with increased respiratory symptoms but causality has not been established. After cigarette smoking, exposure to environmental tobacco smoke and radon are the most common causes of lung cancer. Homeowners can improve the air quality in their homes, often with relatively simple measures, which should provide health benefits.


Helicobacter pylori and peptic ulcer disease. Current evidence for management strategies.
To review current evidence for primary care physicians who manage Helicobacter pylori in peptic ulcer disease. MEDLINE was searched to August 1997 for randomized controlled trials, systematic overviews, and consensus reports. High-quality recent reviews were often found. Randomized controlled trials presented as abstracts at recent meetings were reviewed. Helicobacter pylori is found in most case of duodental and gastric ulcer, and eradication of H pylori leads to "cure" of ulcer disease and prevention of ulcer complications. Eradication of H pylori is not indicated for gastroesophageal reflux disease. No evidence indicates that screening asymptomatic individuals for H pylori infection reduces the risk of subsequent development of gastric cancer. Controversial areas are the role of H pylori in functional dyspepsia and screening for H pylori before initiating nonsteroidal anti-inflammatory drugs. In primary care, H pylori can be detected using serologic tests or urea breath tests (UBT), but only UBTs can be used to confirm eradication. Whether patients suspected of having ulcers can be managed with an H pylori test-and-treat strategy without initial investigation is controversial. The first-line recommended treatment is 1 week of twice daily triple therapy with a proton pump inhibitor, clarithromycin (Biaxin), and amoxicillin (e.g., Amoxil), or metronidazole (Flagyl). Helicobacter pylori eradication should be first-line therapy in primary care for infected patients with peptic ulcers. Effective H pylori testing methods and treatments are now available.


Prevalence of Multiple Coronary Artery Disease Risk Factors in Kerman: A Population-Based Study in Southeast Iran.
The risk of disease with 1 risk factor is increased by the presence of additional risk factors. The goal of this study was to assess the prevalence of multiple coronary artery disease (CAD) risk factors among adults in Kerman, Iran, to identify the population groups most at risk. The present study included 5900 adults aged between 15 and 75 years in 2011 in Kerman, Iran. They were selected by 1-stage cluster sampling. Blood pressure, fasting blood glucose, lipids, and 6 CAD risk factors were assessed in the study population. Standardized prevalence rates were compared between the genders and age groups using the χ2 test. A P<0.05 was considered statistically significant. All the analyses were performed using Stata, version 14.1. Overall 93.1%, 57.8%, and 26.2% of the patients had at least 1, 2, and 3 risk factors, respectively. The most frequent combinations of risk factors were dyslipidemia plus low physical activity (37.9%), metabolic syndrome (27.7%), dyslipidemia plus abdominal obesity (14.1%), dyslipidemia plus hypertension (HTN) (10%), dyslipidemia plus smoking (8.6%), and HTN plus abdominal obesity (6.3%). The rate of diabetes mellitus plus HTN plus dyslipidemia was 2.8%. Both prevalence and multiplicity of the risk factors increased by age, and they were mostly higher in the women. Almost 60% of the patients had at least 2 CAD risk factors and only 7% were risk-factor-free. Given that the population is ageing, community health authorities should seek to lessen the burden of these risk factors, almost all of which are preventable.


Stereotactic body radiotherapy as primary therapy for head and neck cancer in the elderly or patients with poor performance.
Stereotactic body radiotherapy (SBRT) is increasingly used to treat a variety of tumors, including head and neck squamous cell carcinoma (HNSCC) in the recurrent setting. While there are published data for re-irradiation using SBRT for HNSCC, there are limited data supporting its use as upfront treatment for locally advanced disease. Here, we describe three patients who received SBRT as the primary treatment for their HNSCC along with a review of the current literature and discussion of future pathways. The three cases discussed tolerated treatment well with manageable acute toxicities and had either a clinical or radiographic complete response to therapy. Head and neck squamous cell carcinoma presents a unique challenge in the elderly, where medical comorbidities make it difficult to tolerate conventional radiation, often given with a systemic sensitizer. For these individuals, providing a shortened course using SBRT may offer an effective alternative.


Oestrogen receptor alpha is required for biochanin A-induced apolipoprotein A-1 mRNA expression in HepG2 cells.
Epidemiological studies have indicated that soya consumption may produce a better plasma lipid profile. The effect may be attributed to the phyto-oestrogens in soya. The red clover (Trifolium pratense) isoflavone biochanin A has a chemical structure similar to those phyto-oestrogens found in soya beans, and is marketed as a nutraceutical for alleviating postmenopausal symptoms. In the present study we investigated the effect of biochanin A on the mRNA expression of ApoA-1 in the hepatic cell line HepG2. Real-time PCR revealed that biochanin A increased ApoA-1 mRNA abundance in cells expressing oestrogen receptor (ER) alpha. Without ERalpha transfection, biochanin A had no effect on mRNA abundance. In order to study the transcriptional control, a fragment of the 5'-flanking region of the ApoA-1 gene was amplified and inserted in a firefly luciferase reporter plasmid. The reporter assay indicated that the transactivation of the ApoA-1 promoter was induced by biochanin A in HepG2 cells transfected with the ERalpha expression plasmid. This induction was reduced by the anti-oestrogen ICI 182,780, whereas the inhibitors of protein kinase (PK) C, PKA, or mitogen-activated kinase (ERK) had no suppressive effect. The present study illustrated that biochanin A might up regulate hepatic apoA-1 mRNA expression through an ER-dependent pathway.


Curcumin: A new candidate for melanoma therapy?
Melanoma remains among the most lethal cancers and, in spite of great attempts that have been made to increase the life span of patients with metastatic disease, durable and complete remissions are rare. Plants and plant extracts have long been used to treat a variety of human conditions; however, in many cases, effective doses of herbal remedies are associated with serious adverse effects. Curcumin is a natural polyphenol that shows a variety of pharmacological activities including anti-cancer effects, and only minimal adverse effects have been reported for this phytochemical. The anti-cancer effects of curcumin are the result of its anti-angiogenic, pro-apoptotic and immunomodulatory properties. At the molecular and cellular level, curcumin can blunt epithelial-to-mesenchymal transition and affect many targets that are involved in melanoma initiation and progression (e.g., BCl2, MAPKS, p21 and some microRNAs). However, curcumin has a low oral bioavailability that may limit its maximal benefits. The emergence of tailored formulations of curcumin and new delivery systems such as nanoparticles, liposomes, micelles and phospholipid complexes has led to the enhancement of curcumin bioavailability. Although in vitro and in vivo studies have demonstrated that curcumin and its analogues can be used as novel therapeutic agents in melanoma, curcumin has not yet been tested against melanoma in clinical practice. In this review, we summarized reported anti-melanoma effects of curcumin as well as studies on new curcumin formulations and delivery systems that show increased bioavailability. Such tailored delivery systems could pave the way for enhancement of the anti-melanoma effects of curcumin.


Temperature and Nutrient Levels Correspond with Lineage-Specific Microdiversification in the Ubiquitous and Abundant Freshwater Genus Limnohabitans.
Most freshwater bacterial communities are characterized by a few dominant taxa that are often ubiquitous across freshwater biomes worldwide. Our understanding of the genomic diversity within these taxonomic groups is limited to a subset of taxa. Here, we investigated the genomic diversity that enables Limnohabitans, a freshwater genus key in funneling carbon from primary producers to higher trophic levels, to achieve abundance and ubiquity. We reconstructed eight putative Limnohabitans metagenome-assembled genomes (MAGs) from stations located along broad environmental gradients existing in Lake Michigan, part of Earth's largest surface freshwater system. De novo strain inference analysis resolved a total of 23 strains from these MAGs, which strongly partitioned into two habitat-specific clusters with cooccurring strains from different lineages. The largest number of strains belonged to the abundant LimB lineage, for which robust in situ strain delineation had not previously been achieved. Our data show that temperature and nutrient levels may be important environmental parameters associated with microdiversification within the Limnohabitans genus. In addition, strains predominant in low- and high-phosphorus conditions had larger genomic divergence than strains abundant under different temperatures. Comparative genomics and gene expression analysis yielded evidence for the ability of LimB populations to exhibit cellular motility and chemotaxis, a phenotype not yet associated with available Limnohabitans isolates. Our findings broaden historical marker gene-based surveys of Limnohabitans microdiversification and provide in situ evidence of genome diversity and its functional implications across freshwater gradients.IMPORTANCELimnohabitans is an important bacterial taxonomic group for cycling carbon in freshwater ecosystems worldwide. Here, we examined the genomic diversity of different Limnohabitans lineages. We focused on the LimB lineage of this genus, which is globally distributed and often abundant, and its abundance has shown to be largely invariant to environmental change. Our data show that the LimB lineage is actually comprised of multiple cooccurring populations for which the composition and genomic characteristics are associated with variations in temperature and nutrient levels. The gene expression profiles of this lineage suggest the importance of chemotaxis and motility, traits that had not yet been associated with the Limnohabitans genus, in adapting to environmental conditions.


Lubricant susceptibility of Cellactose and Avicel PH-200: a quantitative relationship.
The lubricant susceptibility of two direct compression excipients, Avicel PH-200 and Cellactose, was determined using a model mix with metamizol sodium (dipyrone) and designed experiments to obtain a quantitative relationship by multiple regression. As a result, a new constant called specific lubricant sensibility Ls is proposed for the comparison of lubricant susceptibility in other drug-excipient systems.


Dynamical insights into (1)pi sigma(*) state mediated photodissociation of aniline.
This article reports a comprehensive study of the mechanisms of H atom loss in aniline (C(6)H(5)NH(2)) following ultraviolet excitation, using H (Rydberg) atom photofragment translational spectroscopy. N-H bond fission via the low lying (1)pi sigma(*) electronic state of aniline is experimentally demonstrated. The (1)pi sigma(*) potential energy surface (PES) of this prototypical aromatic amine is essentially repulsive along the N-H stretch coordinate, but possesses a shallow potential well in the vertical Franck-Condon region, supporting quasibound vibrational levels. Photoexcitation at wavelengths (lambda(phot)) in the range 293.859 nm > or = lambda(phot) > or = 193.3 nm yields H atom loss via a range of mechanisms. With lambda(phot) resonant with the 1(1)pi pi(*) <-- S(0) origin (293.859 nm), H atom loss proceeds via, predominantly, multiphoton excitation processes, resonantly enhanced at the one photon energy by the first (1)pi pi(*) excited state (the 1(1)pi pi(*) state). Direct excitation to the first few quasibound vibrational levels of the (1)pi sigma(*) state (at wavelengths in the range 269.513 nm > or = lambda(phot) > or = 260 nm) induces N-H bond fission via H atom tunneling through an exit barrier into the repulsive region of the (1)pi sigma(*) PES, forming anilino (C(6)H(5)NH) radical products in their ground electronic state, and with very limited vibrational excitation; the photo-prepared vibrational mode in the (1)pi sigma(*) state generally evolves adiabatically into the corresponding mode of the anilino radical upon dissociation. However, as the excitation wavelength is reduced (lambda(phot) < 260 nm), N-H bond fission yields fragments with substantially greater vibrational excitation, rationalized in terms of direct excitation to 1(1)pi pi(*) levels, followed by coupling to the (1)pi sigma(*) PES via a 1(1)pi pi(*)/(1)pi sigma(*) conical intersection. Changes in product kinetic energy disposal once lambda(phot) approaches approximately 230 nm likely indicate that the photodissociation pathways of aniline proceed via direct excitation to the (higher) 2(1)pi pi(*) state. Analysis of the anilino fragment vibrational energy disposal-and thus the concomitant dynamics of (1)pi sigma(*) state mediated photodissociation-provides a particularly interesting study of competing sigma(*) <-- pi and pi(*) <-- pi absorption processes and develops our appreciation of the photochemistry of aromatic amines. It also allows revealing comparisons with simple amines (such as ammonia and methylamine) as well as the isoelectronic species, phenol. This study yields a value for the N-H bond strength in aniline, D(0)(H-anilino) = 31630+/-40 cm(-1).


Computer simulations of the signalling network in FLT3 +-acute myeloid leukaemia - indications for an optimal dosage of inhibitors against FLT3 and CDK6.
Mutations in the FMS-like tyrosine kinase 3 (FLT3) are associated with uncontrolled cellular functions that contribute to the development of acute myeloid leukaemia (AML). We performed computer simulations of the FLT3-dependent signalling network in order to study the pathways that are involved in AML development and resistance to targeted therapies. Analysis of the simulations revealed the presence of alternative pathways through phosphoinositide 3 kinase (PI3K) and SH2-containing sequence proteins (SHC), that could overcome inhibition of FLT3. Inhibition of cyclin dependent kinase 6 (CDK6), a related molecular target, was also tested in the simulation but was not found to yield sufficient benefits alone. The PI3K pathway provided a basis for resistance to treatments. Alternative signalling pathways could not, however, restore cancer growth signals (proliferation and loss of apoptosis) to the same levels as prior to treatment, which may explain why FLT3 resistance mutations are the most common resistance mechanism. Finally, sensitivity analysis suggested the existence of optimal doses of FLT3 and CDK6 inhibitors in terms of efficacy and toxicity.


Epidemiology, sexual risk behavior, and HIV prevention practices of men who have sex with men using GRINDR in Los Angeles, California.
Young men who have sex with men (YMSM) are at alarming risk for HIV acquisition, demonstrating the highest rates of incident infection of any age-risk group. GRINDR is a global positioning service-based social networking application popular with YMSM for sexual partnering. To assess the characteristics of YMSM who use GRINDR, we conducted a computer-assisted self-interview-based survey of 375 YMSM using GRINDR in metropolitan Los Angeles, recruited using the GRINDR platform. The median age was 25 (interquartile range, 22-27) years old, 42.4 % caucasian, 6.4 % African American, 33.6 % Latino, and 14.1 % Asian/Pacific Islander. Participants reported high rates of sexual partnering and unprotected anal intercourse (UAI). The majority (70 %) of those reporting unprotected anal intercourse reported low perception of HIV-acquisition risk. Of the participants, 83.1 % reported HIV testing within the past 12 months; 4.3 % had never been HIV tested. Of the participants, 4.5 % reported HIV-positive serostatus; 51.7 % indicated that they would be interested in participating in a future HIV prevention trial. Latinos were more likely than either caucasians or African Americans to endorse trial participation interest (odds ratio, 1.9; 95 % confidence interval [1.1-3.3]). HIV-positive test results were associated with increased number of anal sex partners in the past 3 months (adjusted odds ratio (AOR), 1.53 [0.97-2.40]), inconsistent inquiry about partners' serostatus (AOR, 3.63 [1.37-9.64]), reporting the purpose for GRINDR use including "friendship" (AOR, 0.17 [0.03-1.06), and meeting a sexual partner in a bookstore in the past 3 months (AOR, 33.84 [0.99-1152]). Men recruited via GRINDR were high risk for HIV acquisition or transmission and interested in clinical trial participation, suggesting potential for this method to be used for recruitment of YMSM to HIV prevention trials.


Autophagy is essential for mitochondrial clearance in mature T lymphocytes.
Macroautophagy plays an important role in the regulation of cell survival, metabolism, and the lysosomal degradation of cytoplasmic material. In the immune system, autophagy contributes to the clearance of intracellular pathogens, MHCII cross-presentation of endogenous Ags, as well as cell survival. We and others have demonstrated that autophagy occurs in T lymphocytes and contributes to the regulation of their cellular function, including survival and proliferation. Here we show that the essential autophagy gene Atg7 is required in a cell-intrinsic manner for the survival of mature primary T lymphocytes. We also find that mitochondrial content is developmentally regulated in T but not in B cells, with exit from the thymus marking a transition from high mitochondrial content in thymocytes to lower mitochondrial content in mature T cells. Macroautophagy has been proposed to play an important role in the clearance of intracellular organelles, and autophagy-deficient mature T cells fail to reduce their mitochondrial content in vivo. Consistent with alterations in mitochondrial content, autophagy-deficient T cells have increased reactive oxygen species production as well as an imbalance in pro- and antiapoptotic protein expression. With much recent interest in the possibility of autophagy-dependent developmentally programmed clearance of organelles in lens epithelial cells and erythrocytes, our data demonstrate that autophagy may have a physiologically significant role in the clearance of superfluous mitochondria in T lymphocytes as part of normal T cell homeostasis.


Combined modality radioimmunotherapy. Promise and peril.
Single-agent radioimmunotherapy (RIT), although potentially useful for slowing solid tumor growth, has not been effective in curing aggressive tumors, such as breast cancer. These cancers typically have p53 mutations and are less susceptible to apoptosis, the apparent mechanism of cell death from low dose-rate radiation. Thus, synergistic or combined modality radioimmunotherapy (CMRIT) agents are needed to increase radiosensitivity for therapeutic enhancement without additive toxicity. To assess synergy in CMRIT in a breast cancer xenograft model, we evaluated RGD peptide EMD 121974, an inhibitor of alpha(v)beta(3) integrin; paclitaxel, an antimicrotubule; IMC-C225, a monoclonal antibody to epidermal growth factor receptor (EGFR); and bcl-2 antisense oligonucleotide G3139. Groups of mice received (90)Y-DOTA-ChL6 in combination with each agent. Tumor size, survival, and blood counts were monitored for efficacy and toxicity. Immunopathologic evaluation of apoptosis was performed at selected time points after RIT and RIT + RGD CMRIT. CMRIT with RGD peptide increased apoptosis and resulted in 57% cures, compared with 0% cures with RIT alone. CMRIT with paclitaxel after RIT increased cures to 88%, compared with 25% cures with RIT before paclitaxel administration. CMRIT with IMC-C225 resulted in up to 20% cures if given before RIT. A time-dependent increase in toxicity was observed with IMC-C225 after RIT. CMRIT with bcl-2 antisense G3139 resulted in no cures and an increased rate of regrowth compared with RIT alone. Some combined modality therapies resulted in higher numbers of cures, while others decreased cures and responses and increased toxicity compared with RIT alone. These results support the potential for CMRIT but illustrate the complexity of predicting the efficacy and toxicity and the importance of the relationship between dose and sequence of administration.


A Novel Approach to Addressing an Unintended Consequence of Direct to Room: The Delay of Initial Vital Signs.
The concept of "direct to room" (DTR) and "immediate bedding" has been described in the literature as a mechanism to improve front-end, emergency department (ED) processing. The process allows for an expedited clinician-patient encounter. An unintended consequence of DTR was a time delay in obtaining the initial set of vital signs upon patient arrival. This retrospective cohort study was conducted at a single, academic, tertiary-care facility with an annual census of 94,000 patient visits. Inclusion criteria were all patients who entered the ED from 11/1/15 to 5/1/16 and between the hours of 7 am to 11 pm. During the implementation period, a vital signs station was created and a personal care assistant was assigned to the waiting area with the designated job of obtaining vital signs on all patients upon arrival to the ED and prior to leaving the waiting area. Time to first vital sign documented (TTVS) was defined as the time from quick registration to first vital sign documented. The pre-implementation period, mean TTVS was 15.3 minutes (N= 37,900). The post-implementation period, mean TTVS was 9.8 minutes (N= 39,392). The implementation yielded a 35% decrease and an absolute reduction in the average TTVS of 5.5 minutes (p<0.0001). This study demonstrated that the coupling of registration and a vital signs station was successful at overcoming delays in obtaining the time to initial vital signs.


Soluble vascular endothelial growth factor receptor-1 is reduced in patients with resistant hypertension after renal denervation.
Renal denervation (RDN) has been shown in several studies to reduce blood pressure (BP) in patients with resistant hypertension (RH). Data on potential biomarkers associated with BP changes remain scarce. We evaluated whether soluble vascular endothelial growth factor receptor (sVEGFR-1) is affected by the procedure. A total of 57 patients with RH participated in this study. BP and heart rate were recorded at baseline and at 3 months follow-up, at which time blood samples were collected to determine the levels of sVEGFR-1, VEGF-A, VEGF-C, nitric oxide (NO), soluble vascular adhesion molecule 1 and soluble intracellular adhesion molecule 1. None of the biomarkers had a predictive value that could identify responders vs non-responders to RDN. However, sVEGFR-1 concentration was dramatically reduced after RDN (5913±385 vs 280±57 pg ml-1, P<0.001). At the same time VEGF-A levels were significantly increased (10.0±3.0 vs 55.5±7.9 pg ml-1, P<0.001), without significant changes in VEGF-C. NO levels were significantly increased after RDN in the whole group (82.6±6.2 vs 106.9±7.8 μM, P=0.021). Interestingly, the elevation in NO levels at 3 months was only seen in patients who demonstrated a reduction in systolic BP of ⩾10 mm Hg (78.9±8.3 vs 111.6±11.7 μM, P=0.018). We report a significant reduction in sVEGFR-1 levels after RDN procedure, which was accompanied by a significant increase in VEGF-A concentration as well as NO. Changes in plasma cytokines were not quantitatively linked to magnitude of BP reduction. An RDN-induced reduction in sVEGFR-1 plasma levels and increase in VEGF-A would raise the VEGF-A/sVEGFR-1 ratio, thereby increasing VEGF-A bioavailability to act on its full-length receptor and may contribute to the BP-lowering effect potentially via NO-mediated pathways.


The Relationship between Capital Domains and Resilience in Facing the COVID-19 Pandemic in Indonesia.
Strengthening disaster resilience is important to protect existing development and in anticipation of various disasters and risks due to disasters such as the COVID-19 pandemic. This study aims to determine resilience among individuals in dealing with the COVID-19 pandemic in Indonesia based on the capital domains. This study used a cross-sectional design with 97 Indonesian people and was conducted using an online survey in May-December 2020. Data were analysed using multivariable logistic regression. The results showed that 45.36% of the respondents had low resilience. Respondents whose expenses increased had 6.36 times higher odds of good resilience compared to respondents whose expenses decreased (AOR=6.36,95%CI=1.26-32,p=0.025). Respondents whose expenses were not affected had 12.32 times higher odds of having good resilience than respondents whose expenses were reduced (AOR=12.32,95%CI=1.82-83.40, p=0.01). Respondents with larger families had 32% lower odds of having good resilience than those with fewer family members (AOR=0.68, 95%CI=0.47-0.98, p=0.038). Respondents with no quarantine facilities had 65% lower odds of good resilience than those with quarantine facilities (AOR=0.35, 95%CI 0.13-0.95, p=0.04). Economic and physical capital as the part of capital domains showed a significant association with resilience during COVID-19 pandemics. Economic capital variables that had association with resilience were money expenses and the number of family members in household. Physical capital had a relationship with resilience were the availability of quarantine facilities. Government could encourage cooperation within the community to share economic resources. Local government could provide isolation facilities in local area.


[Interactions of circadian biorhythms of the immune and endocrine systems in mice].
The original and reported data on circadian biorhythms of the immune and endocrine systems are summarized. A hypothetic scheme of the circadian organization of lymphocyte redistribution, proliferation and metabolism in mice is provided, interactions of circadian biorhythms and circadian fluctuations of functional activity of the immune system are demonstrated. It has been shown that circadian rhythms of the immunologic parameters are dependent on the regulative influence of hypophyseal hormones, glucocorticoids, and thymic endocrine factors. Interactions of the immune and endocrine systems in different phases of the circadian cycle have been specified.