Dependency of human neck reflex responses on the bandwidth of pseudorandom anterior-posterior torso perturbations.
The vestibulocollic (VCR) and cervicocollic (CCR) reflexes are essential to stabilize the head-neck system and to deal with unexpected disturbances. This study investigates how neck reflexes contribute to stabilization and modulate with perturbation properties. We hypothesized that VCR and CCR modulate with the bandwidth of the perturbation and that this modulation is maintained across amplitudes and influenced by the eyes being open or closed. Seated subjects were perturbed in an anterior-posterior direction. The perturbations varied in bandwidth from 0.3 Hz to a maximum of 1.2, 2.0, 4.0, and 8.0 Hz, at three amplitudes, and with eyes open and closed. Frequency response functions of head kinematics and neck muscle EMG demonstrated substantial changes with bandwidth and vision and minor changes with amplitude, which through closed-loop identification were attributed to neural (reflexive) modulation. Results suggest that both reflexes were attenuated when perturbations exceeded the system's natural frequency, thereby shifting from a head-in-space to a head-on-trunk stabilization tendency. Additionally, results indicate that reflexive and mechanical stiffness marginally exceed the negative stiffness due to gravity; a stabilization strategy which minimizes effort. With eyes closed, reflexes were attenuated further, presumably due to a reduced ability to discriminate self-motion, driving the system to a head-on-trunk stabilization strategy at the highest bandwidth. We conclude that VCR and CCR modulate with perturbation bandwidth and visual feedback conditions to maintain head-upright posture, but are invariant across amplitude changes.


Pre-diabetes tsunami: incidence rates and risk factors of pre-diabetes and its different phenotypes over 9 years of follow-up.
To investigate the incidence of pre-diabetes and its different phenotypes and the related risk factors during 9 years of follow-up. A total of 5879 people (2597 men and 3282 women) aged ≥ 20 years, free of diabetes and pre-diabetes, took part in the study. Multivariable Cox proportional hazard models were used to evaluate hazard ratios (HR) and 95% confidence intervals (CI) for all potential risk factors. Overall, 853 men and 902 women developed pre-diabetes. Incidence rates of pre-diabetes were 46.1 per 1000 person-years in men and 36.8 per 1000 person-years in women, while isolated impaired fasting glucose had the highest incidence rate among all pre-diabetes phenotypes. In both sexes, age, family history of diabetes, fasting plasma glucose and 2-hour post-challenge plasma glucose were related to incident pre-diabetes. Among women, waist-to-height ratio [HR: 1.02 (1.00-1.03)] and being divorced/widowed compared with married [HR: 0.67 (0.52-0.87)] were significant predictors of pre-diabetes; whereas among men, community-based intervention [HR: 0.79 (0.68-0.90)], higher level of education and being single [HR: 0.77 (0.6-0.97)] were protective against progression to pre-diabetes. Moreover, hip circumference among women [HR: 0.95 (0.93-0.98)] and current smoking among men [HR: 1.69 (1.15-2.48)] were related to incident combined impaired fasting glucose and impaired glucose tolerance. More than 4% of the Iranian population develop pre-diabetes each year, emphasizing the important role of socio-economic factors (marital status, education and smoking habits) and community-based intervention in progression to impaired glucose regulations. Thus, emergent intervention is necessary to halt the tsunami of pre-diabetes among the Iranian population.


Validation of a taxonomy of ambulatory nursing practice.
Ambulatory care is a complex and challenging nursing specialty. This survey of 33 ambulatory nursing administrators addressed the roles and responsibilities of nurses in ambulatory care settings.


Identification of intervention patients at increased risk.
Many patients who once would have been classified as being at high risk are now deemed candidates for interventional cardiologic procedures. Definitions of risk thereby warrant reconsideration. Although the angiographic characteristics of lesions clearly identify patients at increased risk of adverse outcomes after angioplasty, important components such as thrombus may go unrecognized. Angioscopy provides a more precise means of identifying thrombus, but its use is not feasible in all patients scheduled for angioplasty. A triage system developed on the basis of clinical criteria is therefore desirable. Prospective data have suggested that the degree of risk is high in patients with unstable angina (particularly when refractory to medical therapy) and those who have recently undergone successful thrombolytic therapy for myocardial infarction. After stent implantation, patients who receive full anticoagulation therapy are at high risk of bleeding and subacute thrombosis, which may lead to myocardial infarction. New preventive strategies are required to optimize outcomes in patients with clinical characteristics indicative of high risk.


Inhibition of brain choline uptake by isoarecolone and lobeline derivatives: implications for potential vector-mediated brain drug delivery.
Delivery of certain compounds to brain is restricted by the nature of the blood-brain barrier (BBB). Many valuable pharmaceuticals are excluded from the CNS due to hydrophilicity or charge. These limitations have been overcome by numerous methods. One method we use is to take advantage of saturable nutrient transporters located at the barrier. These systems transport hydrophilic and charged nutrients into brain such as choline, a quaternized neurotransmitter precursor. Using knowledge of their substrate specificity, it is possible to deliver agents into brain using these nutrient carriers. In this report, derivatives of lobeline and isoarecolone were evaluated to determine if they may gain access to brain by the blood-brain barrier basic amine transporter using the in situ brain perfusion technique. These compounds do bind the blood-brain barrier basic amine transporter and may enter brain by this transport system.


Involvement of vagal pathway in the anti-secretory effect of a novel xanthine derivative.
The inhibitory action of a novel xanthine derivative, 3-ethyl-1-(6-hydroxy-6-methylheptyl)-7-propylxanthine (A90 6119) on gastric acid secretion was studied in rats. In conscious pylorus-ligated rats, A90 6119 (3 mg/kg intraduodenally, i.d.), inhibited gastric acid output stimulated by carbachol and by 2-deoxy-D-glucose by 49% and 100% respectively. Basal acid secretion was inhibited by 61% by 10 mg/kg, i.d. A90 6119. In urethane anesthetized stomach-lumen-perfused rats, A 90 6119 at 1 and 3 mg/kg, i.d. significantly reduced the acid secretion stimulated by 2-deoxy-D-glucose, by 83% and 100%, respectively. The stable thyrotropin-releasing hormone (TRH) analog, RX 77368, injected intracisternally (i.c.) at a 30 ng dose, induced concomitant increases in acid secretion and gastric mucosal blood flow. A90 6119 (10 micrograms/rat, i.c.) inhibited by 93% and 132% the increase in acid secretion and gastric mucosal blood flow induced by i.c. injection of TRH analog, respectively. These data suggest that the anti-secretory effect of A90 6119 involves inhibition of both central and peripheral vagal cholinergic pathways.


Pyrite as a sustainable catalyst in electro-Fenton process for improving oxidation of sulfamethazine. Kinetics, mechanism and toxicity assessment.
The degradation of 0.20 mM sulfamethazine (SMT) solutions was investigated by heterogeneous electro-Fenton (EF) process using pyrite as source of Fe(2+) (catalyst) and pH regulator in an undivided electrochemical cell equipped either with a Pt or a BDD anode and carbon-felt as cathode. Effect of pyrite concentration and applied current on the oxidative degradation kinetics and mineralization efficiency has been studied. The higher oxidation power of the process, named "Pyrite-EF″ using BDD anode was demonstrated. Pyrite-EF showed a better performance for the oxidation/mineralization of the drug SMT in comparison to the classic EF process: 95% and 87% TOC removal by Pyrite-EF with BDD and Pt anodes, respectively, versus 90% and 83% by classical EF with BDD and Pt anodes, respectively. The rate constant of the oxidation of SMT by OH was determined by the competition kinetics method and found to be 1.87 × 10(9) mol(-1) L s(-1). Based on the identified reaction intermediates by HPLC and GS-MS, as well as released SO4(2-), NH4(+) and NO3(-) ions, a plausible reaction pathway was proposed for the mineralization of SMT during Pyrite-EF process. Toxicity assessment by means of Microtox method revealed the formation of some toxic intermediates during the treatment. However, toxicity of the solution was removed at the end of treatment.


Molecular identification of Ageratum enation virus, betasatellite and alphasatellite molecules isolated from yellow vein diseased Amaranthus cruentus in India.
Natural occurrence of yellow vein disease on Amaranthus cruentus was observed at Lucknow, India in the year 2008. The causal virus was successfully transmitted through whiteflies (Bemisia tabaci) from diseased A. cruentus to healthy seedlings of A. cruentus and other test species which indicated begomovirus infection. The begomovirus DNA-A, betasatellite, and alphasatellite components associated with yellow vein disease were amplified by rolling circle amplification using Ø-29 DNA polymerase from diseased A. cruentus and characterized by their sequence analyses. The begomovirus DNA-A genome contained six ORFs: AV2 and AV1 in virion sense and AC3, AC2, AC1, and AC4 in complementary sense strand; and a non-translated intergenic region having the conserved geminiviral nonanucleotide sequence. The virus isolate showed 97-99% sequence identities and close phylogenetic relationships with various isolates of Ageratum enation virus (AgEV); therefore, the isolate under study was identified as AgEV. The beta- and alphasatellite molecules were also identified to be associated with the disease based on their high sequence identities and close phylogenetic relationships with the respective molecules reported worldwide. Co-infiltration of agro-infectious clones of AgEV DNA-A and its betasatellite DNA induced leaf curl and enation symptoms after 25-35 days on A. cruentus, Nicotiana benthamiana, and N. glutinosa plants. We report the association of AgEV, betasatellite and alphasatellite components with yellow vein disease of A. cruentus from India.


Kinetics of ibuprofen effect on platelet and endothelial prostanoid release.
Reciprocal control of platelet function in the circulation has been proposed for the platelet-produced platelet proaggregatory prostanoid thromboxane A2 (TxA2) and the vascular endothelium-produced antiaggregatory prostanoid prostacyclin (PGI2). Forty drug-free healthy subjects were given a single dose of ibuprofen (0, 8, 10, 12, or 14 mg/kg) in a randomized, double-blind study. Blood samples were drawn 0, 2, 4, and 6 hours and 7 days after dosing for determination in serum (from untreated or in vitro indomethacin-treated portions of the blood) of TxA2 and PGI2 by radioimmunoassay of their stable metabolites (TxB2 and 6-keto-PGF1 alpha). Maximal platelet release of TxA2 (untreated serum) was lower in all drug groups 2, 4, and 6 hours after dosing. There was no significant decrease in PGI2 release. All doses of ibuprofen (except 0 mg/kg) induced essentially identical plasma levels at the times of measurement (postpeak decline), and effects could not be distinguished by dose for 8, 10, 12, or 14 mg/kg at these times. It is concluded that ibuprofen induces antiplatelet effects for at least 6 hours while preserving normal antiplatelet mechanisms.


Genetics of aging bone.
With aging, the skeleton experiences a number of changes, which include reductions in mass and changes in matrix composition, leading to fragility and ultimately an increase of fracture risk. A number of aspects of bone physiology are controlled by genetic factors, including peak bone mass, bone shape, and composition; however, forward genetic studies in humans have largely concentrated on clinically available measures such as bone mineral density (BMD). Forward genetic studies in rodents have also heavily focused on BMD; however, investigations of direct measures of bone strength, size, and shape have also been conducted. Overwhelmingly, these studies of the genetics of bone strength have identified loci that modulate strength via influencing bone size, and may not impact the matrix material properties of bone. Many of the rodent forward genetic studies lacked sufficient mapping resolution for candidate gene identification; however, newer studies using genetic mapping populations such as Advanced Intercrosses and the Collaborative Cross appear to have overcome this issue and show promise for future studies. The majority of the genetic mapping studies conducted to date have focused on younger animals and thus an understanding of the genetic control of age-related bone loss represents a key gap in knowledge.


Maspin nuclear localization is linked to favorable morphological features in pulmonary adenocarcinoma.
Maspin, a mammary homologue of Serine Protease Inhibitors, has been shown to inhibit tumor progression and metastasis. Recently, its biological functions have been linked to its subcellular localization. Specifically, a nuclear, opposed to a combined nuclear and cytoplasmic localization has been associated with increased survival in human malignancies, including non-small cell lung cancer (NSCLC). However, it is not known whether transformation affects maspin expression during lung carcinogenesis, and whether its subcellular localization correlates with the morphological features of NSCLC. To address these questions, we studied maspin expression in a model of transformation of bronchial epithelial cells and in resected NSCLC. We found that decreased maspin accompanied chemical transformation of normal immortalized bronchial epithelial cells BEAS 2B. Immunohistochemistry revealed maspin expression to be virtually universal in NSCLC, occurring in 72/77 Adenocarcinoma (ACa), and 46/46 squamous cell carcinoma (SqCCa). SqCCa showed almost exclusively a combined nuclear-cytosolic stain. In contrast, nuclear maspin, but not combined nuclear-cytoplasmic maspin significantly correlated with low histological grade, lower proliferative rate, absence of invasion, and negative p53 stain in ACa. These data support the hypothesis that nuclear localization of maspin may stratify subtypes of NSCLC with favorable clinical-pathological features.


Short-term effects of two fusarium toxins, diacetoxyscirpenol and neosolaniol monoacetate, in male Wistar rats.
This study compared the pathological and haematological effects of neosolaniol monoacetate in male Wistar rats with those of diacetoxyscirpenol, a highly toxic trichothecene mycotoxin. Both toxins caused statistically significant decreases in erythrocyte counts and increased the proportion of larger platelets compared to controls when dosed at 1 mg/kg body weight three times/wk for up to 5 wk. Lesions caused by treatment with either toxin at this dosage level were mild and were seen--mainly after 2-4 wk--in the actively dividing cells of the thymus, spleen, lymph nodes and bone marrow. Reduced severity or disappearance of the lesions was noted towards the end of the treatment period. The type and severity of the toxic effects of neosolaniol monoacetate appeared to be similar to those of diacetoxyscirpenol.


Characterizing the microbiota of wooden boards used for cheese ripening.
Wooden boards are commonly used for aging artisan cheeses. Although considered critical to the development of desired flavors and aromas, knowledge about the microbial communities associated with these boards is limited. To begin to address this need, we performed a 16S ribosomal RNA analysis of the bacterial communities present on the surface and within 5 wooden boards used for cheese ripening that were obtained from 3 cheese-processing facilities. The 5 boards were dominated by bacteria in the phyla Actinobacteria, Firmicutes, and Proteobacteria and displayed differences in both diversity and richness. Analysis of these boards also identified significant board-to-board variation. A total of 288 operational taxonomic units were identified across all samples, with 7 operational taxonomic units forming a core microbiota across all boards. Taken together, these data reflect the cheese-ripening environment, which appears to select for salt- and cold-tolerant bacteria.


The protective effects of L-ascorbic acid and DL-alpha-tocopherol on cultured rat embryos treated with xanthine/xanthine oxidase.
Abnormalities of the neural suture were observed in cultured rat embryos exposed to oxygen radicals generated by xanthine and xanthine oxidase. The distribution of the severity of these abnormalities was altered by the addition of L-ascorbic acid (AA) or DL-alpha-tocopherol (AT). The antioxidant effect of AA and AT were probably responsible for the protection of the embryos from the damaging effects of oxygen radicals.


The Gene Polymorphism of IL-17 G-152A is Associated with Increased Colonization of Streptococcus pneumoniae in Young Finnish Children.
Streptococcus pneumoniae is a common respiratory pathogen, and up to 50% of children acquire S. pneumoniae in their nasopharynx during the first 12 months of life. The cytokine interleukin-17A (IL-17A) plays an important role in host defense against extracellular bacterial pathogens. We investigated the effect of IL-17 G-152A polymorphism on pneumococcal colonization in children. Nasopharyngeal swabs and blood samples were collected from healthy Finnish children at 2.6 (N = 405), 13 (N = 198) and 24 (N = 176) months of age. Of them, 160 had both nasopharyngeal swabs and blood samples at each time point. The semiquantitative culture method was used for bacterial culture, Sequenom iPlex Gold System for IL-17A genotyping and Luminex 200 for serum IL-17A determination. The frequency of IL-17 G-152A genotypes G/G, G/A and A/A was 36%, 45% and 19% in 405 studied subjects, respectively. The colonization rates of S. pneumoniae increased from 10% at 2.6 months to 33% at 24 months of age. Significantly higher pneumococcal colonization was found in subjects with A/A genotype at 13 and 24 months of age compared with those of G/G (RR, 2.30; P = 0.02; RR, 1.91, P = 0.03). This genotype was associated with lower levels of serum IL-17A, and only 6% of subjects with A/A had detectable serum IL-17A compared with 75% and 33% of subjects with G/G and G/A (P < 0.001 and P < 0.01), respectively. Our results indicate that IL-17 G-152A is associated with increased colonization rate of S. pneumoniae in young children, suggesting that IL-17A plays an important role in protection against pneumococcal colonization.


HNF-1β as an immunohistochemical marker for distinguishing chromophobe renal cell carcinoma and hybrid oncocytic tumors from renal oncocytoma.
The histologic features of renal oncocytoma (RO) are similar to those for the more aggressive chromophobe renal cell carcinoma (ChRCC). To assess immunohistochemical markers of the two, the sensitivity and specificity of cytokeratin 7 (CK7) and C-kit, as well as hepatocyte nuclear factor-1β (HNF-1β), were analyzed. Typical cases of ChRCC and RO at Severance Hospital between July 2014 and July 2018 were selected retrospectively. Among 44 cases, 17 were unanimously compatible with ChRCC, 16 were RO, and 11 cases were indeterminate. Samples from all selected cases were used for immunostaining with antibodies against CK7, C-kit, HNF-1β, and CD10. Immunostaining demonstrated complete loss of HNF-1β expression in 11 out of 17 (64.7%) ChRCC cases and a partial, but significant loss in > 50% of tumor cells in the remaining 6 cases (35.3%). In contrast, HNF-1β expression was preserved in tumor cells of RO cases. Fourteen of 17 ChRCC cases (82.4%) were diffusely positive for CK7, whereas cases of RO were focal positive or negative. C-kit staining did not show a significant difference between ChRCC and RO. Two of five ChRCC cases showing diffuse immunoreactivity for CD10 had poor prognoses of local invasion, distant metastasis, or death. Loss of HNF-1β expression is a useful marker with which to diagnose ChRCC, especially in cases with confusing histologic findings or equivocal CK7 staining. Additionally, CD10 staining in high-grade ChRCC aids in diagnosis and prediction of the clinical prognosis.


Cardiac electrophysiologic effects of parathyroid hormone in the guinea pig.
The cardiac electrophysiologic effects of parathyroid hormone (PTH) were studied in three different experimental models. Purified synthetic human parathyroid hormone (hPTH 1-84), at a dose of 30 ng/g body weight (BW), prolonged the QT interval of surface ECGs in intact guinea pigs. To further clarify the mechanisms of the QT prolongation caused by hPTH, the action potentials of guinea pig papillary muscle were recorded by conventional microelectrode techniques. hPTH (10(-7)M) prolonged the action potential duration without changing the action potential amplitude, resting potential, maximal upstroke velocity of the action potential, or maximal repolarization rate. hPTH affected only the plateau phase, in a concentration-dependent fashion. The half-maximum concentration was 6.8 x 10(-8)M for action potential duration at 30% repolarization (APD30), 3.2 x 10(-8)M for APD50, and 2.1 x 10(-8)M for APD90. In isolated single guinea pig ventricular cells, the patch clamp method was used to record the slow inward calcium current (ICa) and delayed rectifier potassium current (IK) responsible for the action potential plateau phase. hPTH increased the peak amplitude of ICa at + 10mV by an average of 42%, and increased IK at + 10mV by 85%. These results indicate that, in ventricular muscle, hPTH prolongs the action potential duration and QT interval by the balance of the prolongation effect on APD by enhancing the slow inward calcium current and the shortening effect on APD by enhancing the delayed rectifier potassium current.


Incidence, staff awareness and mortality of patients at risk on general wards.
The aim of this study was to estimate the incidence, staff awareness and subsequent mortality of patients with abnormal vital signs on general wards in a Danish university hospital. Prospective data collection in two surgical and three medical wards at Herlev University Hospital, Copenhagen. Study personnel measured vital signs of all patients present on the wards at random points during the evening and interviewed nursing staff about patients with abnormal vital signs. Simplified medical emergency team (MET) calling criteria were used to define abnormal vital signs. None. During the 2-month data collection period, 877 patients were included in the study and 155 (18%) had abnormal vital signs. The 30-day mortality in this group was 13% compared to 5% among patients with normal vital signs (p<0.0001). Of the 155 patients with abnormal signs, nursing staff were not aware of all of the patient's abnormalities in 67 (43%) cases. For 20 patients (13%), staff were aware of some of their abnormalities, while for 52 patients (34%), staff were aware of all their abnormalities. One out of five patients in the general wards developed abnormal vital signs during the 2-month study period and these patients had a 3-fold increased 30-day mortality. For almost half of the patients, nursing staff were unaware of their abnormal vital signs. Strategies to improve identification of patients at risk should be an initial step in preventing serious adverse events on the general wards.


[Nuchal cord between 37 and 42 completed weeks of gestation--diagnosis and prognostic value].
To investigate the ability of transabdominal ultrasound to detect nuchal cord(s) between 37 and 42 completed weeks of gestation (w.g.) and to assess its prognostic value in relation with the perinatal outcome. Transabdominal ultrasound examination using gray-scale and color Doppler imaging was performed in 86 singleton pregnancies between 37 and 42 completed w.g. in a prospective study. In 36 cases the presence of nuchal cord(s) was suspected. Nuchal cords were classified as with one, two or three loops. The outcome of labor and delivery was obtained from hospital records. The sensitivity of ultrasound for the presence of single-loop nuchal cord was 68.1%, while the specificity, positive and negative predictive value was 77.2%, 53.5% and 86.3%, respectively. The sensitivity and specificity of transabdominal ultrasound in diagnosing single-loop nuchal cord between 37 and 42 w.g. is relatively high. However, the detection rate for multiple loops of nuchal cord is even higher. Single-loop nuchal cords are not associated with increased risk of Cesarean section or vaginal instrumental delivery.


Synthesis and evaluation of 1,2,3-dithiazole inhibitors of the nucleocapsid protein of feline immunodeficiency virus (FIV) as a model for HIV infection.
We disclose a series of potent anti-viral 1,2,3-dithiazoles, accessed through a succinct synthetic approach from 4,5-dichloro-1,2,3-dithiazolium chloride (Appel's salt). A series of small libraries of compounds were screened against feline immunodeficiency virus (FIV) infected cells as a model for HIV. This approach highlighted new structure activity relationship understanding and led to the development of sub-micro molar anti-viral compounds with reduced toxicity. In addition, insight into the mechanistic progress of this system is provided via advanced QM-MM modelling. The 1,2,3-dithiazole represents a versatile scaffold with potential for further development to treat both FIV and HIV.


Impact of COVID-19 lockdown on the atmospheric boundary layer and instability process over Indian region.
The abrupt reduction in the human activities during the first lockdown of the COVID-19 pandemic created unprecedented changes in the background atmospheric conditions. Several studies reported the anthropogenic and air quality changes observed during the lockdown. However, no attempts are made to investigate the lockdown effects on the Atmospheric Boundary Layer (ABL) and background instability processes. In this study, we assess the lockdown impacts on the ABL altitude and instability parameters (Convective Available Potential Energy (CAPE) and Convective Inhibition Energy (CINE)) using WRF model simulations. Results showed a unique footprint of COVID-19 lockdown in all these parameters. Increase in the visibility, surface temperature and wind speed and decrease in relative humidity during the lockdown is noticed. However, these responses are not uniform throughout India and are significant in the inland compared to the coastal regions. The spatial variation of temperature (wind speed) and relative humidity shows an increase and decrease over the Indo Gangetic Plain (IGP) and central parts of India by 20% (100%) and 40%, respectively. Increase (80%) in the ABL altitude is larger over the IGP and central parts of India during lockdown of 2020 compared to similar time period in 2015-2019. This increase is attributed to the stronger insolation due to absence of anthropogenic activity and other background conditions. At the same time, CAPE decreased by 98% in the IGP and central parts of India, where it shows an increase in other parts of India. A prominent strengthening of CINE in the IGP and a weakening elsewhere is also noticed. These changes in CAPE and CINE are mainly attributed to the dearth of saturation in lower troposphere levels, which prevented the development of strong adiabatic ascent during the lockdown. These results provide a comprehensive observation and model-based insight for lockdown induced changes in the meteorological and thermo-dynamical parameters.


[The characteristics of the action of potable mineral waters on the postradiation recovery processes in rats receiving different doses of gamma irradiation].
In experiments on 54 white noninbred male rats it was shown that drinking mineral water containing sulphate, calcium and sodium ions (Moskovskaia mineral water) activates postradiation regenerative processes in the thymus and the liver and normalizes functional activity of CCS-system in blood plasma if it was taken 28 days after whole-body 1 Gy gamma-radiation. This positive effect was less marked after 5 Gy gamma-radiation. Silicon and boron containing mineral water under the above conditions proved less effective.


The effect of tryptase from human mast cells on human prekallikrein.
Tryptase, the dominant protease in human mast cells, was examined for its effect on human prekallikrein. Tryptase in the presence and absence of heparin failed to activate prekallikrein as shown in a spectrophotometric assay for kallikrein employing benzoy 1-pro-phe-arg-p-nitroanilide. Treated prekallikrein was converted to active kallikrein by bovine trypsin. Prekallikrein cleavage products were analyzed by electrophoresis in polyacrylamide gels under denaturing conditions (+/- reduction). Tryptase caused no apparent cleavage under conditions where trypsin caused complete cleavage. Thus, tryptase, which has previously been shown to lack kallikrein and kininase activities, neither activates nor destroys prekallikrein.


Quantitative Assessment Parameters of Peripapillary Regions with Branch Retinal Vein Occlusion by Using Optical Coherence Tomography Angiography.
To investigate the baseline parameters of peripapillary regions in both eyes of patients with unilateral branch retinal vein occlusion (BRVO) using optical coherence tomography angiography (OCTA) and their association with best-corrected visual acuity (BCVA). Forty-eight unilateral BRVO patients were enrolled. The 4.5 × 4.5 mm disc angiogram was acquired in the BRVO eyes and fellow eyes using the OCTA. Radial peripapillary capillary (RPC), whole vessel density, and retinal nerve fiber layer (RNFL) thickness in different regions and optic nerve head (ONH) analysis were automatically calculated. The partition includes the whole image, peripapillary, superior hemifield, inferior hemifield, eight equally divided sectors, and nine evenly divided square areas. All vessel density and capillary vessel density in the whole and peripapillary regions of BRVO eyes were significantly lower than those in fellow eyes. The RNFL peripapillary thickness in BRVO eyes was significantly higher than those in fellow eyes. In eyes with supertemporal vein occlusion, all vessel density both in the superior hemifield and in the G12 region was significantly reduced compared with that in the fellow eyes. The capillary vessel density was significantly lower in the superior hemifield, superior temporal (ST), superior nasal (SN), and temporal superior (TS) areas than in the fellow eyes. The RNFL thickness in the NI, IN, TI, and TS sectors was significantly higher than in fellow eyes (all P < 0.05). OCTA provided quantitative information on peripapillary vascular density and RNFL thickness changes in BRVO. Branch retinal vein occlusion not only affects the blood vessel density in the macular area but also decreases the radial peripapillary capillaries. The capillary density is mainly affected in the affected hemifield but not in the unaffected hemifield.


Clinical implications of postnatal alterations in body water distribution.
Substantial alterations take place in the quantity and distribution of body water compartments after birth. Clinical management must be tailored to the pace of postnatal adaptation, and the neonatal physician must be aware of these alterations in order to promote both normal physiological change and growth.


Progressive MS: from pathophysiology to drug discovery.
Progressive multiple sclerosis (MS) will be a major area of research interest for years to come. No treatments exist and success in the field will generalise to other neurological conditions where neurodegeneration coexists with neuroinflammation. The issue is complex, and interdisciplinary approaches - uniting scientists with different competences (neurobiology, immunogenetics, etc.) and 'mindsets' (academia and industry) - will be decisive. The International Progressive MS Alliance is catalysing this process through various initiatives, the most recent of which was a meeting where scientists from academia (also outside the MS field) and from industry reviewed data and strategies to determine the next steps towards the translation of current knowledge into effective therapies.Key findings are:(i). Concerted efforts are essential to prioritise pathogenetic mechanisms according to impact on the disease and druggability.(ii). Combination therapies will probably be needed, possibly early in the disease, along with new trial designs and treatment schedules.(iii). Drug screenings are a pragmatic approach hopefully enriched by the use of neural and oligodendrocyte progenitors differentiated from induced pluripotent stem cells (iPSCs).(iv). The field of network biology will increase our ability to predict therapeutic targets.(v). Genome-wide association studies (GWAS) must try to identify variants associated with disease progression.


Excessive irisin increases oxidative stress and apoptosis in murine heart.
Irisin is an exercise-related myokine. The abundance of irisin is associated with many diseases, such as myocardial infarction, chronic kidney disease, metabolic syndrome, obesity, and diabetes mellitus. In cardiomyocytes, irisin modulates the mitochondrial thermogenesis, regulates ischemic responses, and affects calcium signaling. Previous studies suggested that irisin increases cardiomyoblast mitochondrial functions and protects ischemic and reperfusion injury in ex vivo murine heart. In human, clinical studies have shown that acute myocardial infarction patients with more elevated serum irisin abundances are associated with increased major adverse cardiovascular events. However, the mechanisms responsible for this discrepancy between in myocardial infarction patients and ex vivo murine heart is unclear. Based on the clinical observations, we hypothesized that excessive irisin might lead to mitochondrial dysfunctions and cardiomyocyte damages. Our data showed that overexpression of irisin in mice with the adenovirus resulted in enhanced mitochondrial respiration with a higher oxygen consumption rate. Enhanced irisin expression in heart and irisin treatment in cardiomyocytes increased reactive oxygen species production. Furthermore, irisin treatment in cardiomyocytes enhanced the apoptosis and the cleaved caspase 9 levels in hypoxic condition. Pathway analysis in the murine heart with the overexpression of irisin showed that angiopoietin-Tie2, IL-8, IL-13, TGF-β, and thrombopoietin signaling were affected by irisin. Collectively, these results supported that excessive irisin causes mitochondrial overdrive with a higher reactive oxygen species production, which results in increased apoptosis of cardiomyocytes in a hypoxic environment.


Response surface optimization of a rapid ultrasound-assisted extraction method for simultaneous determination of tetracycline antibiotics in manure.
A rapid and cleanup-free ultrasound-assisted extraction method is proposed for the simultaneous extraction of oxytetracycline, tetracycline, chlortetracycline, and doxycycline in manure. The analytes were determined using high-performance liquid chromatography with ultraviolet detector. The influence of several variables on the efficiency of the extraction procedure was investigated by single-factor experiments. The temperature, pH, and amount of extraction solution were selected for optimization experiment using response surface methodology. The calibration curves showed good linearity (R (2) > 0.99) for all analytes in the range of 0.1-20 μg/mL. The four antibiotics were successfully extracted from manure with recoveries ranging from 81.89 to 92.42% and good reproducibility (RSD, <4.06%) under optimal conditions, which include 50 mL of McIlvaine buffer extraction solution (pH 7.15) mixed with 1 g of manure sample, extraction temperature of 40°C, extraction time of 10 min, and three extraction cycles. Method quantification limits of 1.75-2.32 mg/kg were obtained for the studied compounds. The proposed procedure demonstrated clear reductions in extraction time and elimination of cleanup steps. Finally, the applicability to tetracyclines antibiotics determination in real samples was evaluated through the successful determination of four target analytes in swine, cow manure, and mixture of animal manure with inorganic fertilizer.


Electron spectroscopic imaging of the nuclear landscape.
Our understanding of sub-nuclear organisation is largely based on fluorescence and electron microscopy methods. Conventional electron microscopy, which depends on heavy atom contrast agents, provides excellent contrast of condensed chromatin and some sub-nuclear structures such as the nucleolus. Unfortunately, other components, 10-nm chromatin fibres for example, do not contrast well. Electron spectroscopic imaging partially overcomes this limitation. In particular, phosphorus and nitrogen mapping provide sufficient contrast and resolution to visualise 10-nm chromatin fibres, while providing an opportunity to distinguish protein-based from nucleic acid-based supramolecular structures, such as the cores of nuclear bodies. Electron spectroscopic imaging, therefore, offers an approach to address many questions related to the functional organisation of the interior of the cell nucleus, which is illustrated in this chapter.


Racial Disparities in Recurrence and Overall Survival in Patients With Locoregional Colorectal Cancer.
The purpose of this study was to determine the association between race and long-term cancer outcomes (recurrence and overall survival) within a population of US patients with locoregional colorectal cancer (CRC). A cohort study of primary patient data merged with the National Cancer Database as part of a Commission on Cancer Special Study was performed. The study population was a random sample of patients undergoing surgery for stage I to III CRC between years 2006 and 2007 with 5 years of follow-up. Propensity-weighted multivariable Cox regression was performed with pooled results to yield statistical inferences. Prespecified sensitivity analysis was performed only for patients who received guideline concordant care (GCC) of primary CRC. All statistical tests were 2-sided. The study population included 8176 patients, 9.9% (n = 811) Black and 90.1% (n = 7365) White. Black patients were more likely to be uninsured or underinsured, have lower household income, and lower educational status (all P < .001). Rates of GCC were higher among Black vs White patients with colon cancer (76.9% vs 72.6%, P = .02), and Black and White patients with rectal cancer were treated with radiation at similar rates (69.1% vs 66.6%, P = .64). Black race was independently associated with increased risk of recurrence (hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.26 to 1.73) and mortality (HR = 1.37, 95% CI = 1.18 to 1.59). In sensitivity analysis of only patients who received GCC, observed effects for recurrence (HR = 1.51, 95% CI = 1.27 to 1.79) and overall survival (HR = 1.40, 95% CI = 1.18 to 1.66) persisted. Despite higher rates of GCC for CRC, Black patients experience a higher risk of recurrence and mortality compared with White patients.


Multiple Fused Anthracenes as Helical Polycyclic Aromatic Hydrocarbon Motif for Chiroptical Performance Enhancement.
Polycyclic aromatic hydrocarbons consisting of three fused anthracene units were designed as new π-conjugated compounds having helical structures. These expanded helicenes were synthesized by Pt-catalyzed cycloisomerization of the corresponding ethynyl-substituted precursors. The nonplanar and helical structure was confirmed by X-ray analysis and DFT calculations, and the barrier to helical inversion was estimated to be 34 kJ mol-1 . The enantiomers of the diphenyl derivative were successfully resolved by chiral HPLC. Enantiopure samples showed good chiroptical performance in the CD (|Δϵ| 1380 L mol-1 cm-1 ) and CPL (|glum | 0.013) spectra, and these values were considerably large for simple organic molecules. The unique chiroptical properties are discussed on the basis of the molecular structure and the electronic state with the aid of time-dependent DFT calculations.


Benefits and constrains of covalency: the role of loop length in protein stability and ligand binding.
Protein folding is governed by non-covalent interactions under the benefits and constraints of the covalent linkage of the backbone chain. In the current work we investigate the influence of loop length variation on the free energies of folding and ligand binding in a small globular single-domain protein containing two EF-hand subdomains-calbindin D9k. We introduce a linker extension between the subdomains and vary its length between 1 to 16 glycine residues. We find a close to linear relationship between the linker length and the free energy of folding of the Ca2+-free protein. In contrast, the linker length has only a marginal effect on the Ca2+ affinity and cooperativity. The variant with a single-glycine extension displays slightly increased Ca2+ affinity, suggesting that the slightly extended linker allows optimized packing of the Ca2+-bound state. For the extreme case of disconnected subdomains, Ca2+ binding becomes coupled to folding and assembly. Still, a high affinity between the EF-hands causes the non-covalent pair to retain a relatively high apparent Ca2+ affinity. Our results imply that loop length variation could be an evolutionary option for modulating properties such as protein stability and turnover without compromising the energetics of the specific function of the protein.


Pathogenic amoebas from brackish and ocean sediments, with a description of Acanthamoeba hatchetti, n. sp.
Acanthamoeba culbertsoni was isolated from a sewage-spoil dump site near Ambrose Light, New York Bight. A second species, Acanthamoeba hatchetti, n. sp., was isolated from Brewerton Channel, Baltimore Harbor, Maryland. Both species killed laboratory mice after infection by the intranasal route.


Increased pulmonary artery diastolic-pulmonary wedge pressure gradient after cardiopulmonary bypass.
In 29 patients undergoing elective coronary artery bypass grafting, the diastolic pulmonary arterial pressure-pulmonary capillary wedge pressure gradient (DPAP-PCWP) and related haemodynamic parameters were determined before and after induction of anaesthesia, immediately after cardiopulmonary bypass (CPB) and one and three hours after CPB. The DPAP-PCWP gradient remained unchanged after induction of anaesthesia but was significantly increased after CPB. A gradient of 5 mmHg or greater was observed in 16 patients after CPB, whereas none of the patients showed such a gradient before CPB. A significant correlation was found between the change in DPAP-PCWP and the change in pulmonary vascular resistance (PVR). It is concluded that DPAP should not be used as a substitute of PCWP in the early postbypass period without frequent confirmation of the presence of the normal small DPAP-PCWP gradient. Since an increase of PVR may impair right ventricular ejection, we recommend the routine measurement of DPAP-PCWP gradient in the postbypass period.


Tubulin evolution: an electrophoretic and immunological analysis.
This paper summarizes a survey of the electrophoretic behavior of the tubulins of 23 species (mostly protists) as well as their reactivity towards 4 anti-tubulin antibodies (raised against two ciliate tubulins and two vertebrate ones). Some generalizations concerning the relative migration rates of alpha VS beta tubulin could be made, in particular the alpha/beta inversion, first described in Physarum was extended to several ciliates. Antivertebrate tubulin antibodies displayed a very broad spectrum of reactions, reacting with virtually all the species tested. They appear to correspond to auto-antibodies no exclusively directed against species specific determinants. In contrast, the two anti-ciliate tubulin antibodies displayed a narrow species specificity reacting only with a limited subset of protists. They were shown to be specific for a small number of immunological determinants present on ciliate tubulins. This allowed a rough evaluation of evolutionary relatedness between the various groups of protists analyzed. The results are discussed within the framework of a number of published phyllogenies and shown to be in striking agreement with some of the schemes.


Does disrespect and abuse during childbirth differ between public and private hospitals in Southeast Nigeria.
Disrespect and Abuse (D&A) during childbirth represents an important barrier to skilled birth utilization, indicating a problem with quality of care and a violation of women's human rights. This study compared prevalence of D&A during childbirth in a public and a private hospital in Southeast Nigeria. This study was a cross-sectional study among women who gave birth in two specialized health facilities: a public teaching and a private-for-profit faith-based hospital in Southeast Nigeria. In each facility, systematic random sampling was used to select 310 mothers who had given birth in the facility and were between 0-14 weeks after birth. Study participants were recruited through the immunization clinics. Semi-structured, interviewer-administered questionnaires using the Bowser and Hills classification of D&A during childbirth were used for data collection. Data were analyzed using SPSS version 20 at 95% significance level. Mean age of the participants in the public hospital was 30.41 ± 4.4 and 29.31 ± 4.4 in the private hospital. Over three-fifths (191; 61.6%) in the public and 156 women (50.3%) in the private hospital had experienced at least one form of D&A during childbirth [cOR1.58; 95% CI 1.15, 2.18]. Abandonment and neglect [Public153 (49.4%) vs. Private: 91 (29.4%); cOR2.35; 95% CI. 1.69, 3.26] and non-consented care [Public 45 (14.5%) vs. Private 67(21.6%): cOR0.62; 95% CI. 0.41, 0.93] were the major types of D&A during childbirth. Denial of companionship was the most reported subtype of D&A during childbirth in both facilities [Public 135 (43.5%) vs. Private66 (21.3%); cOR2.85; 95% CI. 2.00, 4.06]. Rural residents were less likely to report at least one form of D&A during childbirth (aOR 0.53; CI 0.35-0.79). Although prevalence was high in both facilities, overall prevalence of D&A during childbirth and most subtypes were higher in the public health facility. There is a need to identify contextual factors enabling D&A during childbirth in public and private health care settings.


Spectroscopic-assisted archaeometric studies to determine the production technology of the VI BC Zeus Enthroned statue (Paestum, Italy) and Pre-Roman technology transfer.
This work summarizes the spectroscopic-assisted archaeometric study of the most important terracotta statue of Poseidonia-Paestum (Italy), the so-called Zeus Enthroned (VI sec. BC). The selected analytical strategy combines the mineralogical and molecular information provided by X-Ray diffraction (XRD) and Raman analysis with the elemental data obtained from X-Ray fluorescence (XRF) and Scanning Electron Microscopy coupled to Energy Dispersive Spectrometry (SEM/EDS). To shed light on the raw materials used to create and decorate this unique artwork, the analytical results gathered in this study helped disclosing the applied production technology. As suggested by the detected mineral assemblages, the body was prepared in two steps, using calcareous clay (CC) rich in Mg- and Fe- minerals as raw materials. The inner core and the outer depurated layers were both fired in oxidizing conditions but reaching different temperatures (≥900 °C and 850-900 °C respectively). The statue was decorated by firing manganese- (jacobsite MnFe2O4) and iron- (hematite Fe2O3) oxides in oxidizing conditions. Knowing that the decoration techniques based on the use of Mn-oxides were mastered by Etruscans rather than by Ancient Greeks, the obtained results suggest a transfer of production technology across borders, thus providing an additional clue about the flourishing commercial and cultural exchanges occurred between Greek colonies and Italic pre-Roman societies.


Intracellularly studied excitability changes in coronal-pericruciate neurons following low frequency stimulation of the corticobulbar tract.
Direct intracellular measurements of excitability changes to injected current were made in 116 cortical neurons of awake cats following antidromic or orthodromic activation by repetitive, 1-6 Hz stimulation of the pes pedunculi. The predominant effect seen in antidromically activated cells was a transient decrease in excitability and input resistance. The predominant effect seen in orthodromically (transsynaptically) activated cells was a transient increase in excitability and input resistance. In the absence of accompanying change in rates of spontaneous spike activity, the above results suggest that adaptations supporting the changes in excitability and resistance occur locally to these cells.


Similar behavioural effects of 5-hydroxytryptamine and substance P injected intrathecally in mice.
Intrathecal injection of 5-hydroxytryptamine (5-HT) or of substance P in mice elicited a behavioural syndrome consisting of reciprocal hindlimb scratching and biting or licking, directed towards the caudal parts of the body. 5-Hydroxtryptamine elicited more scratching than did substance P, which in turn caused a greater number of biting or licking responses. The 5-HT-induced responses were mimicked by 5,6-dihydroxytryptamine and inhibited by the 5-HT receptor blocker metergoline. The present findings indicate that 5-HT, injected intrathecally, may have similar effects as substance P in stimulating sensory pathways in the spinal cord.


Constrictive Pericarditis: Etiologic Spectrum, Patterns of Clinical Presentation, Prognostic Factors, and Long-term Follow-up.
Some reports have described a change in the etiologic spectrum of constrictive pericarditis. In addition, data on the relationship between its clinical presentation and etiology are lacking. We sought to describe the etiologies of the disease, their relationship with its clinical presentation and surgical findings, and to identify predictors of poor outcome. We analyzed 140 consecutive patients who underwent surgery for constrictive pericarditis over a 34-year period in a single center. The etiology was idiopathic in 76 patients (54%), acute idiopathic pericarditis in 24 patients (17%), tuberculous pericarditis in 15 patients (11%), purulent pericarditis in 10 patients (7%), and cardiac surgery, radiation and uremia in 5, 3 and 2 patients respectively (4%, 2% and 1%). Mean duration of symptoms before pericardiectomy was 19 months (standard deviation, 44 months), the most acute presentation being for purulent pericarditis (26 days [range, 7-60 days]) and the most chronic for idiopathic cases (29 months [range, 4 days-360 months]). Perioperative mortality was 11%. There was no difference in mortality between etiologies. Median follow-up was 12 years (range, 0.1-33.0 years) in which 50 patients died. In a Cox-regression analysis, age at surgery, advanced New York Heart Association functional class (III to IV) and previous acute idiopathic pericarditis were associated with increased mortality during follow-up. Most cases of constrictive pericarditis are idiopathic. Cardiac surgery and radiation accounted for a minority of cases. Etiologic investigations are warranted only in acute or subacute presentations. Age, advanced functional class, and previous acute idiopathic pericarditis are associated with increased mortality.


Application of antibiotic-derived fluorescent probes to bacterial studies.
Fluorescent probes are extensively applied as useful tools for imaging and determining dynamic processes in bacterial cells. In particular, antibiotic-derived fluorescent probes which can visualize the presence or the localization of antibiotics within bacteria through the monitoring of changes in fluorescence signal, are particularly useful. They form an emerging set of tools for studying the mode of action of their parent antibiotics and examining bacterial resistance and persistence, with the long-term goal of developing fresh approaches to the treatment of drug-resistant bacterial infections. In this chapter, we discuss the applications of antibiotic-based fluorescent probes to visualize bacteria, focusing on the techniques we have utilized to study their localization, penetration and efflux. We describe detailed protocols for analysis of bacteria using microscopy, flow cytometry, and plate reader-based methods based on these probes.


High-performance metabolic profiling of plasma from seven mammalian species for simultaneous environmental chemical surveillance and bioeffect monitoring.
High-performance metabolic profiling (HPMP) by Fourier-transform mass spectrometry coupled to liquid chromatography gives relative quantification of thousands of chemicals in biologic samples but has had little development for use in toxicology research. In principle, the approach could be useful to detect complex metabolic response patterns to toxicologic exposures and to detect unusual abundances or patterns of potentially toxic chemicals. As an initial study to develop these possible uses, we applied HPMP and bioinformatics analysis to plasma of humans, rhesus macaques, marmosets, pigs, sheep, rats and mice to determine: (1) whether more chemicals are detected in humans living in a less controlled environment than captive species and (2) whether a subset of plasma chemicals with similar inter-species and intra-species variation could be identified for use in comparative toxicology. Results show that the number of chemicals detected was similar in humans (3221) and other species (range 2537-3373). Metabolite patterns were most similar within species and separated samples according to family and order. A total of 1485 chemicals were common to all species; 37% of these matched chemicals in human metabolomic databases and included chemicals in 137 out of 146 human metabolic pathways. Probability-based modularity clustering separated 644 chemicals, including many endogenous metabolites, with inter-species variation similar to intra-species variation. The remaining chemicals had greater inter-species variation and included environmental chemicals as well as GSH and methionine. Together, the data suggest that HPMP provides a platform that can be useful within human populations and controlled animal studies to simultaneously evaluate environmental exposures and biological responses to such exposures.


Pharmacoepidemiological safety studies in children: a systematic review.
In order to identify challenges in pediatric pharmacoepidemiological safety studies, we assessed the characteristics of such (published) studies. Relevant articles from inception to 2013 were retrieved from Embase and Medline. We sequentially screened titles, abstracts and full texts with independent validation. We systematically collected data regarding general information, study methods and results. Out of 4825 unique articles, 268 full texts (5.6%) were retained; 147 (54.9%) pertained to drugs rather than vaccines. Considering the 268 studies, 202 (75.4%) concerned children and adolescents (2 to 11 years) and 14 (5.3%) included preterm newborns. Most studies originated from North America (154 [57.5%]) or Europe (92 [34.3%]). Only 47 studies (17.5%) were privately funded. The majority (174 [64.9%]) were cohort studies. Out of 268 studies, 196 (73.1%) collected data retrospectively; paper medical charts were the most common data source for the exposures (85 [31.7%]) and outcomes (122 [45.5%]). Only 3 (2.0%) drug-only studies investigated rarely used drugs. Considering all 268 studies, only 27 (10.1%) reported sample size or power calculation. Most (75 [51.0%]) drug-only studies corrected confounding by multivariate modeling unlike stratification in 66 (55.9%) vaccine-only studies. Considering 75 child-only studies without any statistically significant result, 41 (54.7%) did not discuss lack of power. Although the field of pediatric pharmacoepidemiology is steadily developing evaluation seldom includes neonates, is mainly focused on few drug classes and safety outcomes and concerns mainly drug use in developed countries. Small study size is a specific challenge in pediatrics. Reporting should be improved. © 2016 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.


Ferric-Induced Pancreatic Injury Involves Exacerbation of Cholinergic and Proteolytic Activities, and Dysregulation of Metabolic Pathways: Protective Effect of Caffeic Acid.
The protective effect of caffeic acid on ferric-induced pancreatic injury was investigated using ex vivo and in silico models. Incubation of pancreatic tissues with Fe2+ led to significant depleted levels of glutathione (GSH) and SOD and catalase activities, with concomitant elevated levels of malondialdehyde (MDA) and nitric oxide (NO) and acetylcholinesterase and α-chymotrypsin activities. Treatment with caffeic acid led to significant reversion of these levels and activities. Molecular docking revealed a higher binding affinity of caffeic acid with acetylcholinesterase via hydrogen bonding, Pi-Pi stacking, and Van der Waals interactions. FTIR spectroscopy of pancreatic metabolite revealed little or no effect by caffeic acid on functional groups in ferric-induced injured pancreas. The LC-MS analysis of the metabolites revealed Fe2+ caused a 20% depletion of the normal metabolites, with concomitant generation of glyceraldehyde and 3,4-dihydroxymandelaldehyde. Treatment with caffeic acid led to the restoration of TG(22:4(7Z,10Z,13Z,16Z)/24:0/22:5(7Z,10Z,13Z,16Z,19Z)) and dTDP-D-glucose, while depleting glyceraldehyde as well as activating gluconeogenesis. These results indicate the ability of caffeic acid to protect against ferric toxicity by exacerbating antioxidative activities, with concomitant inhibition of MDA and NO levels while deactivating metabolic pathways linked to oxidative stress.


Multiple primary cancers in Indian population: metachronous and synchronous lesions.
A retrospective study of 177 patients attending Tata Memorial Hospital over a period of 40 years from 1942 through 1981 is presented. These patients who had "primary lesions" in the head and neck region, breast, esophagus, lung, and elsewhere as carcinoma or sarcoma developed "second primary" at different sites, after the treatment for the primary lesion after a variable period over years--as "metachronous lesions" (139 patients). Another group of patients presented with "double primary" at initial clinical examination and investigations, and these were "synchronous" lesions (38 patients). The analysis brings out the relationship of these lesions in both groups to each other with reference to habits in Indian population, viz, pan chewing, tobacco smoking, and alcohol consumption and time interval and histological variations among these lesions. An interesting relationship has been observed in certain aerodigestive tract primary lesions developing second cancer due to continued effect of "carcinogens," as habits are hard to die even after developing cancer. Analysis also brings out an interesting observation of involvement of "physiologically and anatomically" related organs developing second cancer at an interval or concurrently. A solitary pulmonary nodule or an opacity in a patient with extrathoracic cancer should not be considered as "metastatic" unless proved otherwise; metachronous lesions need to be treated energetically, adequately, efficiently, and aggressively in certain clinical situations for better results and salvage.


Increased duration of laser environmental enrichment increased broiler physical activity and pen-wide movement without altering tibia measurements.
Inactivity and leg disorders negatively impact broiler welfare. Enrichment designed to increase barn complexity may encourage physical exercise. The study aim was to implement a second-generation laser enrichment device, previously shown to increase broiler activity, for extended periods of time and to measure behavior and tibia quality. A total of 1,360 Ross 708 broilers in 40 pens of 34 were assigned to laser enrichment or control (no laser enrichment) for 49 d. Seventy focal birds were randomly selected on d 0 for individual behavior analysis. Laser-enriched birds were exposed to 6-min laser periods 4 times daily. A 3-min novel object test was performed on all pens and tonic immobility was induced on 1 bird/pen on wk 1 and 6. Focal bird time budget and walking distance and pen-wide laser-following behavior and movement were obtained during laser periods d 0 to 8 and 1 d/wk through wk 7. Right tibias were collected from focal birds on d 49 for dual energy x-ray absorptiometry and bone breaking analysis. Time spent active during laser periods was increased on d 3, 6, and 8 and wk 2 to 3 in laser-enriched vs. control focal birds (P = 0.04). Time at the feeder was increased in laser-enriched focal birds on d 0, 3 to 4, and 8 and wk 2 and 4 (P < 0.01). Distance walked during laser periods was increased in laser-enriched focal birds on d 1, 3 to 5, 8, and wk 2 compared to the control (P < 0.01). Pen-wide movement was increased on d 0, 2, 4 to 8, and wk 1 to 5 and 7 in laser-enriched vs. control birds (P < 0.01). More laser-enriched broilers were within 25 cm of the novel object at 1 min 30 s than the control (P = 0.03), and latency to approach the novel object was reduced in both treatments at wk 6 compared to wk 1 (P < 0.01). Tonic immobility duration was increased by 123 s on wk 6 compared to wk 1, regardless of treatment (P < 0.01). Daily laser enrichment for extended periods increased bird activity without inducing fearfulness or altering tibia measures.


Nerve conduction studies: basic concepts and patterns of abnormalities.
As a fundamental component of the electrodiagnostic evaluation, nerve conduction studies provide valuable quantitative and qualitative insights into neuromuscular function. Nerve conduction studies are useful in the identification and characterization of several neuromuscular disorders, particularly disorders of peripheral nerve. Abnormalities of nerve conduction studies may anticipate specific pathologic processes, such as demyelination or axonal loss, and may provide precise localization of focal nerve lesions. As with other elements of the electrodiagnostic evaluation, nerve conduction studies must be performed with careful attention to technique and must be interpreted in a clinical context.


Safety and efficacy of apatinib in patients with advanced gastric or gastroesophageal junction adenocarcinoma after the failure of two or more lines of chemotherapy (AHEAD): a prospective, single-arm, multicenter, phase IV study.
Apatinib, a highly selective VEGFR2 inhibitor, significantly improved efficacy versus placebo as a third- and later-line treatment for advanced gastric cancer in phase 2 and 3 trials. This prospective, single-arm, multicenter phase IV AHEAD study was conducted to verify the safety and efficacy of apatinib in patients with advanced or metastatic gastric or gastroesophageal adenocarcinoma after at least two lines of systematic therapy in clinical practice settings. Patients with advanced gastric cancer who had previously failed at least two lines of chemotherapy received oral apatinib until disease progression, death or unacceptable toxicity. The primary endpoint was safety. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Adverse events were summarized by the incidence rate. Median OS and PFS were estimated using the Kaplan-Meier method. ORR, DCR, OS at 3 and 6 months, and PFS at 3 and 6 months were calculated, and their 95% CIs were estimated according to the Clopper-Pearson method. Between May 2015 and November 2019, a total of 2004 patients were enrolled, and 1999 patients who received at least one dose of apatinib were assessed for safety. In the safety population, 87.9% of patients experienced treatment-related adverse events (TRAEs), with the most common hypertension (45.2%), proteinuria (26.5%), and white blood cell count decreased (25.3%). Additionally, 51% of patients experienced grade ≥ 3 TRAEs. Fatal TRAEs occurred in 57 (2.9%) patients. No new safety concerns were reported. Among the 2004 patients included in the intention-to-treat population, the ORR was 4.4% (95% CI, 3.6-5.4%), and DCR was 35.8% (95% CI, 33.7-38.0%). The median PFS was 2.7 months (95% CI 2.2-2.8), and the median OS was 5.8 months (95% CI 5.4-6.1). The findings in the AHEAD study confirmed the acceptable and manageable safety profile and clinical benefit of apatinib in patients with advanced gastric cancer as a third- or later-line of treatment. This study was registered with ClinicalTrials.gov NCT02426034. Registration date was April 24, 2015.


Adipokines and systemic inflammation in weight-losing lung cancer patients.
Cancer cachexia is a devastating condition leading to loss of function and independence, decreased performance status, decreased quality of life, and poor prognosis. Adipokines play a role in a wide variety of physiological or pathological processes, including immunity and inflammation, in addition to having significant effects on metabolism and lipogenesis. The objective of the present study was to investigate the relationship of adipokines and systemic inflammation in weight-losing advanced-stage non-small-cell lung cancer (NSCLC) patients. Sixty-three male NSCLC patients (stages III and IV) and 25 age- and sex-matched controls were included. NSCLC patients were further divided into subgroups as those with a>5% weight loss in last 6 months and those who did not. Serum leptin, adiponectin, and TNF-α concentrations were measured by ELISA using commercially available kits. The positive acute-phase reactants (APR) CRP, leukocyte, ferritin, thrombocyte, and fibrinogen were higher in the NSCLC group. Serum albumin level (which is a negative APR) was lower in the cancer group, whereas there was no difference in transferrin level between the groups. TNF-α and leptin concentrations were similar in the cancer group and the control group, whereas adiponectin was lower in the cancer group. There was a difference in thrombocyte and transferrin levels between patients with and without weight loss, whereas CRP, TNF-α, and adiponectin levels were similar. Leptin was lower in weight-losing cancer patients. However, there was no correlation between adipokines and markers of systemic inflammation. These results revealed a lack of association between adipokine levels and systemic inflammation with cancer cachexia.


Increases in the seaward river flux of nutrients driven by human migration and land-use changes in the tide-influenced delta.
Most large megacities are located on areas adjacent to tide-influenced deltas. However, contribution of megacities to seaward nutrient fluxes in tide-influenced deltas are poorly quantified in regional and global levels. We analyzed nutrient concentrations and water current data for a large and tide-influenced delta, the Changjiang (Yangtze River) since 1980. Concentrations, species ratios and fluxes of nutrients in tide-influenced delta has been found to differ dramatically from those at upstream. Over the period 2004 to 2015, the seaward nutrient fluxes of dissolved inorganic nitrogen and dissolved silica increased by 5%-10%, but dissolved inorganic phosphorus increased by 15%-20%, in the tide-influenced delta of the Changjiang. Consequently, the DIP/DIN decreases by 11% and DIP/DSi increases by 14% at the river mouth relative to those farther upstream the tidal limit. The legacy and/or recycled contribution accounts for 10%-30% of this increased nutrient flux, hence additional sources are predominantly those involving anthropogenic land-use changes. These findings have implications not only for the Changjiang but also for other riverine systems with respect to management strategy. Nutrient dynamics in tide-influenced deltas near urban areas should receive increased research and policy attention. By not considering nutrient sources in tide-influenced deltas, knowledge of the seaward fluxes and species ratios of nutrients from land sources is incomplete and can be biased, to the point that assessments of their impacts on adjacent marine environments may be inaccurate and mitigation policies therefore ineffective.


Gender Disparities in Complications, Costs, and Mortality After Emergency Gastrointestinal Surgery in Kenya.
Little is known about the impact of gender on emergency surgery within Kenya. Therefore, we aimed to investigate the association of gender on outcomes of postoperative complications, health care costs, and mortality. We evaluated an established cohort of patients undergoing emergency gastrointestinal surgery in rural Kenya between January 1st, 2016 and June 30th, 2019. Utilizing logistic regression, we examined the association between self-reported patient gender and the outcomes of postoperative complications and mortality. A generalized linear model was created for total hospital costs, inflation-adjusted in international dollars purchasing power parity, to examine the impact of gender. Confounding factors were controlled by Africa Surgical Outcomes Study Surgical Risk Score. Among 484 patients reviewed, 149 (30.8%) were women. 165 (34.1%) patients developed complications, with women experiencing more than men (40.9% versus 31.0%; P = 0.03) and longer hospital stays (median 6 days (4-9) versus 5 (4-7); P = 0.02). After controlling for Africa Surgical Outcomes Study Surgical Risk Score, odds of developing complications for women were 1.67 (95% confidence interval: 1.09-2.55; P = 0.019) times higher than men, and the odds of death were 2.38 (95% confidence interval: 1.12-5.09; P = 0.025) times greater for women than men, despite similar failure-to-rescue rates and intensive care unit utilization. Total hospital costs were increased for women by 531 international dollars purchasing power parity (117-946; P = 0.012) when compared to men, attributed to longer lengths of stay. These findings demonstrate that a discrepancy exists between men and women undergoing emergency gastrointestinal surgery in our setting. Further exploration of the underlying causes of this inequity is necessary for quality improvement for women in rural Kenya.


Brachial plexus meningioma, report of a case with immunohistochemical and ultrastructural examination.
Peripheral nerve meningiomas are exceedingly rare neoplasms of controversial origin; only four cases have been reported. Proposed origins of ectopic meningiomas include extradural trapping of arachnoid cells during embryogenesis, ectopic migration of arachnoid cell nests with the developing peripheral nerve, and metaplasia of mature peripheral nerve sheath cells or a common progenitor cell. In this report of a meningioma of the brachial plexus, immunohistochemical and ultrastructural examinations of the tumor matched all the criteria of a traditional meningioma but failed to clarify the origins of such neoplasms.


Metabolic profiling and targeted lipidomics reveals a disturbed lipid profile in mothers and fetuses with intrauterine growth restriction.
Fetal growth may be impaired by poor placental function or maternal conditions, each of which can influence the transfer of nutrients and oxygen from the mother to the developing fetus. Large-scale studies of metabolites (metabolomics) are key to understand cellular metabolism and pathophysiology of human conditions. Herein, maternal and cord blood plasma samples were used for NMR-based metabolic fingerprinting and profiling, including analysis of the enrichment of circulating lipid classes and subclasses, as well as the number of sub-fraction particles and their size. Changes in phosphatidylcholines and glycoproteins were prominent in growth-restricted fetuses indicating significant alterations in their abundance and biophysical properties. Lipoprotein profiles showed significantly lower plasma concentrations of cholesterol-intermediate density lipoprotein (IDL), triglycerides-IDL and high-density lipoprotein (HDL) in mothers of growth-restricted fetuses compared to controls (p < 0.05). In contrast, growth-restricted fetuses had significantly higher plasma concentrations of cholesterol and triglycerides transporting lipoproteins [LDL, IDL, and VLDL, (p < 0.005; all)], as well as increased VLDL particle types (large, medium and small). Significant changes in plasma concentrations of formate, histidine, isoleucine and citrate in growth-restricted fetuses were also observed. Comprehensive metabolic profiling reveals that both, mother and fetuses of pregnancies complicated with fetal growth restriction have a substantial disruption in lipid metabolism.


Optimal timing of surgical intervention following adult laryngeal trauma.
Laryngeal trauma is an infrequent diagnosis with a scarcity of published data. We aim to further define the factors associated with positive surgical outcomes of adult laryngeal trauma. Multi-institution database analysis. Of the 1.9 million trauma cases from the National Trauma Database (NTDB), 564 adult trauma events were selected with ICD-9 codes specific to laryngeal trauma. Laryngeal trauma was seen predominately in white (61.5%), middle-aged (40.6 years), male (83.7%) patients experiencing blunt (70.7%) laryngeal injury with multiorgan system (92.2%) trauma. There was an overall 17.9% mortality rate. Within the 564 cases, 133 direct laryngoscopies, 185 tracheostomies, 53 laryngeal suturing, and 60 laryngeal fracture repairs were performed. In univariate negative binomial regression models, trauma severity (P ≤ .01), placement of tracheostomy (P lt; .01), and delayed tracheostomy placement (P = .04, .03, .048) were associated with increased ventilator dependence, intensive care unit (ICU) stay, and overall hospital admission duration. Multivariate regression models demonstrated significant associations between tracheostomy performed within 24 hours and shortened ICU stay (P = .03, β = -.28, SE = 1.7) and overall hospital stay (P = .009, β = -.23, SE = 3.1). The NTDB allows study of the largest laryngeal trauma cohort in modern literature. Although complexities arise in the treatment of laryngeal traumas, when indicated, surgical airway should be placed within 24 hours of presentation to improve the overall hospital course.


Factors influencing cumulative radiation dose from percutaneous intra-abdominal abscess drainage in the setting of inflammatory bowel disease.
Patients with inflammatory bowel disease (IBD) are at risk for intra-abdominal abscesses requiring CT-guided drainage. These patients are at baseline risk of high cumulative radiation exposure from imaging, which may be exacerbated by CT-guided drainage. This study aimed to determine the radiation dose associated with percutaneous drainage in the setting of IBD and identify risk factors associated with high exposure. An IRB-approved single-center retrospective study was performed to identify patients with IBD who underwent percutaneous abscess drainage over a 5-year period. An episode of drainage was defined from drain placement to removal, with all intervening procedures and diagnostic CT scans included in the cumulative radiation dose. The mean cumulative effective dose for a drainage episode was 47.50 mSv. The mean duration of a drainage episode was 68.7 days. Patients with a cumulative dose greater than 50 mSv required higher number of follow-up visits compared to patients with less than 50 mSv (6.9 vs. 3.5, p = 0.003*). Patients with higher cumulative dose were also more likely to require drain upsize (54% vs. 13%, p = 0.01*) or additional drain placement (63% vs 24%, p = 0.03*) compared to patients with lower dose. Intra-abdominal abscess drainage may be associated with significant cumulative radiation exposure. Requirement of drain upsizing or additional drain placement were associated with higher cumulative radiation dose, which may be related to more severe underlying inflammatory bowel disease.


Enhanced DNA Profiling of the Semen Donor in Late Reported Sexual Assaults: Use of Y-Chromosome-Targeted Pre-amplification and Next Generation Y-STR Amplification Systems.
In some cases of sexual assault the victim may not report the assault for several days after the incident due to various factors. The ability to obtain an autosomal STR profile of the semen donor from a living victim rapidly diminishes as the post-coital interval is extended due to the presence of only a small amount of male DNA amidst an overwhelming amount of female DNA. Previously, we have utilized various technological tools to overcome the limitations of male DNA profiling in extended interval post-coital samples including the use of Y-chromosome STR profiling, cervical sample, and post-PCR purification permitting the recovery of Y-STR profiles of the male DNA from samples collected 5-6 days after intercourse. Despite this success, the reproductive biology literature reports the presence of spermatozoa in the human cervix up to 7-10 days post-coitus. Therefore, novel and improved methods for recovery of male profiles in extended interval post-coital samples were required. Here, we describe enhanced strategies, including Y-chromosome-targeted pre-amplification and next generation Y-STR amplification kits, that have resulted in the ability to obtain probative male profiles from samples collected 6-9 days after intercourse.


Large- and small-scale effects of habitat structure on rates of predation: how percent coverage of seagrass affects rates of predation and siphon nipping on an infaunal bivalve.
Landscape ecology, predominantly a terrestrial discipline, considers the effect of large-scale (tens of meters to kilometers) spatial patterns of habitats on ecological processes such as competition, predation, and flow of energy. In this study, a landscape-ecology approach was applied to a marine soft-sediment environment to examine rates of predation and transfer of secondary production in and around vegetated habitats. Seagrass beds naturally occur in a variety of spatial configurations from patches 1-10s of meters across with interspersed unvegetated sediments (i.e., patchy coverage) to more continuous coverage with little or no bare sediment. I designed experiments to address how percent coverage of seagrass in a 100-m2 area of seafloor, and the spatial arrangement (degree of patchiness or fragmentation) of an equal area (100 m2) of vegetation affected predation (lethal) and siphon nipping (sublethal) intensity on an infaunal bivalve, Mercenaria mercenaria (hard clam). Measures of seagrass density and biomass with different percent coverage of seagrass were also made. When clams were placed in both the vegetated and unvegetated portions of the seafloor nearly twice as many clams were recovered live with 99% seagrass cover than with 23% seagrass cover, while survivorship was intermediate with 70% cover. Cropping of clam siphons from both the vegetated and unvegetated sediments was also affected by the amount of seagrass cover in a 100-m2 area of seafloor: mean adjusted siphon weights were approximately 76% heavier from the 99% seagrass cover treatment than from the 70% or 23% cover treatments. Survivorship of clams placed within an equal area of seagrass in very patchy, patchy, and continuous spatial configurations was 40% higher in the continuous seagrass treatment than in either of the two patchy treatments. This study demonstrates that transfer of secondary production in the form of predation and cropping on an infaunal organism is altered as the percent cover of seagrass changes. While large-scale changes in the amount and spatial patterning of vegetation may affect habitat utilization patterns and foraging HGLoopbehavior, increased seagrass density and biomass with increased percent coverage of seagrass limit any conclusions concerning predator foraging behavior and feeding success in response to patch shapes and sizes. Instead, local changes in seagrass characteristics provide the most compelling explanation for the observed results.


High incidence of trigger finger after carpal tunnel release: a systematic review and meta-analysis.
Trigger finger (TF) often occurs after carpal tunnel release (CTR), but the mechanism and outcomes remain inconsistent. This study evaluated the incidence of TF after CTR and its related risk factors. PubMed, Embase, and Scopus databases were searched up to 27 August 2022, with the following keywords: "carpal tunnel release" and "trigger finger". Studies with complete data on the incidence of TF after CTR and published full text. The primary outcome was the association between CTR and the subsequent occurrence of the TF and to calculate the pooled incidence of post-CTR TF. The secondary outcomes included the potential risk factors among patients with and without post-CTR TF as well as the prevalence of the post-CTR TF on the affected digits. Ten studies with total 10,399 participants in 9 studies and 875 operated hands in one article were included for meta-analysis. CTR significantly increases the risk of following TF occurrence (odds ratio=2.67; 95% CI 2.344-3.043; P <0.001). The pooled incidence of TF development after CTR was 7.7%. Women were more likely to develop a TF after CTR surgery (odds ratio=2.02; 95% CI 1.054-3.873; P =0.034). Finally, the thumb was the most susceptible fingers, followed by middle and ring fingers. High incidence of TF comes after CTR, and women were more susceptible than man. Clinicians were suggested to notice the potential risk of TF after CTR in clinical practice. Level III, meta-analysis.


Studies of alteration of hepatic cholesterol metabolism in puromycin-induced nephrotic syndrome in rats.
Hypercholesterolemia frequently accompanies the nephrotic syndrome, but the mechanism responsible for elevation of plasma cholesterol is poorly understood. Specifically, the contribution of abnormal hepatic cholesterol metabolism to elevated concentrations of serum cholesterol has never been studied in depth. The objective of the present study was to define the alteration of hepatic cholesterol metabolism in puromycin induced nephrotic syndrome in rats. Studies involved measurements of specific activities of four enzymes participating in the maintenance of hepatic cholesterol metabolism: HMG-CoA-reductase, the rate limiting enzyme of cholesterol synthesis; cholesterol 7 alpha-hydroxylase, the rate limiting enzyme in bile acid synthesis; acyl CoA: cholesterol acyltransferase, the enzyme responsible for esterification of cholesterol; and cholesterol ester hydrolase (CEH), an enzyme which hydrolyzes cholesterol. Multiple injections of puromycin resulted in a production of nephrotic syndrome with massive proteinuria, hypoalbuminemia, hypercholesterolemia, ascites and edema. HMG-CoA-reductase (nmol/hr/mg protein) and cholesterol 7 alpha-hydroxylase activities (nmol/hr/mg protein) in rats with nephrotic syndrome were not statistically significant as compared to control rats (4.0 +/- 0.7 and 2.0 +/- 0.6 vs. 3.3 +/- 0.4 and 1.6 +/- 0.2), respectively. Our results also demonstrate, for the first time, that the normal diurnal rhythm in HMG-CoA reductase activity is no longer present in the nephrotic animals. The activities in the nephrotics in the day was 4.0 nmol/hr/mg and at night, 3.9 nmol/hr/day, compared to the control values of 3.3 nmol/hr/mg in the day and 6.9 nmol/hr/mg at night. ACAT activities were 428 +/- 78 versus 302 +/- 64 pmol/min/mg/protein (P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)


Iron supplementation during pregnancy.
As pregnancy proceeds most women show hematologic changes suggesting iron deficiency. In this study iron dynamics are investigated by determining concentrations of hemoglobin, serum ferritin and serum transferrin in two groups of pregnant women. One group did not receive iron, the other received 105 mg iron/day. Without iron supplementation normal maternal iron stores are almost exhausted during the second and third trimester of pregnancy.


Bilateral tear film alterations in patients with unilateral quiescent herpes simplex keratitis.
To evaluate bilateral tear function and corneal sensitivity in patients with unilateral quiescent herpes simplex keratitis (HSK) and determine the correlation between corneal sensitivity and tear secretion in both eyes. Thirty-five patients diagnosed with unilateral quiescent HSK and 35 heathy controls were included in this study. Bilateral tear osmolarity, Schirmer's test, the tear break-up time (TBUT) and corneal sensitivity were measured in all participants. In the HSK group, both eyes demonstrated a significant increase in tear osmolarity, and a decrease in Schirmer's test and the TBUT compared with healthy controls (All p < 0.001). The bilateral tear osmolarity and Schirmer's test were similar, but the TBUT (4.9 ± 2.1 versus 7.4 ± 2.0 second; p < 0.001) and corneal sensitivity (35.1 ± 1.9 versus 54.3 ± 0.8 mm; p < 0.001) were significantly lower in the affected eyes. The bilateral tear osmolarity, Schirmer's test and the TBUT were significantly correlated with corneal sensitivity of the affected eye (All p < 0.001). When corneal sensitivity of the unaffected eye was treated as a control variable, tear osmolarity (R = -0.626, p < 0.001), Schirmer's test (R = 0.739, p < 0.001) and the TBUT (R = 0.691, p < 0.001) of the unaffected eyes were still significantly correlated with the corneal sensitivity of the affected eyes. Unilateral quiescent HSK causes bilateral tear impairment, which depends on the loss of corneal sensitivity in the affected eye. In the affected eye with severe corneal sensitivity loss, bilateral dry eye occurred.


Conceptions of authority within contemporary social work practice in managed mental health care organizations.
This article examines how social workers may use their authority to create managed mental health care organizations that support the principles and values of professional social work practice. By exploring research and theoretical contributions from a multidisciplinary perspective, the author suggests ways that social workers may incorporate empowerment strategies into their organizational practices to create more socially responsible and humane mental health organizations.


Computational Models for Predictive Cardiac Ion Channel Pharmacology.
A wealth of experimental data exists describing the elementary building blocks of complex physiological systems. However, it is increasingly apparent in the biomedical sciences that mechanisms of biological function cannot be observed or readily predicted via study of constituent elements alone. This is especially clear in the longstanding failures in prediction of effects of drug treatment for heart rhythm disturbances. These failures stem in part from classical assumptions that have been made in cardiac antiarrhythmic drug development - that a drug operates by one mechanism via one target receptor that arises from one gene.


Subcutaneous and sublingual immunotherapy in children: complete update on controversies, dosing, and efficacy.
For this review, articles on immunotherapy dosing in pediatric respiratory allergy were identified via PubMed, through congressional abstracts for 2008, in reference lists of recent review articles, and via personal communication with experts. In pediatric subcutaneous immunotherapy (SCIT), doses shown to be effective, mostly in aluminium-adsorbed preparations administered every 6 weeks, contain 20 microg of group 5 major allergen, 12 microg Bet v 1, 15 microg Fel d 1, and 5 to 20 microg Der p 1. Evidence indicates that SCIT prevents new sensitizations and asthma onset 7 years after discontinuation and reduces symptoms 12 years after a 5-year SCIT course, even though skin reactivity returns. Consistent evidence of effect exists for sublingual immunotherapy in pediatric respiratory allergy with daily 15- to 25-microg grass group 5 major allergen and 6 microg Bet v 1. Der p/f doses of 0.8/0.4 microg three times weekly (up to 27/57 microg daily) demonstrate inconsistent findings. Evidence of effect exists for SCIT in pediatric allergic rhinitis and asthma as treatment and preventive management. Evidence of effect exists for sublingual immunotherapy in pediatric allergic rhinoconjunctivitis and seasonal asthma. Similar results are doubtful for perennial asthma.


Role of phosphatidylinositol signaling pathway in the development of cross-resistance of tumor cells to hormonal cytostatics and hypoxia.
Long-term in vitro culturing of CaOv ovarian adenocarcinoma cells in the presence of a synthetic analogue of glucocorticoid hormone dexamethasone allowed us to obtain a subline of CaOv/D cells resistant to the antiproliferative effect of dexamethasone and characterized by high resistance to hypoxia. It was found that CaOv/D cells are characterized by constitutive increase in phosphatidylinositol 3-kinase expression and hypersecretion of vascular endothelial growth factor VEGF-A. Culturing of cells under hypoxic conditions was accompanied by a significant increase in phosphatidylinositol 3-kinase expression and VEGF-A synthesis. Experiments with cell transfection with phosphatidylinositol 3-kinase catalytic subunit proved its participation in the regulation of VEGF-A synthesis and maintenance of cell growth under condition of hypoxia. Our results indicate that coordinated activation of phosphatidylinositol 3-kinase and VEGF-A can be a factor determining the development of cross-resistance of tumor cells to hormonal cytostatics and hypoxia.


Cerebral microinfarcts: a systematic review of neuropathological studies.
Vascular cognitive impairment is an umbrella term for cognitive dysfunction associated with and presumed to be caused by vascular brain damage. Autopsy studies have identified microinfarcts as an important neuropathological correlate of vascular cognitive impairment that escapes detection by conventional magnetic resonance imaging (MRI). As a frame of reference for future high-resolution MRI studies, we systematically reviewed the literature on neuropathological studies on cerebral microinfarcts in the context of vascular disease, vascular risk factors, cognitive decline and dementia. We identified 32 original patient studies involving 10,515 people. The overall picture is that microinfarcts are common, particularly in patients with vascular dementia (weighted average 62%), Alzheimer's disease (43%), and demented patients with both Alzheimer-type and cerebrovascular pathology (33%) compared with nondemented older individuals (24%). In many patients, multiple microinfarcts were detected. Microinfarcts are described as minute foci with neuronal loss, gliosis, pallor, or more cystic lesions. They are found in all brain regions, possibly more so in the cerebral cortex, particularly in watershed areas. Reported sizes vary from 50 μm to a few mm, which is within the detection limit of current high-resolution MRI. Detection of these lesions in vivo would have a high potential for future pathophysiological studies in vascular cognitive impairment.


Impact of deceased organ donor injection drug use on donor culture positivity and recipient outcomes.
Due to the ongoing opioid epidemic in the United States, deceased organ donors increasingly have a history of injection drug use (IDU), raising concerns about infectious risks to solid organ transplant (SOT) recipients. We sought to determine how recent IDU among deceased organ donors impacted donor culture results and recipient outcomes. A retrospective cohort study was performed at three transplant centers. Exposed donors were those with "recent IDU" (in the prior 12 months). Primary outcomes included (1) positive donor cultures for bacteria or Candida species, (2) recipient bacterial or Candida infection within 3 months posttransplant, and (3) recipient graft failure or death within 12 months posttransplant. Mixed effects multivariable regression models were used to evaluate the relationship between recent donor IDU and each outcome. A total of 658 SOT recipients who received organs from 394 donors were included. Sixty-six (17%) donors had a history of recent IDU. Recent IDU in donors was associated with a significantly increased odds of donor culture positivity (aOR 3.65, 95% CI 1.06-12.60, p = .04) but was not associated with SOT recipient infection (aHR 0.98, 95% CI 0.71-1.36, p = .92) or graft failure or death (aHR 0.67, 95% CI 0.29-1.51, p = .33). Donors with recent IDU are more likely to have positive cultures, but their recipients' outcomes are unaffected, suggesting organs from donors with recent IDU may be safely utilized.


Characteristics and Prognosis of Patients With Fibromuscular Dysplasia in a Population of Spontaneous Coronary Artery Dissections (from the French Registry of Spontaneous Coronary Artery Dissections "DISCO").
Spontaneous coronary artery dissection (SCAD) and fibromuscular dysplasia (FMD) are pathologies that appear to be closely related. This study compares the characteristics of the FMD population to the non-FMD population in a SCAD cohort. It thus assesses the involvement of the FMD phenotype in a SCAD population. From the data of the French DISCO registry, we included patients with a diagnosis of SCAD and in whom a search for FMD was performed. We collected the following characteristics of this population: the clinical and angiographic presentation, the data concerning the management, and the events occurring during the follow-up. In the 373 SCADs confirmed in the DISCO registry, we obtained imaging data for 340 of them. FMD was found in 45% of cases. The mean age was higher in the FMD group, 53.2 ± 8.8 years, versus 50.1 ± 11 years in the non-FMD group. High blood pressure and postmenopausal status were significantly higher in the FMD group. Clinical presentation, angiographic data, and management were comparable. The major adverse cardiac event rate and recurrence rate were not different between the 2 groups after 1 year of follow-up. In conclusion, we confirmed a 45% prevalence of FMD in the SCAD population. The median age was higher in the FMD group, suggesting that FMD may develop over time. The rate of major adverse cardiac events and recurrence were similar in the FMD group versus the non-FMD group after 1 year of follow-up.


An adventitious viral contaminant in commercially supplied A549 cells: identification of infectious bovine rhinotracheitis virus and its impact on diagnosis of infection in clinical specimens.
The isolation and identification of an adventitious viral agent, infectious bovine rhinotracheitis virus, in one lot of A549 cells from a commercial supplier is described in this report. The presence of infectious bovine rhinotracheitis virus in A549 cells was unexpected and has caused problems in the diagnosis of infections in clinical specimens in three laboratories.


Distribution of molecular breast cancer subtypes among Tunisian women and correlation with histopathological parameters: a study of 194 patients.
According to the immunohistochemical test of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (Her-2), breast cancer can be divided into 4 molecular subtypes: luminal A, luminal B, Her-2, and basal-like. The purpose of this study is to correlate these subtypes with clinicopathological features. We have selected from the files of our Pathology Department 194 breast carcinomas which had already been studied for ER, PR, and Her-2, diagnosed between January 2008 and October 2009. The cases were classified into 4 molecular subtypes. The clinicopathological characteristics of each subtype were compared. The luminal A subtype was the most prevalent (51.5%). The basal-like and Her-2 subtypes were significantly correlated to a large tumor size, a high tumor grade, and a high-volume nodal involvement (≥4). On multivariate analysis, patients with the Her-2 and basal-like subtypes were 4.2 (95% CI, 1.3-13.5) times more likely to have developed metastases in four or more lymph nodes than those with luminal tumors. Our analysis revealed that the Her-2 and basal-like subtypes are correlated with factors associated with a poor prognosis. The luminal A subtype is the commonest subtype, showing that breast cancer in Tunisia has no aggressive phenotype.


RNA editing of AMPA receptor subunit GluR-B: a base-paired intron-exon structure determines position and efficiency.
A functionally critical position (Q/R site) of the AMPA receptor subunit GluR-B is controlled by RNA editing that operates in the nucleus, since in brain and clonal cell lines of neural origin, unspliced GluR-B transcripts occur edited in the Q/R site CAG codon and, additionally, in intronic adenosines. Transfection of GluR-B gene constructs into PC12 cells revealed that the proximal part of the intron downstream of the unedited exonic site is required for Q/R site editing. This intron portion contains an imperfect inverted repeat preceding a 10 nt sequence with exact complementarity to the exon centered on the unedited codon. Single nucleotide substitutions in this short intronic sequence or its exonic complement curtailed Q/R site editing, which was recovered by restoring complementarity in the respective partner strand. Base conversion in the channel-coding region of GluR-B directed by base paired sequences may be executed by a ubiquitous nuclear adenosine deaminase specific for double-stranded RNA.


Electronic structure and UV spectrum of fenofibrate in solutions.
The structure and UV spectra of fenofibrate have been evaluated in gas phase and in solutions using time dependent density functional theory (TDDFT) method at the B3LYP/6-31G(d), B3LYP/6-311G(d,p) and B3LYP/6-311++G(d,p) levels. The solvent effects have been taken into account based on the polarizable continuum model (PCM). The computed results appear that the introduction of dielectric medium has slight effect on the molecular geometry of fenofibrate. There is one allowed excited state presenting the strongest oscillator strength in the UV region, which is associated with the HOMO-->LUMO and HOMO-1-->LUMO transition both in gas phase and in solutions. The prediction of the lambda(max) in THF, ethanol and DMSO is 285 nm, 286 nm and 287 nm, respectively, which are in a good agreement with experimental data of 284 nm, 285 nm and 288 nm. The results demonstrate that TDDFT-PCM is a useful tool for study of the electronic absorption in solutions.