Re-evaluating Safe Osmolarity for Peripheral Parenteral Nutrition in Neonatal Intensive Care Patients.
To reach nutrition goals for neonatal patients, institutions often exceed the American Society for Parenteral and Enteral Nutrition recommended maximum of 900 mOsm/L for peripheral parenteral nutrition (PPN). Evidence is limited regarding the safety of PPN osmolarities above this maximum, specifically in neonatal patients. The purpose of this study was to determine if PPN with osmolarities ≥ 1000 mOsm/L is associated with an increased rate of line-related complications. This retrospective study included infants admitted to the Penn State Health Children's Hospital NICU from January 1, 2013, through July 31, 2018, who were receiving PPN, to assess if solutions with osmolarities ≥ 1000 mOsm/L versus < 1000 mOsm/L are associated with increased rates of line-related complications. A total of 200 patients were included in the study, and 618 individual PPN days were analyzed. Baseline patient characteristics were similar between groups. The PPN osmolarities ranged from 610 to 1267 mOsm/L. Overall, the incidence of line-related complications for PPN < 1000 (n = 342 PPN days) and ≥ 1000 mOsm/L (n = 276 PPN days) was 28.9% and 29.0%, respectively (OR 1.00 [95% CI 0.72-1.40, p = 0.99]). Irrespective of PPN osmolarity, infants weighing > 1.5 kg had significantly greater odds of experiencing line complications compared with patients < 1 kg, but showed no difference compared with patients weighing 1 to 1.5 kg. There were no significant differences in the incidence of line-related complications in NICU patients receiving PPN with osmolarities 1000 to 1250 versus < 1000 mOsm/L.


Myopericarditis in tuberculous pericardial effusion: prevalence, predictors and outcome.
The prevalence, predictors and outcome of myopericarditis in patients with tuberculous (TB) pericarditis are unknown. Eighty-one patients (mean age±SD, 36.1±13.3 years; 54 (66.7%) men; 58 (71.6%) HIV seropositive) with TB pericarditis were recruited between January 2006 and September 2008. Myopericarditis was defined as echocardiographic LV systolic dysfunction (immediately after pericardiocentesis), elevated peripheral blood troponin T (>0.03 ng/mL), or elevated peripheral blood creatine kinase (CK >174 IU/L) with a CK:CK-myocardial band (MB) mass ratio of >6%. The outcome measure was case fatality rate at 6 months of follow-up. Myopericarditis was present in 43 (53.1%) patients. Patients with myopericarditis, as compared with those without, were more likely to be HIV seropositive (35 (81.4%) vs 23 (60.5%) respectively, p=0.038) and have lower peripheral CD4 count (median (IQR) 98 (54-290) vs 177 (104-429), p=0.026). Electrocardiographic ST segment elevation was more common in myopericarditis (15 (36.6%) vs 4 (10.8%), p=0.008) and predicted myopericarditis independently of CD4 count on multiple logistic regression analysis (OR 4.36, 95% CI 1.34 to 17.34, p=0.0132). At 6 months, 14 (18%) patients had died with no significant difference between those with or without myopericarditis (6/42 (14%) vs 8/36 (22%), respectively (p=0.363)). Myopericarditis is common in TB pericardial effusion and associated with HIV-related immunosuppression. It can be identified by electrocardiographic ST-elevation, particularly when peripheral CD4 count is low. There was no significant difference in case fatality rate in those with or without myopericarditis.


On the problems related to natural wet bulb temperature indirect evaluation for the assessment of hot thermal environments by means of WBGT.
This paper deals with the indirect evaluation of the natural wet bulb temperature, t (nw), one of the two quantities forming the basis of the well-known wet bulb globe temperature (WBGT) index, considered worldwide to be a suitable and user-friendly tool for the preliminary assessment of hot thermal environments. This quantity can be measured by a wet bulb thermometer (a temperature sensor covered with a wetted wick naturally ventilated) or, if this is not available, calculated from other microclimatic parameters (i.e. the air temperature, the globe temperature, the air velocity, and the humidity) using a quite trivial energy balance equation. Because of the strong non-linear structure of such an equation, the risk of a multiplicity of steady state solutions could result in the failure to obtain a reliable index evaluation. To dispel all doubts, this work carries out an in-depth analysis of the heat balance equation to be solved for the indirect evaluation of the natural wet bulb temperature. A preliminary investigation of each heat flow term involved in the heat balance on the sensor has been carried out; in a second phase a special continuation method has been implemented, highlighting the effect of microclimatic parameters on the multiplicity of solutions. Results show that under free convection the evaluation produces a single solution only under uniform conditions, whereas in the presence of even slight differences between the air temperature and the mean radiant temperature, there can be as many as three solutions. This phenomenon, if confirmed by a further experimental investigation, could become a difficult matter since a sensor, in principle, has to read a unique value of the quantity measured. In any case, from a numerical point of view, the presence of many values of tnw greatly reduces the possibility of an indirect WBGT calculation from the other involved physical quantities; as a consequence, the indirect evaluation of WBGT should be clearly avoided based on ISO 7243 Standard.


Serratus Plane Block for Persistent Pain after Partial Mastectomy and Axillary Node Dissection.
Persistent pain after breast cancer surgery (PPBCS) is defined as chronic neuropathic pain that persists for more than 3 months after surgery. The pain can be sufficiently severe to cause long-term disabilities and interfere with sleep and daily life. Serratus plane block (SPB) is a novel, ultrasound-guided regional anesthetic technique that is suggested to achieve complete anesthesia of the anterolateral chest wall. Here, we demonstrate the efficacy of SPB as one of the treatment modalities for patients with PPBCS. A 73-year-old woman underwent a left partial mastectomy and axillary node dissection for breast cancer. Four months after surgery, she experienced burning pain with nocturnal exacerbation rated 10/10 on a numerical rating scale (NRS), hot flashes, numbness, and hyperesthesia of the left axilla. Pharmacological therapy did not improve her symptoms, and 15 months after the surgery, she experienced depression. We treated her with SPB with 10 mL of 1% lidocaine; this treatment was repeated 10 times over 6 months at 2- to 4-week intervals and she was simultaneously treated with pharmacological, physical, and cognitive behavioral therapy. With her improved pain control, she was able to perform physical therapy and subsequently experienced marked improvement in her functional status and ability to perform daily activities. She has not required any interventional pain management since the last SPB performed 11 months ago. SPB represents one of the treatment modalities for PPBCS and is an advantageous technique because it can be performed more safely and easily than neuraxial approaches.


Elevated plasma levels of lipopolysaccharide and high mobility group box-1 protein are associated with high viral load in HIV-1 infection: reduction by 2-year antiretroviral therapy.
To investigate plasma levels of high mobility group box-1 protein (HMGB1), a marker of tissue necrosis and immune activation, as well as lipopolysaccharide (LPS), a marker of bacterial translocation, in HIV-1-infected patients. We studied 32 HIV-1-positive patients who had responded to antiretroviral therapy with undetectable viremia after 2 years, 10 nonresponders and 19 healthy controls. HMGB1 was analyzed by ELISA, and LPS by Lamilus colometric assay. Nonparametric statistics were applied. In naive HIV-1 patients, HMGB1 and LPS were elevated as compared with controls (P < 0.001). LPS levels were higher in African and Oriental patients compared with whites (P = 0.007). Notably, viral load was two-fold higher in patients with LPS, and HMGB1 was above median as compared with other patients (P = 0.005). This association was largely driven by African patients, who had a five-fold increased viral load in the presence of elevated LPS and HMGB1. After 2 years of effective antiretroviral therapy, LPS was reduced to the same median level as in the control group (P < 0.001), and HMGB1 was also reduced (P = 0.001), whereas no reductions were seen in nonresponders. The new findings are the association of elevated plasma levels of LPS and HMGB1 with high viral load, as well as the normalized levels of LPS, and the reduction of HMGB1 after 2 years of effective antiretroviral therapy. As LPS and HMGB1 tend to form immunologically active complexes in vitro, we propose that such complexes may be involved in the immune activation and pathogenesis of HIV-1 infection.


Dose optimization during drug development: whether and when to optimize.
The goal of dose optimization during drug development is to identify a dose that preserves clinical benefit with optimal tolerability. Traditionally, the maximum tolerated dose in a small phase I dose escalation study is used in the phase II trial assessing clinical activity of the agent. Although it is possible that this dose level could be altered in the phase II trial if an unexpected level of toxicity is seen, no formal dose optimization has routinely been incorporated into later stages of drug development. Recently it has been suggested that formal dose optimization (involving randomly assigning patients between 2 or more dose levels) be routinely performed early in drug development, even before it is known that the experimental therapy has any clinical activity at any dose level. We consider the relative merits of performing dose optimization earlier vs later in the drug development process and demonstrate that a considerable number of patients may be exposed to ineffective therapies unless dose optimization is delayed until after clinical activity or benefit of the new agent has been established. We conclude that patient and public health interests may be better served by conducting dose optimization after (or during) phase III evaluation, with some exceptions when dose optimization should be performed after activity shown in phase II evaluation.


Glutathione peroxidase-2 and selenium decreased inflammation and tumors in a mouse model of inflammation-associated carcinogenesis whereas sulforaphane effects differed with selenium supply.
Chronic inflammation and selenium deficiency are considered as risk factors for colon cancer. The protective effect of selenium might be mediated by specific selenoproteins, such as glutathione peroxidases (GPx). GPx-1 and -2 double knockout, but not single knockout mice, spontaneously develop ileocolitis and intestinal cancer. Since GPx2 is induced by the chemopreventive sulforaphane (SFN) via the nuclear factor E2-related factor 2 (Nrf2)/Keap1 system, the susceptibility of GPx2-KO and wild-type (WT) mice to azoxymethane and dextran sulfate sodium (AOM/DSS)-induced colon carcinogenesis was tested under different selenium states and SFN applications. WT and GPx2-KO mice were grown on a selenium-poor, -adequate or -supranutritional diet. SFN application started either 1 week before (SFN4) or along with (SFN3) a single AOM application followed by DSS treatment for 1 week. Mice were assessed 3 weeks after AOM for colitis and Nrf2 target gene expression and after 12 weeks for tumorigenesis. NAD(P)H:quinone oxidoreductases, thioredoxin reductases and glutathione-S-transferases were upregulated in the ileum and/or colon by SFN, as was GPx2 in WT mice. Inflammation scores were more severe in GPx2-KO mice and highest in selenium-poor groups. Inflammation was enhanced by SFN4 in both genotypes under selenium restriction but decreased in selenium adequacy. Total tumor numbers were higher in GPx2-KO mice but diminished by increasing selenium in both genotypes. SFN3 reduced inflammation and tumor multiplicity in both Se-adequate genotypes. Tumor size was smaller in Se-poor GPx2-KO mice. It is concluded that GPx2, although supporting tumor growth, inhibits inflammation-mediated tumorigenesis, but the protective effect of selenium does not strictly depend on GPx2 expression. Similarly, SFN requires selenium but not GPx2 for being protective.


Long-term control of renal blood flow: what is the role of the renal nerves?
We have developed a system for long-term continuous monitoring of cardiovascular parameters in rabbits living in their home cage to assess what role renal sympathetic nerve activity (RSNA) has in regulating renal blood flow (RBF) in daily life. Blood pressure, heart rate, locomotor activity, RSNA, and RBF were recorded continuously for 4 wk. Beginning 4-5 days after surgery a circadian rhythm, dependent on feeding time, was observed. When averaged over all days RBF to the innervated and denervated kidneys was not significantly different. However, control of RBF around these mean levels was dependent on the presence of the renal sympathetic nerves. In particular we observed episodic elevations in heart rate and other parameters associated with activity. In the denervated kidney, during these episodic elevations, the increase in renal resistance was closely related to the increase in arterial pressure. In the innervated kidney the renal resistance response was significantly more variable, indicating an interaction of the sympathetic nervous system. These results indicate that whereas overall levels of RSNA do not set the mean level of RBF the renal vasculature is sensitive to episodic increases in sympathetic nerve activity.


Factors influencing thigh muscle volume change with cycling exercises in acute spinal cord injury - a secondary analysis of a randomized controlled trial.
Objective: To conduct a per-protocol analysis on thigh muscle volume outcomes from the Spinal Cord Injury and Physical Activity (SCIPA) Switch-On Trial.Design: Secondary analysis from an assessor-blind randomized, controlled trial.Setting: Four acute/sub-acute hospitals in Australia and New Zealand.Participants: 24 adults (1 female) within four weeks of motor complete or incomplete spinal cord injury (SCI)Intervention: Functional electrical stimulation-assisted cycling (FESC) or passive cycling (PC) 4x/week for 12 weeks.Outcome Measures: Whole thigh and muscle group volumes calculated from manually segmented MR images.Results: 19/24 participants completed ≥ twelve weeks of the intervention. Five participants experienced hypertrophy (4 FESC; 1 PC) and eight attenuation of atrophy (<20% volume loss) (3 FESC; 5 PC) in thigh muscle volume. Six participants were non-responders, exhibiting atrophy >20% (3 FESC; 3 PC). Mean (SD) change for FESC was -2.3% (25.3%) and PC was -14.0% (12.3%). After controlling for baseline muscle volumes, a strong significant correlation was found between mean weekly exercise frequency and quadriceps and hamstring volumes (r=6.25, P=0.006), regardless of mode. Average watts was highly correlated to quadriceps volumes only (r=5.92, P=0.01), while total number of sessions was strongly correlated with hamstring volumes only (r=5.91, P=0.01).Conclusion: This per-protocol analysis of FESC and PC early after SCI reports a partial response in 42% and a beneficial response in 25% of patients who completed 12 weeks intervention, regardless of mode. Strong correlations show a dose-response according to exercise frequency. Characteristics of non-responders are discussed to inform clinical decision-making.


Growth of hyperactive children on maintenance regimen of methylphenidate.
The growth in height and weight of 86 hyperactive children receiving methylphenidate hydrochloride (average, 40 mg/day for up to four years) was compared with general population norms on recently updated growth charts. A significant decrease in height percentile was apparent after 2, 3, and 4 years of treatment but not after one year. A significant loss in weight percentile occurred onward from the first year of treatment. Dosage was significantly associated with the decrease in height and weight percentile. Greater initial height and weight were associated with greater growth decrements. The use of adjunctive thioridazine hydrochloride (mean, 87 mg/day) did not influence the growth of children receiving methylphenidate. Although the magnitude of the growth suppressant effect in groups was small (dosage accounted for only 2% of the variance in final height), the results suggest that clinicians should monitor the growth of hyperactive children receiving stimulants and consider dosage reduction in individual cases should evidence of growth suppression occur.


Cropping System Diversification Reduces Severity and Incidence of Soybean Sudden Death Syndrome Caused by Fusarium virguliforme.
Current management of sudden death syndrome (SDS) of soybean, caused by Fusarium virguliforme, focuses on planting resistant varieties and improving soil drainage; however, these measures are not completely effective. A 6-year study evaluated the effects of cropping system diversification on SDS and soybean yield. SDS, root health, yield, and F. virguliforme density in soil were assessed in a naturally infested field trial comparing a 2-year cropping system consisting of a corn-soybean rotation and synthetic fertilizer applications with 3- and 4-year cropping systems consisting of corn-soybean-oat + red clover and corn-soybean-oat +alfalfa-alfalfa rotations, respectively, with both manure and low synthetic fertilizer rates. In 5 of 6 years, SDS incidence and severity were lower and yield higher in the 3- and 4-year systems than in the 2-year system. SDS severity and incidence were up to 17-fold lower in the diversified systems than in the 2-year system. Incidence and severity of SDS explained 45 to 87% of the variation in yield. Plants in the 2-year system generally showed more severe root rot and lower plant weights than plants in the diversified systems. F. virguliforme density in soil was up to fivefold greater in the 2-year system compared with the 4-year system. The processes responsible for the suppression of SDS and yield protection in the diversified cropping systems still need to be determined.


Room-Temperature Giant Charge-to-Spin Conversion at the SrTiO3-LaAlO3 Oxide Interface.
The two-dimensional electron gas (2DEG) formed at the interface between SrTiO3 (STO) and LaAlO3 (LAO) insulating layer is supposed to possess strong Rashba spin-orbit coupling. To date, the inverse Edelstein effect (i.e., spin-to-charge conversion) in the 2DEG layer is reported. However, the direct effect of charge-to-spin conversion, an essential ingredient for spintronic devices in a current-induced spin-orbit torque scheme, has not been demonstrated yet. Here we show, for the first time, a highly efficient spin generation with the efficiency of ∼6.3 in the STO/LAO/CoFeB structure at room temperature by using spin torque ferromagnetic resonance. In addition, we suggest that the spin transmission through the LAO layer at a high temperature range is attributed to the inelastic tunneling via localized states in the LAO band gap. Our findings may lead to potential applications in the oxide insulator based spintronic devices.


Epidemiology of concussion in collegiate and high school football players.
Despite evolutionary changes in protective equipment, head injury remains common in football. We investigated concussion in football and associated epidemiologic issues such as 1) incidence of injury, 2) common signs and symptoms, and 3) patterns in making return-to-play decisions. We received 242 of 392 surveys (62%) that were sent to high school and collegiate certified athletic trainers at the beginning of three football seasons. Of the 17,549 football players represented, 888 (5.1%) sustained at least one concussion, and 131 (14.7% of the 888) sustained a second injury during the same season. The greatest incidence of concussion was found at the high school (5.6%) and collegiate division III (5.5%) levels, suggesting that there is an association between level of play and the proportion of players injured. Players who sustained one concussion in a season were three times more likely to sustain a second concussion in the same season compared with uninjured players. Contact with artificial turf appears to be associated with a more serious concussion than contact with natural grass. Only 8.9% of all injuries involved loss of consciousness, while 86% involved a headache. Overall, 30.8% of all players sustaining a concussion returned to participation on the same day of injury.


The mediating role of psychological capital on the association between occupational stress and depressive symptoms among Chinese physicians: a cross-sectional study.
Although occupational stress is an identified predictor of depressive symptoms, the mechanism behind the association is not well understood. The purpose of this study was to examine how psychological capital (PsyCap), a positive psychological state, mediates the association between occupational stress and depressive symptoms among Chinese physicians. A cross-sectional survey was conducted in Liaoning Province, China, during September-October 2010. Self-administered questionnaires including items on depressive symptoms assessed by the Center for Epidemiologic Studies Depression Scale, occupational stress assessed by the effort-reward imbalance scale and PsyCap estimated by a 24-item Psychological Capital Questionnaire, together with age, gender, marital status and education were distributed to 1300 physicians employed in large general hospitals. The final sample consisted of 998 participants. Asymptotic and resampling strategies were used to examine how PsyCap mediates the association between occupational stress and depressive symptoms. Both the effort/reward ratio (ERR) and overcommitment were significantly associated with depressive symptoms among male and female physicians. There was a gender difference in the mediating role of PsyCap on the occupational stress-depressive symptoms association. For male physicians, PsyCap did not mediate the association between occupational stress and depressive symptoms. For female physicians, ERR and overcommitment were negatively associated with PsyCap, and PsyCap was negatively associated with depressive symptoms. As a result, PsyCap significantly mediated the associations of ERR and overcommitment with depressive symptoms. The proportion of PsyCap mediation was 19.07% for ERR, and 24.29% for overcommitment. PsyCap could be a positive resource for combating depressive symptoms in Chinese physicians. In addition to reducing occupational stress, PsyCap development should be included in depression prevention and treatment strategies, especially for female physicians.


Craniopharyngiomas of the third ventricle: trans-lamina terminalis approach.
Craniopharyngiomas usually grow on the cisternal surface of the hypothalamic region; these tumors can also grow from the infundibulum or tuber cinereum on the floor of the third ventricle, developing exclusively into the third ventricle. The aim of the present work was to establish the usefulness of the pterional trans-lamina terminalis approach for the removal of these tumors. Eight patients who were surgically treated for craniopharyngiomas located exclusively within the third ventricle were considered. The initial symptoms were acute hydrocephalus in two cases, psychological disturbances in two, amenorrhea in two, headaches in one, and hypopituitarism in one. The diagnoses were established, in all cases except one, with magnetic resonance imaging. In all cases, the tumor completely filled the third ventricle. Total removal of the lesion was achieved in seven cases. One patient underwent partial removal. In the immediate postoperative period, no major complications were observed. Five patients required replacement hormonal therapy. All patients returned to a normal life. Many months after surgery, two patients exhibited psychological disturbances and died, the first because of voluntary withdrawal of replacement therapy (12 mo after surgery) and the second because of a severe imbalance in body fluids and electrolytes, with a subsequent hyperosmolar coma (27 mo after surgery). Only one patient who underwent initial total removal experienced a small recurrence of the lesion (30 mo after surgery); after 3 years, the lesion exhibited unchanged size. In our experience, the trans-lamina terminalis approach is a valid choice for the removal of purely intraventricular craniopharyngiomas. These tumors can be removed without significant sequelae related to the surgical approach. The proximity to the hypothalamus requires accurate neuroendocrine and electrolyte control in the postoperative period, in some cases even years after surgery.


Experimental and bioinformatic evidence that raspberry leaf blotch emaravirus P4 is a movement protein of the 30K superfamily.
Emaravirus is a recently described genus of negative-strand RNA plant viruses. Emaravirus P4 protein localizes to plasmodesmata, suggesting that it could be a viral movement protein (MP). In the current study, we showed that the P4 protein of raspberry leaf blotch emaravirus (RLBV) rescued the cell-to-cell movement of a defective potato virus X (PVX) that had a deletion mutation in the triple gene block 1 movement-associated protein. This demonstrated that RLBV P4 is a functional MP. Sequence analyses revealed that P4 is a distant member of the 30K superfamily of MPs. All MPs of this family contain two highly conserved regions predicted to form β-strands, namely β1 and β2. We explored by alanine mutagenesis the role of two residues of P4 (Ile106 and Asp127) located in each of these strands. We also made the equivalent substitutions in the 29K MP of tobacco rattle virus, another member of the 30K superfamily. All substitutions abolished the ability to complement PVX movement, except for the I106A substitution in the β1 region of P4. This region has been shown to mediate membrane association of 30K MPs; our results show that it is possible to make non-conservative substitutions of a well-conserved aliphatic residue within β1 without preventing the membrane association or movement function of P4.


Analysis of RNA editing in plastids.
Chloroplast mRNAs can be subject to posttranscriptional pyrimidine-to-pyrimidine conversions at highly specific sites. This RNA modification mechanism shows a high degree of similarity to plant mitochondrial editing but differs markedly from, and is most likely evolutionarily unrelated to, all other RNA editing systems. The study of RNA editing processes in chloroplasts has been largely hampered by the lack of in vitro editing systems; however, considerable insights into the recognition mechanisms of individual editing sites have come from in vivo approaches. Chloroplast transformation proved to be a particularly useful tool to study plastid RNA editing. In this article, specific methods for the analysis of chloroplast RNA editing are discussed. Detailed experimental procedures are provided for (i) the purification of chloroplasts and (ii) the stable genetic transformation of higher plant plastids.


Effects of selected functional groups on nanoplastics transport in saturated media under diethylhexyl phthalate co-contamination conditions.
The production and degradation of plastic remains can result in nanoplastics (NPs) formation. However, insufficient information regarding the environmental behaviors of NPs impedes comprehensive assessment of their significant threats. In this study, the transport behavior of unmodified NPs (PSNPs), carboxyl-modified NPs (PSNPs-COOH), and amino-modified NPs (PSNPs-NH2) was investigated using column experiments in the presence and absence of goethite (GT) and diethylhexyl phthalate (DEHP). Quantum chemical computation was performed to reveal the transport mechanisms. The results showed that GT decreased the transport of NPs and the presence of DEHP decreased it further. Van der Waals forces and small electrostatic interactions coexisted between the PSNPs and GT and caused deposition. Ligand exchange caused greater deposition of PSNPs-COOH on GT-coated sand than that of PSNPs. Although hydrogen bonding existed between the DEHP and NPs with functional groups, an increase in the positive charge and chemical heterogeneity of the collector was the main reason for DEHP promoting the deposition of NPs. Because of low absolute negative zeta potential values, PSNPs-NH2 was sensitive to chemical heterogeneity, and thus fully deposited (over 96.9%) in GT and GT-DEHP-coated columns. Generally, the deposition of NPs due to chemical heterogeneity was more significant than that due to the formation of chemical bonds and van der Waals, electrostatic, and hydrogen interactions. Our results highlight that the surface charge and functional groups significantly influence the transport behaviors of NPs and elucidate the fate of NPs in the terrestrial environment.


The maize macrohairless1 locus specifically promotes leaf blade macrohair initiation and responds to factors regulating leaf identity.
The leaf surfaces of almost all plant species possess specialized epidermal cell types that form hairs or trichomes. Maize leaves produce three distinct types of hairs, the most prominent being the macrohairs that serve as a marker for adult leaf identity and may contribute to insect resistance. This report describes the maize macrohairless1 (mhl1) locus, which promotes macrohair initiation specifically in the leaf blade. Each of seven recessive mhl1 mutant alleles significantly reduces or eliminates macrohairs in the leaf blade. The mhl1 mutations block macrohair initiation rather than interfering with macrohair morphogenesis. Genetic mapping placed mhl1 within bin 4 on chromosome 9. A second independently segregating locus was found to partially suppress the mhl1 mutant phenotype in certain genetic backgrounds. Macrohair density was observed to increase during early adult vegetative development and then progressively decline, suggesting macrohair initiation frequency is affected by factors that act throughout shoot development. Genetic analyses demonstrated that mhl1 acts in the same pathway but downstream of factors that either promote or repress adult leaf identity. Thus, mhl1 plays a key role in integrating developmental programs that regulate leaf identity during shoot development with those that specify macrohair initiation within the leaf blade.


Interferon-gamma promotes abortion due to Brucella infection in pregnant mice.
The mechanisms of abortion induced by bacterial infection are largely unknown. In the present study, we investigated abortion induced by Brucella abortus, a causative agent of brucellosis and facultative intracellular pathogen, in a mouse model. High rates of abortion were observed for bacterial infection on day 4.5 of gestation, but not for other days. Regardless of whether fetuses were aborted or stayed alive, the transmission of bacteria into the fetus and bacterial replication in the placenta were observed. There was a higher degree of bacterial colonization in the placenta than in other organs and many bacteria were detected in trophoblast giant cells in the placenta. Intracellular growth-defective virB4 mutant and attenuated vaccine strain S19 did not induce abortion. In the case of abortion, around day 7.5 of gestation (period of placental development), transient induction of IFN-gamma production was observed for infection by the wild type strain, but not by the virB4 mutant and S19. Neutralization of IFN-gamma, whose production was induced by infection with B. abortus, served to prevent abortion. These results indicate that abortion induced by B. abortus infection is a result of transient IFN-gamma production during the period of placental development.


Fire Simulation and Cardiovascular Health in Firefighters.
Rates of myocardial infarction in firefighters are increased during fire suppression duties, and are likely to reflect a combination of factors including extreme physical exertion and heat exposure. We assessed the effects of simulated fire suppression on measures of cardiovascular health in healthy firefighters. In an open-label randomized crossover study, 19 healthy firefighters (age, 41±7 years; 16 males) performed a standardized training exercise in a fire simulation facility or light duties for 20 minutes. After each exposure, ex vivo thrombus formation, fibrinolysis, platelet activation, and forearm blood flow in response to intra-arterial infusions of endothelial-dependent and -independent vasodilators were measured. After fire simulation training, core temperature increased (1.0±0.1°C) and weight reduced (0.46±0.14 kg, P<0.001 for both). In comparison with control, exposure to fire simulation increased thrombus formation under low-shear (73±14%) and high-shear (66±14%) conditions (P<0.001 for both) and increased platelet-monocyte binding (7±10%, P=0.03). There was a dose-dependent increase in forearm blood flow with all vasodilators (P<0.001), which was attenuated by fire simulation in response to acetylcholine (P=0.01) and sodium nitroprusside (P=0.004). This was associated with a rise in fibrinolytic capacity, asymptomatic myocardial ischemia, and an increase in plasma cardiac troponin I concentrations (1.4 [0.8-2.5] versus 3.0 [1.7-6.4] ng/L, P=0.010). Exposure to extreme heat and physical exertion during fire suppression activates platelets, increases thrombus formation, impairs vascular function, and promotes myocardial ischemia and injury in healthy firefighters. Our findings provide pathogenic mechanisms to explain the association between fire suppression activity and acute myocardial infarction in firefighters. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01812317.


Predictors of neurofeedback treatment outcome in binge-eating disorder: An exploratory study.
Knowledge on predictors for treatment response to psychotherapy in binge-eating disorder (BED) is mixed and not yet available for increasingly popular neurofeedback (NF) treatment targeting self-regulation of aberrant brain activity. This study examined eating disorder- and psychopathology-related predictors for NF treatment success in BED. Patients with BED (N = 78) were randomized to 12 sessions of real-time functional near-infrared spectroscopy (rtfNIRS)-NF, targeting individual prefrontal cortex signal up-regulation, electroencephalography (EEG)-NF, targeting down-regulation of fronto-central beta activity, or waitlist (WL). The few studies assessing predictors for clinical outcomes after NF and evidenced predictors for psychotherapy guided the selection of baseline eating disorder-related predictors, including objective binge-eating (OBE) frequency, eating disorder psychopathology (EDP), food cravings, and body mass index (BMI), and general psychopathology-related predictors, including depressive and anxiety symptoms, impulsivity, emotion dysregulation, and self-efficacy. These questionnaire-based or objectively assessed (BMI) predictors were regressed on outcomes OBE frequency and EDP as key features of BED at post-treatment (t1) and 6-month follow-up (t2) in preregistered generalized mixed models (https://osf.io/4aktp). Higher EDP, food cravings, and BMI predicted worse outcomes across all groups at t1 and t2. General psychopathology-related predictors did not predict outcomes at t1 and t2. Explorative analyses indicated that lower OBE frequency and higher self-efficacy predicted lower OBE frequency, and lower EDP predicted lower EDP after the waiting period in WL. Consistent with findings for psychotherapy, higher eating disorder-related predictors were associated with higher EDP and OBE frequency. The specificity of psychopathological predictors for NF treatment success warrants further examination. This exploratory study firstly assessed eating disorder- and psychopathology-related predictors for neurofeedback treatment outcome in binge-eating disorder and overweight. Findings showed an association between higher eating disorder symptoms and worse neurofeedback outcomes, indicating special needs to be considered in neurofeedback treatment for patients with a higher binge-eating disorder symptom burden. In general, outcomes and assignment to neurofeedback treatment may be improved upon consideration of baseline psychological variables.


Molecular and functional analysis of the novel cfr(D) linezolid resistance gene identified in Enterococcus faecium.
To characterize the novel cfr(D) gene identified in an Enterococcus faecium clinical isolate (15-307.1) collected from France. The genome of 15-307.1 was entirely sequenced using a hybrid approach combining short-read (MiSeq, Illumina) and long-read (GridION, Oxford Nanopore Technologies) technologies in order to analyse in detail the genetic support and environment of cfr(D). Transfer of linezolid resistance from 15-307.1 to E. faecium BM4107 was attempted by filter-mating experiments. The recombinant plasmid pAT29Ωcfr(D), containing cfr(D) and its own promoter, was transferred to E. faecium HM1070, Enterococcus faecalis JH2-2 and Escherichia coli AG100A. As previously reported, 15-307.1 belonged to ST17 and was phenotypically resistant to linezolid (MIC, 16 mg/L), vancomycin and teicoplanin. A hybrid sequencing approach confirmed the presence of several resistance genes including vanA, optrA and cfr(D). Located on a 103 kb plasmid, cfr(D) encoded a 357 amino acid protein, which shared 64%, 64%, 48% and 51% amino acid identity with Cfr, Cfr(B), Cfr(C) and Cfr(E), respectively. Both optrA and cfr(D) were successfully co-transferred to E. faecium BM4107. When expressed in E. faecium HM1070 and E. faecalis JH2-2, pAT29Ωcfr(D) did not confer any resistance, whereas it was responsible for an expected PhLOPSA resistance phenotype in E. coli AG100A. Analysis of the genetic environment of cfr(D) showed multiple IS1216 elements, putatively involved in its mobilization. Cfr(D) is a novel member of the family of 23S rRNA methyltransferases. While only conferring a PhLOPSA resistance phenotype when expressed in E. coli, enterococci could constitute an unknown reservoir of cfr(D).


Peritoneal fluid environment in endometriosis. Clinicopathological implications.
Endometriosis is a puzzling disorder with obscure pathogenesis. The objective of this review was to evaluate the complex role of peritoneal fluid in the etiopathogenesis of endometriosis. Several studies suggest that peritoneal fluid is a key inflammatory environment associated with endometriosis. Many active substances (cytokines, growth factors, hormones and oxidative stress parameters) have been identified in endometriosis patients at different stages of the disease. Inflammatory mediators may be involved in the endometriosis associated-infertility and possibly pain. Furthermore, these mediators may represent a non surgical method for diagnosing endometriosis. Better understanding of the mechanism of cytokines, growth factor and reactive oxygen species production and detoxification and further investigation of their effects on the peritoneal fluid environment are essential to obtain new insight into this disease and eventually develop novel diagnostic and therapeutic remedies.


Redundancy and compensation in axon guidance: genetic analysis of the Drosophila Ptp10D/Ptp4E receptor tyrosine phosphatase subfamily.
Drosophila has six receptor protein tyrosine phosphatases (RPTPs), five of which are expressed primarily in neurons. Mutations in all five affect axon guidance, either alone or in combination. Highly penetrant central nervous system (CNS) and motor axon guidance alterations are usually observed only when specific combinations of two or more RPTPs are removed. Here, we examine the sixth RPTP, Ptp4E, which is broadly expressed. Ptp4E and Ptp10D are closely related type III RPTPs. Non-drosophilid insect species have only one type III RPTP, which is closest to Ptp10D. We found that Ptp4E mutants are viable and fertile. We then examined Ptp4E Ptp10D double mutants. These die before the larval stage, and have a mild CNS phenotype in which the outer longitudinal 1D4 bundle is frayed. Ptp10D Ptp69D double mutants have a strong CNS phenotype in which 1D4 axons abnormally cross the midline and the outer and middle longitudinal bundles are fused to the inner bundle. To examine if Ptp4E also exhibits synthetic phenotypes in combination with Ptp69D, we made Ptp4E Ptp69D double mutants and Ptp4E Ptp10D Ptp69D triple mutants. No phenotype was observed in the double mutant. The triple mutant phenotype differs from the Ptp10D Ptp69D phenotype in two ways. First, the longitudinal tracts appear more normal than in the double mutant; two or three bundles are observed, although they are disorganized and fused. Second, axons labelled by the SemaIIB-tauMyc marker often cross in the wrong commissure. We also examined motor axon guidance, and found that no phenotypes are observed in any Ptp4E double mutant combination. However, triple mutants in which Ptp4E Ptp10D was combined with Ptp69D or Ptp52F exhibited stronger phenotypes than the corresponding Ptp10D double mutants. Type III RPTPs are required for viability in Drosophila, since Ptp4E Ptp10D double mutants die before the larval stage. Unlike Ptp10D, Ptp4E appears to be a relatively minor player in the control of axon guidance. Strong phenotypes are only observed in triple mutants in which both type III RPTPs are eliminated together with Ptp69D or Ptp52F. Our results allow us to construct a complete genetic interaction matrix for all six of the RPTPs.


[Autonomous cardioneuropathy in patients with coronary heart disease].
This paper reports the results of an electron microscopic study of the sinoatrial node in deceased patients with CHD in whom high-resolution rhythmocardiography revealed autonomous cardioneuropathy. Non-specific morphological changes in pacemaker cells of the sinoatrial node (swelling and disintegration of mitochondria, incorporation of calcium and accumulation of lipofuscin in mitochondria) can be regarded as manifestations of ischemic insufficiency of cardiac tissue perfusion. The rhythmocardiograms of such patients showed signs of autonomous cardioneuropathy manifest as the sharply decreased amplitude of all vegetative waves. The spectral power pattern was dominated by inefficient humoral-metabolic regulation due to suppression of protective parasympathetic regulation.


Exploring the origins of grey matter damage in multiple sclerosis.
Multiple sclerosis is characterized at the gross pathological level by the presence of widespread focal demyelinating lesions of the myelin-rich white matter. However, it is becoming clear that grey matter is not spared, even during the earliest phases of the disease. Furthermore, grey matter damage may have an important role both in physical and cognitive disability. Grey matter pathology involves both inflammatory and neurodegenerative mechanisms, but the relationship between the two is unclear. Histological, immunological and neuroimaging studies have provided new insight in this rapidly expanding field, and form the basis of the most recent hypotheses on the pathogenesis of grey matter damage.


[Randomized controlled observation on head point-through-point therapy for treatment of insomnia].
To observe the therapeutic effect of head point-through-point therapy on insomnia and to probe the mechanism. Seventy-one cases of insomnia were randomly divided into a head penetration needling group (n=36) and a routine acupuncture group (n=35). In the head penetration needling group, Shenting (GV 24)-through-anterior Shencong (EX-HN 1), bilateral Toulinqi (GB 15)-through-bilateral Shencong (EX-HN 1), posterior Shencong-through-Qiangjian (GV 18) were selected; and in the routine acupuncture group, Baihui (CV 20), Yintang (EX-HN 3), Sishencong (EX-HN 1), Neiguan (PC 6), etc. were selected. After treatment of 30 days, their therapeutic effects, cumulative scores of Pittsburgh Sleep Quality Index (PSQI) and plasma serotonin contents before and after treatment were compared. Results The total effective rate of 91.7% in the head penetration needling group was better than 77.1% in the routine acupuncture group (P < 0.05), and the improvement of sleep quality, falling asleep time and the total cumulative score of PSQI in the head penetration needling group was superior to that in the routine acupuncture group (P < 0.05), and plasma serotonin was significantly increased in the head penetration needling group with a significant difference as compared with that in the routine acupuncture group (P < 0.05). The therapeutic effect of head penetration needling is better than that of the routine acupuncture, and the mechanism is related with regulation of serotonin metabolism.


Oviposition preference for and positional avoidance of acetic acid provide a model for competing behavioral drives in Drosophila.
Selection of appropriate oviposition sites is essential for progeny survival and fitness in generalist insect species, such as Drosophila melanogaster, yet little is known about the mechanisms regulating how environmental conditions and innate adult preferences are evaluated and balanced to yield the final substrate choice for egg-deposition. Female D. melanogaster are attracted to food containing acetic acid (AA) as an oviposition substrate. However, our observations reveal that this egg-laying preference is a complex process, as it directly opposes an otherwise strong, default behavior of positional avoidance for the same food. We show that 2 distinct sensory modalities detect AA. Attraction to AA-containing food for the purpose of egg-laying relies on the gustatory system, while positional repulsion depends primarily on the olfactory system. Similarly, distinct central brain regions are involved in AA attraction and repulsion. Given this unique situation, in which a single environmental stimulus yields 2 opposing behavioral outputs, we propose that the interaction of egg-laying attraction and positional aversion for AA provides a powerful model for studying how organisms balance competing behavioral drives and integrate signals involved in choice-like processes.


Near-field spectroscopic properties of complementary gold nanostructures: applicability of Babinet's principle in the optical region.
We examine the far-field and near-field properties of complementary screens made of nanostructured gold thin films, a rectangular nanowire and a nanovoid, using an aperture-type scanning near-field optical microscope and electromagnetic field calculations, and discuss the applicability of Babinet's principle in the optical region. The far-field transmission spectra of the complementary screens are considerably different from each other. On the other hand, genuine near-field extinction spectra exhibit nearly complementary characteristics. The spatial features of the observed near-field images for the complementary screens show little correlation. We have found from the Fourier analysis of the simulated images that high spatial-frequency components of the electromagnetic fields show mutual spatial correlation. These results suggest that Babinet's principle is applicable to the high spatial-frequency components of electromagnetic fields for the complementary screens.


Mitochondrial DNA copy number and pancreatic cancer in the alpha-tocopherol beta-carotene cancer prevention study.
Diabetes, obesity, and cigarette smoke, consistent risk factors for pancreatic cancer, are sources of oxidative stress in humans that could cause mitochondrial DNA (mtDNA) damage and increase mtDNA copy number. To test whether higher mtDNA copy number is associated with increased incident pancreatic cancer, we conducted a nested case-control study in the Alpha-Tocopherol Beta Carotene Cancer Prevention (ATBC) Study cohort of male smokers, aged 50 to 69 years at baseline. Between 1992 and 2004, 203 incident cases of pancreatic adenocarcinoma occurred (follow-up: 12 years) among participants, with whole blood samples used for mtDNA extraction. For these cases and 656 controls, we calculated ORs and 95% CIs using unconditional logistic regression, adjusting for age, smoking, and diabetes history. All statistical tests were two sided. Higher mtDNA copy number was significantly associated with increased pancreatic cancer risk (highest vs. lowest mtDNA copy number quintile, OR = 1.64, 95% CI = 1.01-2.67, continuous OR = 1.14, 95% CI 1.06-1.23), particularly for cases diagnosed during the first 7 years of follow-up (OR = 2.14, 95% CI = 1.16-3.96, P(trend) = 0.01, continuous OR = 1.21, 95% CI = 1.10-1.33), but not for cases occurring during follow-up of 7 years or greater (OR = 1.14, 95% CI = 0.53-2.45, continuous OR = 1.05, 95% CI = 0.93-1.18). Our results support the hypothesis that mtDNA copy number is associated with pancreatic cancer and could possibly serve as a biomarker for pancreatic cancer development.


Multiple Sclerosis and the LIF/IL-6 Axis: Use of Nanotechnology to Harness the Tolerogenic and Reparative Properties of LIF.
Leukaemia inhibitory factor (LIF) plays a critical role in "stemness" versus "differentiation", a property that underpins the core value of LIF as a therapeutic for both the treatment of autoimmune disease and for promoting tissue repair. This value can be realized using nano-engineering technology, where a new generation of tools can, with unprecedented ability, manipulate biological functions. One striking example is the treatment of multiple sclerosis (MS). The underpinning biology is the newly identified LIF/IL-6 axis in T lymphocytes, which can tilt the behaviour between immune tolerance versus immune attack. This LIF/IL-6 axis is ideally suited to nanotherapeutic manipulation, given its inherent mechanistic simplicity of two mutually opposing feed-forward loops that determine either tolerogenic (LIF) or inflammatory (IL-6) immunity. Using LIF that is formulated in biodegradable nanoparticles (LIF-NP) and targeted to CD4+ T cells, the axis is harnessed towards immune tolerance. This has implications for the treatment of autoimmune diseases, where the clinical burden is immense. It encompasses more than 100 diseases and, in the USA alone, costs more than $100 billion in direct health care costs annually. Other properties of LIF include the promotion of healthy neuro-glial interactions within the central nervous system (CNS), where, in addition to MS, LIF-NP therapy is relevant to inflammatory neurodegenerative diseases that represent a large and increasing need within aging populations. Thirdly, LIF is a reparative growth factor that can maintain genomic plasticity. LIF-NP supports the use of stem cell-based therapies in regenerative medicine plus augment therapeutic benefits within the patient. These core properties of LIF are greatly amplified in value by the advantage of being formulated as nanoparticles, namely (i) targeted delivery, (ii) exploitation of endogenous regulatory pathways and (iii) creation of surrogate micro-stromal niches. We discuss LIF-NP as a means to harness endogenous pathways for the treatment of MS, both to reset immune self-tolerance and to promote repair of myelin that is required to support health within the nervous system.


Percutaneous Drainage of an Iliopsoas Hematoma in a Hemophilia Patient.
In patients with hemophilia, the usual treatment for both iliopsoas hematoma and associated femoral nerve compression is conservative. The case presented herein is a moderate hemophilia A patient with significant femoral neuropathy due to iliopsoas hematoma whose symptoms could not be managed with an aggressive factor VIII replacement program for >2 weeks. An unusual treatment option - percutaneous catheter insertion and aspiration of the hematoma - alleviated the examination findings and reversed his abilities.


Lipidomic changes in the liver of beagle dogs associated with Toxocara canis infection.
A global lipidomic analysis using liquid chromatography-tandem mass spectrometry was performed on the liver of beagle dogs infected with Toxocara canis to profile hepatic lipid species at 12 h post-infection (hpi), 24 hpi, and 36 days post-infection (dpi). This analysis identified six categories and 42 subclasses of lipids, including 173, 64, and 116 differentially abundant lipid species at 12 hpi, 24 hpi, and 36 dpi, respectively. Many of the identified lysophospholipids, such as lysophosphatidylglycerol, lysophosphatidylserine, and lysophosphatidylcholine, may contribute to the migration and development of T. canis during the early infection stage. Pathway analysis revealed significant alterations of several immune-inflammatory pathways, such as the B-cell receptor signaling pathway, the NF-kappa B signaling pathway, and the C-type lectin receptor signaling pathway at 12 and 24 hpi. These findings demonstrate the value of lipidomic profiling in revealing the extent of changes in the composition and abundance of hepatic lipidome caused by T. canis infection and their relevance to the pathophysiology of toxocariasis in beagle dogs.


[Development of human olfactory receptors].
The development of the olfactory epithelium in 7-, 8-, 9-, 10- and 11-week old human fetuses was followed using electron microscopy. The differentiation of receptor and supporting cells and the establishment of Bowman's glands and the formation of olfactory nerve have been observed. In 7 week old fetuses the development of peripheral processes with olfactory knobs, lacking hairs, and of central processes with growth cones penetrating the connective tissue has been followed. A typical olfactory knobs possessing hairs were first found in 9 week old fetuses, the number of those progressively increasing starting from the 10 week age. At the 11th week of the development, completely differentiated olfactory cells were found, which are suggested to be capable of normal olfactory performance.


A comparison of two quality-of-life questionnaires for cancer clinical trials: the functional living index--cancer (FLIC) and the quality of life questionnaire core module (QLQ-C30).
Choosing a measure instrument for a study raises the question of whether instruments designed for the same purpose produce the same results. We investigated this question for two instruments designed to measure subjective quality of life (QOL) in cancer clinical trials: the Functional Living Index-Cancer (FLIC) and the Quality of Life Questionnaire Core module (QLQ-C30). These were administered concurrently to 98 cancer patients. Four patient groups were defined: (1) well, no chemotherapy (n = 23); (2) adjuvant chemotherapy (n = 24); (3) stable disease, active chemotherapy (n = 24); (4) progressive disease (n = 27). Both instruments have global, role, social, emotional, pain, and nausea scales; QLQ-C30 also assesses physical function, cognitive function, and fatigue, while FLIC assesses hardship. Correlation analysis indicated convergent validity for the global, role, emotional, pain and nausea dimensions, but not the social dimension. Both instruments indicated that groups 1 and 2 had better QOL than group 4 in at least one dimension. However, different dimension-specific results meant that qualitatively different conclusions would have been drawn if either instrument had been used singly: FLIC indicated that group 1 had better role function that group 4 and suffered less hardship and that group 1 suffered less nausea than group 3, while the QLQ-C30 data indicated that group 2 had better physical function than group 4. The only consistent result was for pain: both instruments indicated group 4 had more pain than either groups 1 or 2. Thus the choice of QOL instrument for use in a particular trial will affect both the results and conclusions. It is important, therefore, to consider carefully which instrument is most likely to detect important differences relevant to the patients' lives in that setting.


Glomerular endothelial vesicles in a renal allograft: an unusual pattern of immunoglobulin deposition in a patient with biclonal gammopathy of unknown significance.
Paraproteins have varied effects on the kidney on the basis of molecular structure, concentration, and renal function. Prototypical patterns include myeloma cast nephropathy, monoclonal immunoglobulin deposition disease, and amyloid, among others. We report a 69-year-old man with end-stage diabetic nephropathy and biclonal gammopathy of unknown significance. Serum monoclonal immunoglobulin G (IgG)-κ and urine monoclonal free λ light chains were identified during workup for nephrotic syndrome. A native renal biopsy demonstrated diabetic nephropathy, without indication of paraprotein-related pathology. After transplantation, a surveillance biopsy showed endothelialitis (type 2 rejection) and abundant eosinophilic droplets, nearly occluding glomerular capillary loops. Electron microscopy localized tightly packed electron-dense vesicles in glomerular endothelial cells. Immunofluorescence studies revealed IgG-κ-dominant endothelial staining, along with λ monotypic protein resorption droplets in tubules. Two additional biopsies within the following year showed this same paraprotein distribution, with some increase in mesangial sclerosis. Two years after transplant the patient remains asymptomatic with normal creatinine levels. Literature review yields rare cases of immunoglobulin crystalline deposits in multiple glomerular cell types, rarely including endothelial cells; however, this appears to be the first report of monoclonal immunoglobulin vesicles localized solely to endothelial cells. As these vesicles were not seen in the native kidney biopsy, we hypothesize an interaction of alloimmune-mediated endothelial injury and the physiochemical properties of the IgG-κ paraprotein. In addition, this case illustrates simultaneous different patterns of accumulation of monoclonal immunoglobulin and light chain components in this unique patient with biclonal gammopathy of unknown significance.


Is there any association between jugular venous reflux and nonpulsatile subjective tinnitus? A preliminary study of four-dimensional magnetic resonance angiography.
To demonstrate whether there is an association between jugular venous reflux and nonpulsatile subjective tinnitus (NST) using real-time four-dimensional magnetic resonance imaging (MRI) angiography. Patients with unilateral NST who underwent contrast-enhanced MRI with a special protocol were included in the study. Thick slab dynamic maximum intensity projection images were obtained including interleaved stochastic trajectories (TWIST)-MRI examination. All patients were requested to perform Valsalva maneuver during the sequence. Jugular venous reflux grading was performed as follows: absence of reflux or if reflux does not reach the base of the skull: grade 0; if reflux reaches the jugular bulb, but no intracranial contrast is observed: grade 1; and if reflux extends into the intracranial cortical veins and/or the cavernous sinus above the jugular bulb: Grade 2. A total number of 30 patients, 23 male and 7 female, were included in the study. Jugular venous reflux was not identified (Grade 0) in 20 patients. Grade 1 reflux was determined in 7 cases and Grade 2 reflux was observed in 3 cases. Notably, only patients with Grade 2 reflux described worsening of their tinnitus symptoms during the examination and their daily activities as well. NST might also be associated with hemodynamic problems of the venous system and the MRI protocol starting with TWIST accompanied with Valsalva maneuver is not well-known, yet seems to be a feasible and beneficial method to detect potential jugular venous reflux in NST patients.


Loss-To-Follow-Up on Multidrug Resistant Tuberculosis Treatment in Gujarat, India: The WHEN and WHO of It.
Multidrug-resistant Tuberculosis (MDR-TB) is a rising global threat to public health and concerted efforts for its treatment are diluted if the outcomes are not successful, loss to follow up (LFU) being one of them. It is therefore necessary to know the proportion and the associated reasons for LFU and devise effective patient-centered strategies to improve retention in care. A retrospective cohort study was conducted at the MDR-TB treatment site (DR-TB Site)in Central Gujarat among all patients registered from February 2010 to June 2013.LFU patients were defined as those whose treatment was interrupted for two or more consecutive months for any reason. Descriptive statistics, survival analysis and multivariate modeling were used to determine the proportion of patients LFU and to assess associations between LFU and selected demographic and clinical factors. A total of 796 patients were enrolled during the study period; 71.9% were male and the median age was 35 years [Interquartile range (IQR) 27-45].The overall proportion of LFU patients was 153/796 (19.2%).The majority of LFU patients (133/153 i.e.87%) were lost within the first 6 months of treatment. Ambulatory treatment initiation (adjusted Hazards ratio aHR=2.63, CI:1.01-6.86), different providers in IP and CP ( aHR=1.27, CI:1.18-1.38)and culture conversion after more than 4 months of treatment(aHR=1.34, CI: 1.21-1.49)were found to be significantly associated with LFU in multivariate models. A high proportion of LFU among patients on MDR-TB treatment was found in a programmatic setting in India. Clinical but equally important programmatic factors were associated with LFU, accounting for one-fifth of all the outcomes of MDR-TB treatment. Proper training for DOT providers and aggressive counseling and health system strengthening with patient friendly follow up services may help reduce LFU.


Projecting Nature: Agostino Scilla's Seventeenth-Century Fossil Drawings.
In 1670 the Sicilian painter Agostino Scilla (1629-1700) devised an entirely new way of depicting fossils when he wrote and illustrated his Vain Speculation Undeceived by Sense (1670-1671), which argued that fossils were the remains of once living creatures and not mimetic stones. This essay explores the nature of Scilla's graphic innovations, comparing his fossils drawings and Pietro Santi Bartoli's engravings of them to earlier and contemporary images of fossils. Scilla captured the effect of time on nature by infusing his style of drawing with his philosophical understanding of what it means to see and to know. He made his drawing less rich in detail to focus on those which served his purpose. In particular, he made the first use of dotted lines in paleontological illustration to render his images dynamic theoretical interpretations rather than static depictions.


Understanding the management of electronic test result notifications in the outpatient setting.
Notifying clinicians about abnormal test results through electronic health record (EHR) -based "alert" notifications may not always lead to timely follow-up of patients. We sought to understand barriers, facilitators, and potential interventions for safe and effective management of abnormal test result delivery via electronic alerts. We conducted a qualitative study consisting of six 6-8 member focus groups (N = 44) at two large, geographically dispersed Veterans Affairs facilities. Participants included full-time primary care providers, and personnel representing diagnostic services (radiology, laboratory) and information technology. We asked participants to discuss barriers, facilitators, and suggestions for improving timely management and follow-up of abnormal test result notifications and encouraged them to consider technological issues, as well as broader, human-factor-related aspects of EHR use such as organizational, personnel, and workflow. Providers reported receiving a large number of alerts containing information unrelated to abnormal test results, many of which were believed to be unnecessary. Some providers also reported lacking proficiency in use of certain EHR features that would enable them to manage alerts more efficiently. Suggestions for improvement included improving display and tracking processes for critical alerts in the EHR, redesigning clinical workflow, and streamlining policies and procedures related to test result notification. Providers perceive several challenges for fail-safe electronic communication and tracking of abnormal test results. A multi-dimensional approach that addresses technology as well as the many non-technological factors we elicited is essential to design interventions to reduce missed test results in EHRs.


An increase of granulosa cell apoptosis mediates aqueous neem (Azadirachta indica) leaf extract-induced oocyte apoptosis in rat.
Neem plant (Azadirachta indica) has been extensively used in Ayurvedic system of medicine for female fertility regulation for a long time, but its mechanism of action remains poorly understood. Hence, the present study was aimed to determine whether an increase of granulosa cell apoptosis is associated with aqueous neem leaf extract (NLE)-induced oocyte apoptosis. Sexually immature female rats of 20 days old were fed NLE (50 mg/day) for 10 days and then subjected to superovulation induction protocol. The morphological changes in cumulus oocyte complexes (COCs), rate of oocyte apoptosis, hydrogen peroxide (H2O2), total nitrite, and cytochrome c concentrations, inducible nitric oxide synthase (iNOS), cytochrome c, p53, Bcl2 and Bax expressions, deoxyribonucleic acid (DNA) fragmentation, and estradiol 17β level in granulosa cells collected from preovulatory COCs were analyzed. Aqueous NLE increased H2O2 concentration and decreased catalase activity, increased iNOS expression and total nitrite concentration, increased p53, Bax, and p53 expressions but decreased Bcl2 expression, increased cytochrome c concentration and induced DNA fragmentation in granulosa cells. An increased granulosa cell apoptosis resulted in reduced estradiol 17β concentration and induced apoptosis in ovulated oocytes. We conclude that aqueous NLE-induced granulosa cell apoptosis through the mitochondria-mediated pathway, reduced estradiol 17β concentration and induced apoptosis in ovulated oocytes. Thus, granulosa cell apoptosis mediates NLE-induced oocyte apoptosis during female fertility regulation in rat.


[Social-hygienic evaluation of the prevalence of sleep disorders].
According to the data of interviews of 4000 subjects, the incidence of sleep disorders is about 30% in different regions of Russia; for the age group of 20 to 24 years it is 5%, for subjects aged over 60-40%. Fourteen percent of men and twenty-four percent of women of capable age (30-59 years) complain of insufficient sleep. The quality of sleep depends on age, sex, constitutional features (excessive or insufficient body weight), and social characteristics (frequent change of working places, change of place of residence (migrations), family status, and microclimate in a family. Health status is the main factor underlying the formation of various sleep disorders. Subjects suffering from sleep disorders earlier develop age-specific diseases, this indicating that biological age-specific processes are accelerated in this patient population.


Experience with percutaneous dilational tracheostomy.
Percutaneous dilational tracheostomy (PDT) has gained popularity among critical care specialists in the past 10 years. The initial studies in our specialty resulted in essentially banning the procedure as a dangerous substitute for standard operative tracheostomy. Despite this action, more than 1,100 cases of percutaneous tracheostomy have been reported with details on complications. We reviewed all published data and studied 311 patients of our own. A prospective study was performed in 3 groups of patients: 1) 50 patients scheduled for PDT performed in the operating room by a head and neck surgeon (group 1); 2) 50 patients who underwent standard operative tracheostomy performed by the same surgeon (group 2); and 3) 211 patients who underwent bedside PDT by critical care physicians (group 3). The intraoperative complication rates were 0% in group 1, 2% in group 2, and 4% in group 3; the postoperative complication rates were 13%, 4%, and 12%, respectively. There were 2 deaths in group 3, and none in groups 1 or 2. The statistically significant differences among the groups were the superiority of group I over group 3 in intraoperative complications, as well as the lower postoperative complication rate of the standard tracheostomy group. These results show that PDT can be performed with acceptable morbidity rates in relation to published complication rates of standard tracheostomy, but it has no advantage over standard tracheostomy with respect to postoperative morbidity. When they are performed by a head and neck surgeon, the morbidity associated with both standard and percutaneous tracheostomies can be reduced.


Sequence reiteration required for the efficient growth of BK virus.
Compared with wild-type BK virus DNA having tandem triplication of a 68 base pair (bp) element in its transcriptional control region, a mutant viral DNA with a single copy of the 68 bp element induced remarkably delayed virus production in human embryonic kidney (HEK) cells. We molecularly cloned the DNA of progeny viruses using plasmid vector pAT153. Nucleotide sequence analysis of representative clones revealed that all of the altered viral DNAs examined duplicated various segments extending over origin-distal portions of the 68 bp element and their flanking regions. After transfection of HEK cells, most of these rearranged viral DNAs induced viral growth slightly slower than, or at the same rate as, the wild-type viral DNA. Comparison of the structures of these rearranged viral DNAs suggests that reiteration of a 13 bp sequence, which is located in an origin-distal portion of the 68 bp element, is required for the efficient replication of BK virus.


Arterial disease but not hypertension predisposes to varicose veins.
The aim of the study was to find out if persons with cardiovascular diseases (CVD) (arterial disease or hypertension) have additional risk of varicose veins (VV) compared with those without arterial disease (AD) or hypertension. We studied, using a validated questionnaire, the prevalence and incidence of VVs in those with and without CVD in a population of 4903 including 40-, 50- and 60-year-old men and women in Tampere, Finland. During the five years of follow-up, we had a special interest on the appearance of new VVs in those without VVs at entry (n = 3065). We found a higher prevalence of VVs in persons with CVD than in those without CVD (with sex and age adjusted odds ratio [OR] 1.3 [95% confidence interval, CI 1.1-1.5]). The prevalence of VVs was higher in persons with AD (OR 1.7 [CI 1.4-2.2]), but not in persons with hypertension (OR 1.1 [CI 0.9-1.2]) than in those who were free of AD or hypertension, respectively. Subjects with AD had higher incidence of VVs (incidence odds ratio, IOR 1.4 [CI 0.8-2.7]) than subjects without AD and the effect was statistically significant in women (IOR 2.2 [CI 1.1-4.5]). Also the incidence of VVs was more affected by AD than by hypertension (IOR 1.1 [CI 0.7-1.8]). There seems to exist a relatively strong additional risk of VVs in persons with AD and practically none in those with hypertension compared to those without.


The Role of Social Support and Acculturation Factors on Postpartum Mental Health Among Latinas in the MADRES Pregnancy Cohort.
We examined the associations between social support and postpartum mental health in 137 U.S. and foreign-born Latinas in the MADRES pregnancy cohort. We also examined whether language, years in the U.S., and country of birth moderates these relationships. Participants were administered PROMIS support measures 1 month postpartum; the Perceived Stress and Postpartum Distress Measure 3, 6, and 12 months postpartum; and the CESD scale 12 months postpartum. Perceived stress was lower at 6 months postpartum for women reporting higher emotional (p = 0.01), informational (p = 0.03), and instrumental support (p < 0.001); and lower at 12 months postpartum for women reporting higher emotional support (p = 0.01). Distress at 6 months was lower in women reporting higher emotional support (p = 0.03). Interactions suggest that associations were stronger for mothers that speak Spanish, spent fewer years in the U.S., and were born in Central America.


Metabolomics for personalized medicine: the input of analytical chemistry from biomarker discovery to point-of-care tests.
Metabolomics refers to the large-scale detection, quantification, and analysis of small molecules (metabolites) in biological media. Although metabolomics, alone or combined with other omics data, has already demonstrated its relevance for patient stratification in the frame of research projects and clinical studies, much remains to be done to move this approach to the clinical practice. This is especially true in the perspective of being applied to personalized/precision medicine, which aims at stratifying patients according to their risk of developing diseases, and tailoring medical treatments of patients according to individual characteristics in order to improve their efficacy and limit their toxicity. In this review article, we discuss the main challenges linked to analytical chemistry that need to be addressed to foster the implementation of metabolomics in the clinics and the use of the data produced by this approach in personalized medicine. First of all, there are already well-known issues related to untargeted metabolomics workflows at the levels of data production (lack of standardization), metabolite identification (small proportion of annotated features and identified metabolites), and data processing (from automatic detection of features to multi-omic data integration) that hamper the inter-operability and reusability of metabolomics data. Furthermore, the outputs of metabolomics workflows are complex molecular signatures of few tens of metabolites, often with small abundance variations, and obtained with expensive laboratory equipment. It is thus necessary to simplify these molecular signatures so that they can be produced and used in the field. This last point, which is still poorly addressed by the metabolomics community, may be crucial in a near future with the increased availability of molecular signatures of medical relevance and the increased societal demand for participatory medicine.


Non-pharmacological interventions for the treatment of post-stroke fatigue: a systematic review.
Post-stroke fatigue (PSF) affects 50% of stroke survivors. Current guidance on management of this condition is limited. This systematic review and meta-analysis aimed to identify and analyse all randomised clinical trials (RCTs) of non-pharmacological interventions for the treatment of PSF. Six electronic databases were searched from inception to January 2023 for English-language RCTs investigating the efficacy of non-pharmacological interventions versus passive controls in patients with PSF. The primary outcome was fatigue severity at the end of intervention. The Cochrane risk-of-bias (ROB)2 tool was used to assess evidence quality. A total of 7,990 records were retrieved, 333 studies scrutinised and 13 completed RCTs (484 participants) included. Interventions included psychological therapies, physical therapies and brain stimulation. Nine studies provided sufficient data for meta-analysis, of which seven also had follow up data. Fatigue severity was lower in the intervention groups at the end of the intervention compared to control (participants = 310, standardised mean difference (SMD) = -0.57, 95% confidence intervals (CI)s [-0.87 to -0.28]), and at follow up (participants = 112, SMD = -0.36, 95% CIs [-0.83 to 0.10]). Certainty in the effect estimate was downgraded to low for serious risk of bias and imprecision. Subgroup analysis revealed significant benefit with physical therapy and brain stimulation but not psychological therapies, though sample sizes were low. Non-pharmacological interventions improved fatigue but the quality of evidence was low. Further RCTs are needed for PSF management.


Methamphetamine and sildenafil (Viagra) use are linked to unprotected receptive and insertive anal sex, respectively, in a sample of men who have sex with men.
There is evidence that methamphetamine and sildenafil (Viagra) use are associated with sexual risk behaviour among men who have sex with men (MSM). We investigated the association of methamphetamine, sildenafil, and other substance use with unprotected receptive and insertive anal sex among MSM by conducting an encounter specific analysis. Data were from a cross sectional, community based survey of MSM in San Francisco regarding behaviour during their most recent anal sex encounter. Mulitvariate regression analysed independent associations of specific substance use and demographic variables with unprotected anal sex behaviours. The sample (n = 388) was diverse in race/ethnicity, age, income, education, HIV status, and homosexual/bisexual identification. More than half (53%) reported unprotected anal sex, including insertive (29%) and receptive (37%) during their most recent anal sex encounter; 12% reported unprotected insertive and 17% reported unprotected receptive anal sex with an HIV discordant or unknown partner. Methamphetamine was used by 15% and sildenafil was used by 6% of the men before or during the encounter; 2% used both drugs. In multivariate analysis controlling for demographic factors and other substance use, methamphetamine use was associated with unprotected receptive (odds ratio (OR), 2.03; 95% confidence interval (CI), 1.09 to 3.76) and sildenafil use was associated with unprotected insertive (OR, 6.51; CI, 2.46 to 17.24) anal sex. Effects were stronger with HIV discordant or unknown sex partners specifically. Encounter specific associations of methamphetamine and sildenafil use with unprotected receptive and insertive anal sex, respectively, indicate the importance of assessment specificity and tailoring risk reduction efforts to address certain drugs and sexual behavioural roles among MSM.


[The subject in academic literature on healthcare management: notes on the issue of autonomy].
The paper analyses concepts of the 'subject' in academic literature on Healthcare Management. The corpus of the survey consists of papers published in journals in the Collective Health field over the past five years. The papers examined for this analysis consider that (healthcare) work in the context of capitalism is based on an antinomy that we call "autonomy-control", striving to explore the possibilities of surmounting this antinomy in each concept. The analysis lists three different concepts of the subject: psychological-cognitivist, psychoanalytical-subjectivist and historical-communicative. This paper also discusses the relationship between these concepts of subject and their possibilities of producing autonomy on one hand, and the capitalist organization of culture and labor on the other.


Localization of IFN-gamma-activated Stat1 and IFN regulatory factors 1 and 2 in breast cancer cells.
The aim of the present work was to evaluate the induction and localization of Stat1, interferon (IFN) regulatory factor-1 (IRF-1), and IRF-2 after IFN-gamma exposure of human breast cancer cell lines, SKBR3, MDA468, MCF7, and BT20. Results from growth assays, Western staining, electrophoretic mobility shift assay (EMSA), and immunohistochemical staining were collated to test our hypothesis that immunohistochemical analysis of Stat1, IRF-1, and IRF-2 would provide additional information about the functionality of the IFN-gamma signaling pathway in human tumor lines. EMSA results showed that in each of four cell lines, Stat1 expression was increased and demonstrated functional activity after IFN-gamma stimulation. Western and EMSA analysis showed upregulation of IRF-1 but not IRF-2 in each cell line. Confocal microscopy of cells stained for Stat1, IRF-1, and IRF-2 confirmed the results and also provided novel information about the intracellular localization of proteins and intercellular variations in responses. The proportion of cells with IRF-1 stimulation and translocation was positively correlated with the IFN-gamma growth suppression in vitro. In conclusion, using four independent assays, we have demonstrated that heterogeneity in IFN-gamma-mediated upregulation of signal transduction proteins can be detected in vitro and that these differences can explain distinct cellular growth effects.


A roadmap for the functional annotation of protein families: a community perspective.
Over the last 25 years, biology has entered the genomic era and is becoming a science of 'big data'. Most interpretations of genomic analyses rely on accurate functional annotations of the proteins encoded by more than 500 000 genomes sequenced to date. By different estimates, only half the predicted sequenced proteins carry an accurate functional annotation, and this percentage varies drastically between different organismal lineages. Such a large gap in knowledge hampers all aspects of biological enterprise and, thereby, is standing in the way of genomic biology reaching its full potential. A brainstorming meeting to address this issue funded by the National Science Foundation was held during 3-4 February 2022. Bringing together data scientists, biocurators, computational biologists and experimentalists within the same venue allowed for a comprehensive assessment of the current state of functional annotations of protein families. Further, major issues that were obstructing the field were identified and discussed, which ultimately allowed for the proposal of solutions on how to move forward.


Utility of noninvasive imaging modalities in a retina practice.
Fluorescein angiography (FFA) has been the gold standard to understand, diagnose and treat retinal disorders. However, being an invasive procedure it has several limitations including adverse drug reactions. Hence, noninvasive tests that can be repeated during the course of the disease are the need of the hour. The aim of our study was to compare images of patients with retinal microvasculature pathology taken from three different imaging modalities (invasive vs. noninvasive). Lesions were detected more easily and with a greater resolution of morphology on retinal function imaging (RFI) and optical coherence tomography angiography (angio-OCT). Functional integrity of the vessels was better delineated on FFA. RFI and angio-OCT are noninvasive rapid and efficient methods to image vascular conditions with easy repeatability and negligible adverse effects.


Alteration of drug chemosensitivity caused by the adenovirus-mediated transfer of the wild-type p53 gene in human lung cancer cells.
The aim of the present study is to identify the optimal anticancer agents for use in combination with gene therapy using wild-type (wt) p53 gene transfer. We used adenoviral vectors expressing human wt p53 (AdCAp53) and investigated the effects of wt p53 gene transfer in combination with 12 anticancer agents on a human pulmonary squamous cell carcinoma cell line, NCI-H157, and a human pulmonary large cell carcinoma cell line, NCI-H1299. Solutions containing anticancer agents at various concentrations were added followed by the addition of recombinant adenovirus solutions; after a 5-day incubation period, the anticancer activity was then evaluated by a 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carbo xanilide assay. Each 50% inhibitory concentration was calculated based on the dose-response curves. The agents showing a high degree of effectiveness on NCI-H157 cells were cisplatin (CDDP), 5-fluorouracil (5-FU), bleomycin, and 7-ethyl-10-hydroxy-camptothecin (SN-38), an active metabolite of irinotecan (CPT-11); conversely, cyclophosphamide and paclitaxel showed a low degree of effectiveness. Based on these data, an isobologram was performed to investigate the interaction between AdCAp53 and some anticancer agents. A supra-additive effect was thus observed for 5-FU and SN-38 on NCI-H157 cells. An additive effect was also observed for CDDP, paclitaxel, bleomycin, and cyclophosphamide on NCI-H157 cells. CDDP, paclitaxel, 5-FU, and SN-38 had an additive effect on NCI-H1299 cells. No drug showed any subadditive or protective effects. These findings suggest that CPT-11 and 5-FU may thus be useful as possible anticancer agents for use in a combination therapy regimen using wt p53 gene transfer. CDDP and CPT-11 had a significant antitumoral effect on H157 cell xenografts of nude mice in vivo. These results indicate that CPT-11 as well as CDDP would be a candidate for the combination of chemotherapy and gene therapy for non-small cell lung cancer.


Platinum spatula versus Mini-tip Culturette in culturing bacterial keratitis.
To compare the traditional method of culturing bacterial keratitis (platinum spatula) with the use of a commercially available Mini-tip Culturette (Becton-Dickinson, Cockeysville, MD, U.S.A.). An experimental model of bacterial keratitis was created in rabbit corneas by intrastromal injection of bacteria. Cultures were taken of rabbit corneas with both the Mini-tip Culturette and the platinum spatula. Culture results were compared with corneal colony counts. Humans with community-acquired presumed bacterial keratitis were cultured with both the Mini-tip Culturette and the platinum spatula. The sensitivity and specificity of the Mini-tip Culturette method was determined and compared with the platinum-spatula technique. Rabbit keratitis model: 100% of corneas had established infections by colony count. Each ulcer was culture positive with platinum spatula, moist Mini-tip Culturette, and dry Mini-tip Culturette. Human keratitis: Seven patients had culture-negative keratitis with both the Mini-tip Culturette and the platinum spatula. Five patients were culture positive with both the Mini-tip Culturette and the platinum spatula. One of the positive cultures had growth of multiple organisms by using the platinum spatula but not with the Mini-tip Culturette. The sensitivity of the Mini-tip Culturette was 83.3%. The specificity of the Mini-tip Culturette was 100%. Detected organisms included group A beta-hemolytic Streptococcus, S. aureus, coagulase-negative Staphylococcus, Serratia marcescens, and Pseudomonas aeruginosa. The Mini-tip Culturette is a highly specific and moderately sensitive method for culturing bacterial keratitis.


Clinical and radiological repercussions of plexiform neurofibroma in the pelvic region.
The authors report the case of a plexiform neurofibroma located in the pelvis, affecting the bladder, prostate and spine (lumbar/sacral), followed-up for three years and six months. Surgical removal was contraindicated and the patient underwent biannual clinical and radiological follow-up that did not demonstrate any tumor increase. The clinical manifestations of neurofibromatosis type 1 are variable, and the medical team should be attentive to further investigations, considering possible unexpected rare findings. Large pelvic masses may correspond to plexiform neurofibromas, so the diagnostic hypothesis of neurofibromatosis should be taken into consideration.


Toxic effects of environmentally relevant concentrations of naproxen exposure on Daphnia magna including antioxidant system, development, and reproduction.
Naproxen (NPX) is one of common non-prescription non-steroidal anti-inflammatory drugs (NSAIDs) which is widely detected in aquatic environments worldwide due to its high usage and low degradation. NPX exerts anti-inflammatory and analgesic pharmacological effects through the inhibition of prostaglandin-endoperoxide synthase (PTGS), also known as cyclooxygenase (COX). Given its evolutionarily relatively conserved biological functions, the potential toxic effects of NPX on non-target aquatic organisms deserve more attention. However, the ecotoxicological studies of NPX mainly focused on its acute toxic effects under higher concentrations while the chronic toxic effects under realistic concentrations exposure, especially for the underlying molecular mechanisms still remain unclear. In the present study, Daphnia magna, being widely distributed in freshwater aquatic environments, was selected to investigate the toxic effects of environmentally relevant concentrations of NPX via determining the response of the Nrf2/Keap1 signaling pathway-mediated antioxidant system in acute exposure, as well as the changes in life-history traits, such as growth, reproduction, and behavior in chronic exposure. The results showed that the short-term exposure to NPX (24 h and 48 h) suppressed ptgs2 expression while activating Nrf2/Keap1 signaling pathway and its downstream antioxidant genes (ho-1, sod, cat and trxr). However, with prolonged exposure to 96 h, the opposite performance was observed, the accumulation of malondialdehyde (MDA) indicated that D. magna suffered from severe oxidative stress. To maintain homeostasis, the exposed organism may trigger ferroptosis and apoptosis processes with the help of Silent mating type information regulation 2 homologs (SIRTs). The long-term chronic exposure to NPX (21 days) caused toxic effects on D. magna at the individual and population levels, including growth, reproduction and behavior, which may be closely related to the oxidative stress induced by the drug. The present study suggested that more attention should be paid to the ecological risk assessment of NSAIDs including NPX on aquatic non-target organisms.


MEEGIPS-A Modular EEG Investigation and Processing System for Visual and Automated Detection of High Frequency Oscillations.
High frequency oscillations (HFOs) are electroencephalographic correlates of brain activity detectable in a frequency range above 80 Hz. They co-occur with physiological processes such as saccades, movement execution, and memory formation, but are also related to pathological processes in patients with epilepsy. Localization of the seizure onset zone, and, more specifically, of the to-be resected area in patients with refractory epilepsy seems to be supported by the detection of HFOs. The visual identification of HFOs is very time consuming with approximately 8 h for 10 min and 20 channels. Therefore, automated detection of HFOs is highly warranted. So far, no software for visual marking or automated detection of HFOs meets the needs of everyday clinical practice and research. In the context of the currently available tools and for the purpose of related local HFO study activities we aimed at converging the advantages of clinical and experimental systems by designing and developing a comprehensive and extensible software framework for HFO analysis that, on the one hand, focuses on the requirements of clinical application and, on the other hand, facilitates the integration of experimental code and algorithms. The development project included the definition of use cases, specification of requirements, software design, implementation, and integration. The work comprised the engineering of component-specific requirements, component design, as well as component- and integration-tests. A functional and tested software package is the deliverable of this activity. The project MEEGIPS, a Modular EEG Investigation and Processing System for visual and automated detection of HFOs, introduces a highly user friendly software that includes five of the most prominent automated detection algorithms. Future evaluation of these, as well as implementation of further algorithms is facilitated by the modular software architecture.


Tributyl phosphate effects on urine and bladder epithelium in male Sprague-Dawley rats.
Tributyl phosphate (TBP) produces tumors of the bladder urothelium in rats at high doses (700 and 3000 ppm), with greater effects in males than in females. TBP does not produce tumors in mice and it is nongenotoxic. The dose response of TBP effects on urine and urothelium was evaluated in male Sprague-Dawley rats at 0, 200, 700, and 3000 ppm of the diet, 10 rats per group, for 10 weeks. Another group received 3000 ppm TBP plus 12,300 ppm NH4Cl to evaluate the effect of urinary acidification. An additional group of 10 rats received 12,300 ppm NH4Cl. A high-dose recovery group (10 weeks 3000 ppm TBP, then 10 weeks control diet) was included to evaluate reversibility. Urine chemistries for control and TBP-treated animals were similar except for a slight decrease in osmolality and creatinine at the highest dose. Scanning electron microscopic examination of the urine of TBP-treated rats showed no increased or abnormal crystalluria, urinary precipitate, or calculi. The urothelial effects were seen at the two highest doses, but were most severe at 3000 ppm TBP, with ulceration and hemorrhage into the bladder lumen and consequent diffuse papillary and nodular hyperplasia. Dietary NH4Cl acidified the urine but did not prevent the urothelial toxicity and regeneration. The bladder epithelial changes were reversible, but the ulcer repair process was accompanied by submucosal fibrosis. TBP at high doses appears to produce urothelial cytotoxicity with marked regenerative hyperplasia which is reversible upon withdrawal of treatment. The cytotoxicity is likely due to the direct effect of TBP or its metabolites rather than an indirect consequence of urinary changes.


Guanidine hydrochloride inhibits mammalian orthoreovirus growth by reversibly blocking the synthesis of double-stranded RNA.
Millimolar concentrations of guanidine hydrochloride (GuHCl) are known to inhibit the replication of many plant and animal viruses having positive-sense RNA genomes. For example, GuHCl reversibly interacts with the nucleotide-binding region of poliovirus protein 2C(ATPase), resulting in a specific inhibition of viral negative-sense RNA synthesis. The use of GuHCl thereby allows for the spatiotemporal separation of poliovirus gene expression and RNA replication and provides a powerful tool to synchronize the initiation of negative-sense RNA synthesis during in vitro replication reactions. In the present study, we examined the effect of GuHCl on mammalian orthoreovirus (MRV), a double-stranded RNA (dsRNA) virus from the family Reoviridae. MRV growth in murine L929 cells was reversibly inhibited by 15 mM GuHCl. Furthermore, 15 mM GuHCl provided specific inhibition of viral dsRNA synthesis while sparing both positive-sense RNA synthesis and viral mRNA translation. By using GuHCl to provide temporal separation of MRV gene expression and genome replication, we obtained evidence that MRV primary transcripts support sufficient protein synthesis to assemble morphologically normal viral factories containing functional replicase complexes. In addition, the coordinated use of GuHCl and cycloheximide allowed us to demonstrate that MRV dsRNA synthesis can occur in the absence of ongoing protein synthesis, although to only a limited extent. Future studies utilizing the reversible inhibition of MRV dsRNA synthesis will focus on elucidating the target of GuHCl, as well as the components of the MRV replicase complexes.


Oncogenic miRNA-182-5p targets Smad4 and RECK in human bladder cancer.
Onco-miR-182-5p has been reported to be over-expressed in bladder cancer (BC) tissues however a detailed functional analysis of miR-182-5p has not been carried out in BC. Therefore the purpose of this study was to: 1. conduct a functional analysis of miR-182-5p in bladder cancer, 2. assess its usefulness as a tumor marker, 3. identify miR-182-5p target genes in BC. Initially we found that miR-182-5p expression was significantly higher in bladder cancer compared to normal tissues and high miR-182-5p expression was associated with shorter overall survival in BC patients. To study the functional significance of miR-182-5p, we over-expressed miR-182-5p with miR-182-5p precursor and observed that cell proliferation, migration and invasion abilities were increased in BC cells. However cell apoptosis was inhibited by miR-182-5p. We also identified Smad4 and RECK as potential target genes of miR-182-5p using several algorithms. 3'UTR luciferase activity of these target genes was significantly decreased and protein expression of these target genes was significantly up-regulated in miR-182-5p inhibitor transfected bladder cancer cells. MiR-182-5p also increased nuclear beta-catenin expression and while Smad4 repressed nuclear beta-catenin expression. In conclusion, our data suggests that miR-182-5p plays an important role as an oncogene by knocking down RECK and Smad4, resulting in activation of the Wnt-beta-catenin signaling pathway in bladder cancer.


Capnocytophaga spp. contain sulfonolipids that are novel in procaryotes.
A group of unusual sulfonolipids was found in bacteria of the genus Capnocytophaga. One of these lipids, to which we have assigned the trivial name capnine, was isolated in 98% pure form and was identified, by infrared absorption spectrometry, high-resolution mass spectrometry, and other methods, as 2-amino-3-hydroxy-15-methylhexadecane-1-sulfonic acid. Another lipid appears to be an N-acylated version of capnine; after acid hydrolysis, its sulfur was recovered in a form chromatographically indistinguishable from that of capnine. The new lipids are related structurally to sphingosine and the ceramides, respectively, but differ markedly from those compounds in important respects, notably the presence of the sulfonate group. Some Capnocytophaga strains accumulated mostly capnine, whereas others accumulated mostly N-acylcapnine. All seven strains examined were found to contain the new lipids, in amounts ranging from 7 to 16 mumol/g of cells (wet weight). The lipids were found in isolated cell envelopes, where they were present in amounts ranging up to 400 mg/g of envelope protein; they are, accordingly, major cell components.