Differences in demographics and outcomes based on method of consent for a randomised controlled trial on heat loss prevention in the delivery room.
Informed consent is standard in research. International guidelines allow for research without prior consent in emergent situations, such as neonatal resuscitation. Research without prior consent was incorporated in the Vermont Oxford Network Heat Loss Prevention Trial. We evaluated whether significant differences in outcomes exist based on the consent method. Subgroup analysis of infants enrolled in a randomised controlled trial conducted from 2004 to 2010. A multicentre trial with 38 participating centres. Infants born 24-27 weeks of gestation. 3048 infants assessed, 2231 excluded due to fetal congenital anomalies, failure to obtain consent or gestation less than 24 weeks. 817 randomised, 4 withdrew consent, total of 813 analysed. The difference in mortality between consent groups. No significant differences were found in mortality at 36 weeks (80.2%, 77.4%, p=0.492) or 6 months corrected gestational age (80.7%, 79.7%, p=0.765). Infants enrolled after informed consent were more likely to have mothers who had received antenatal steroids (95.2%, 84.0%, p<0.0001). They also had significantly higher Apgar scores at 1 (5.0, 4.4, p=0.019), 5 (7.3, 6.7, p=0.025) and 10 min (7.5, 6.3, p=0.0003). Research without prior consent resulted in the inclusion of infants with different baseline characteristics than those enrolled after informed consent. There were no significant differences in mortality. Significantly higher Apgar scores in the informed consent group suggest that some of the sicker infants would have been excluded from enrolment under informed consent. Research without prior consent should be considered in neonatal resuscitation research.


Obstetric medication and neonatal behavior. Current controversies.
This article reviews the work on the neonatal effects of low drug doses published in the last five years. At the same time, there will be a focus on new developments in perinatal pharmacology and on current controversies in this area. The article includes discussions about neurobehavioral outcome measures and statistics, as well as recommendations for future studies.


Replacement of neuraminidase inhibitor-susceptible influenza A(H1N1) with resistant phenotype in 2008 and circulation of susceptible influenza A and B viruses during 2009-2013, South Africa.
Data on the susceptibility of influenza viruses from South Africa to neuraminidase inhibitors (NAIs) are scarce, and no extensive analysis was done. We aimed to determine oseltamivir and zanamivir susceptibility of influenza A and B virus neuraminidases (NAs), 2007-2013, South Africa. We enrolled participants through national influenza-like illness surveillance, 2007-2013. Influenza diagnosis was by virus isolation and quantitative polymerase chain reaction (qPCR). Drug susceptibility was determined by chemiluminescence-based NA-STAR/NA-XTD assay. Sanger sequencing was used to determine molecular markers of NAI resistance. Forty percent (6341/15 985) of participants were positive for influenza viruses using virus isolation (2007-2009) and qPCR (2009-2013) methods. A total of 1236/6341 (19.5%) virus isolates were generated of which 307/1236 (25%) were tested for drug susceptibility. During 2007-2008, the median 50% inhibitory concentration (IC50 ) of oseltamivir for seasonal influenza A(H1N1) increased from of 0.08 nmol/L (range 0.01-3.60) in 2007 to 73 nmol/L (range 1.56-305 nmol/L) in 2008. Influenza A isolates from 2009 to 2013 were susceptible to oseltamivir [A(H3N2) median IC50 = 0.05 nmol/L (range 0.01-0.08); A(H1N1)pdm09 = 0.11 nmol/L (range 0.01-0.78)] and zanamivir [A(H3N2) median IC50 = 0.56 nmol/L (range 0.47-0.66); A(H1N1)pdm09 = 0.35 nmol/L (range 0.27-0.533)]. Influenza B viruses were susceptible to both NAIs. NAI resistance-associated substitutions H275Y, E119V, and R150K (N1 numbering) were not detected in influenza A viruses that circulated in 2009-2013. We confirm replacement of NAI susceptible by resistant phenotype influenza A(H1N1) in 2008. Influenza A and B viruses (2009-2013) remained susceptible to NAIs; therefore, these drugs are useful for treating influenza-infected patients.


Dietary monounsaturated n-3 and n-6 long-chain polyunsaturated fatty acids affect cellular antioxidant defense system in rats with experimental ulcerative colitis induced by trinitrobenzene sulfonic acid.
The intrarectal administration of trinitrobenzene sulfonic acid in rats induces ulcerative colitis, which results in histological alterations of colonic mucosa, severe modification of the cellular antioxidant defense system, and enhanced production of inflammatory eicosanoids. This study evaluated the influence of different dietary fatty acids, i.e., monounsaturated, n-3, and n-3 + n-6 polyunsaturated fatty acids, on the recovery of the colonic mucosa histological pattern, the cellular antioxidant defense system of colon, and PGE2 and LTB4 colonic mucosa contents in a model of ulcerative colitis induced by intrarectal administration of trinitrobenzene sulfonic acid. Administration of dietary n-3 polyunsaturated fatty acids led to a minimum stenosis score, a higher histological recovery, lower colon alkaline phosphatase and gamma-glutamyltranspeptidase activities, and lower mucosal levels of PGE2 and LTB4 compared with the other two experimental groups. However, glutathione transferase, glutathione reductase, glutathione peroxidase, and catalase activities were lower in the group treated with n-3 polyunsaturated fatty acids than in the groups fed with either the monounsaturated or the n-6 + n-3 polyunsaturated enriched diet. We conclude that n-3 polyunsaturated fatty acids can be administered to prevent inflammation in ulcerative colitis, but they cause a decrease in the colonic antioxidant defense system, promoting oxidative injury at the site of inflammation.


High vitamin A intake during pregnancy modifies dopaminergic reward system and decreases preference for sucrose in Wistar rat offspring.
High multivitamin (HV) content in gestational diets has long-term metabolic effects in rat offspring. These changes are associated with in utero modifications of gene expression in hypothalamic food intake regulation. However, the role of fat-soluble vitamins in mediating these effects has not been explored. Vitamin A is a plausible candidate due to its role in gene methylation. Vitamin A intake above requirements during pregnancy affects the development of neurocircuitries involved in food intake and reward regulation. Pregnant Wistar rats were fed AIN-93G diets with the following content: recommended multivitamins (1-fold multivitamins: RV), high vitamin A (10-fold vitamin A: HA) or HV with only recommended vitamin A (10-fold multivitamins, 1-fold vitamin A: HVRA). Body weight, food intake and preference, mRNA expression and DNA methylation of hippocampal dopamine-related genes were assessed in male offspring brains at different developmental windows: birth, weaning and 14weeks postweaning. HA offspring had changes in dopamine-related gene expression at all developmental windows and DNA hypermethylation in the dopamine receptor 2 promoter region compared to RV offspring. Furthermore, HA diet lowered sucrose preference but had no effect on body weight and expression of hypothalamic genes. In contrast, HVRA offspring showed only at adulthood changes in expression of hippocampal genes and a modest effect on hypothalamic genes. High vitamin A intake alone in gestational diets has long-lasting programming effects on the dopaminergic system that are further translated into decreased sucrose preference but not food intake.


Dynamic cellular responses in plant-microbe interactions.
Encounters between plant cells and both 'friendly' and 'hostile' microbes (such as those in symbiotic and pathogenic interactions, respectively) trigger a range of highly dynamic plant cellular responses. These include reorganization of the cytoskeleton, organelle translocation, vesicle trafficking, and alterations in subcellular protein localization. Recent progress in this borderland that bridges the fields of plant-microbe interactions and cell biology heralds the transition from descriptive phenomenology to the identification and characterization of key molecules that are involved in these processes. Intriguingly, molecular events that occur in plant cells in response to microbes also take place upon abiotic wounding and during fundamental plant developmental processes, such as the tip growth of pollen, root hairs and trichomes. Thus, elementary 'activity modules' that are required for the generation of cell polarity in plant morphogenesis appear to be re-used in both abiotic and biotic stress response pathways.


Penetration of a long stem prosthesis into the knee joint: a complication of total hip replacement.
The unusual occurrence of penetration of the stem of a femoral prosthesis into the knee joint during total hip replacement and the method used to deal with this complecation successfully, without replacing the prosthesis, is described.


Low miR200c expression in tumor budding of invasive front predicts worse survival in patients with localized colon cancer and is related to PD-L1 overexpression.
At the histological level, tumor budding in colon cancer is the result of cells undergoing at least partial epithelial-to-mesenchymal transition. The microRNA 200 family is an important epigenetic driver of this process, mainly by downregulating zinc-finger E-box binding homeobox (ZEB) and transforming growth factor beta (TGF-β) expression. We retrospectively explored the expression of the miR200 family, and ZEB1 and ZEB2, and their relationship with immune resistance mediated through PD-L1 overexpression. For this purpose, we analyzed a series of 125 colon cancer cases and took samples from two different tumor sites: the area of tumor budding at the invasive front and from the tumor center. We found significant ZEB overexpression and a reduction in miR200 in budding areas, a profile compatible with epithelial-to-mesenchymal transition. In multivariate analysis of the cases with localized disease, low miR200c expression in budding areas, but not at the tumor center, was an adverse tumor-specific survival factor (hazard ratio: 0.12; 95% confidence interval: 0.03-0.81; p = 0.02) independent of the clinical stage of the disease. PD-L1 was significantly overexpressed in the budding areas and its levels correlated with a mesenchymal transition profile. These results highlight the importance of including budding areas among the samples used for biomarker evaluation and provides relevant data on the influence of mesenchymal transition in the immune resistance mediated by PD-L1 overexpression.


Met-enkephalin-Arg6-Gly7-Leu8 in large-cored vesicles of splanchnic nerve terminals innervating guinea pig adrenal chromaffin cells.
Met-enkephalin-Arg6-Gly7-Leu8 (Met-Enk-Arg-Gly-Leu)-like immunoreactivity in the guinea pig adrenal medulla was investigated by the peroxidase-antiperoxidase method for light microscopy and by the protein A-gold method for electron microscopy. Because of a distinct Met-Enk-Arg-Gly-Leu-like immunoreactivity in the splanchnic nerve terminals innervating the chromaffin cell, their distribution and structure were clearly demonstrated. With electron microscopy, specific colloidal gold particles representing Met-Enk-Arg-Gly-Leu were localized in large-cored vesicles.


Glucose stimulation of beta-cell DNA replication in the intact rat and in pancreatic islets in suspension culture. Effects of alpha-ketoisocaproic acid, dibutyryl cyclic AMP, and 3-isobutyl-1-methylxanthine in the in vitro system.
DNA replication in pancreatic beta-cells was compared in intact rats maintained hyperglycemic by continuous glucose infusion up to 10 days and in rat islets maintained in suspension culture in RPMI 1640 medium up to 12 days. Replicative activity was evaluated by counting the proportion of labeled beta-cell nuclei after injection or addition of [3H]thymidine. In both experimental systems, DNA replication initially was markedly stimulated by high glucose; then it subsided, even though high levels of glucose were maintained. Culture of pancreatic islets in suspension permitted the study of various treatments on beta-cell DNA replication. Alpha-ketoisocaproic acid, a nonglycolytic substrate for the beta-cell, stimulated DNA replication. 3-Isobutyl-1-methylxanthine (IBMX), in the presence of 4 mM glucose, was a potent stimulator. In many instances the proportion of labeled beta-cell nuclei in islets cultured with IBMX exceeded that obtained with 25 mM glucose. Dibutyryl-cyclic AMP stimulated DNA replication but was not as effective as IBMX. Although the effect of IBMX markedly decreased during the second week of culture, IBMX was much more effective than 25 mM glucose in maintaining DNA replication persistently above basal (4 mM glucose) levels.


Phenylalanine and UVA light for the treatment of vitiligo.
The administration of phenylalanine (Phe) combined with UVA exposure was found to be effective in vitiligo. Phe is an amino acid which constitutes part of the daily dietary protein, and when orally administered in a dose of 50 mg/kg body weight, it results in an elevated plasma level. Since peak concentrations of Phe in the blood are reached between 30 and 45 min after ingestion, UVA exposure was administered at this time. After 4 months (32 treatments) reasonable repigmentation preferentially occurred in the skin area of subcutaneous fat (adipose tissue). Apart from the repigmentation of hypo-pigmented macules, vitiligo patients can tolerate more sun than usual, especially at the vitiliginous lesion, and they experience no sunburn as a result of Phe-UVA therapy. Normal skin also tans very well.


[Investigation and Analysis of the Implementation Status of Enhanced Recovery After Surgery in the Context of Precision Nursing in Xinjiang].
To investigate the current status of surgical nurses' implementation of enhanced recovery after surgery (ERAS) concepts in the context of precision nursing in Xinjiang and to provide a basis for the development of precision nursing of ERAS. By way of convenience sampling, surgical nurses from 8 tertiary-care hospitals were involved in a survey on their ERAS implementation status in March and April 2023 and the results were collected by online questionnaire. A total of 985 valid questionnaires were collected. Out of the 8 hospitals covered in the survey, the orthopedics departments of 7 hospitals have implemented ERAS concepts, accounting for 87.50%. The average score for the ERAS Knowledge, Attitude, and Practice Questionnaire among the surgical nurses was (182.98±17.69), of which, the average score for ERAS knowledge was (13.08±1.51), the average score for ERAS attitude was (88.75±8.30), and the average score for ERAS practice was (81.15±11.96). A total of 61.02% of the surgical nurses implemented ERAS pathways that concentrated on 4-6 pathways, with the prevention of postoperative ileus after surgery being the most commonly implemented pathway, accounting for 498 (50.56%) surgical nurses. A total of 78.48% of the nurses considered work overload to be the most important obstacle to implementing ERAS in the context of precision nursing. Poor multidisciplinary team collaboration and poor awareness of implementation among the nurses ranked the second and the third, accounting for 74.92% and 71.57%, respectively, of the surgical nurses. ERAS has won the approval of surgical nurses in Xinjiang, but it is still not widely implemented in all surgical fields. In addition, the quantity and quality of ERAS pathways implemented still need to be further improved. The development of ERAS in the context of precision nursing remains a long-term challenge.


Combining community resurvey data to advance global change research.
More and more ecologists have started to resurvey communities sampled in earlier decades to determine long-term shifts in community composition and infer the likely drivers of the ecological changes observed. However, to assess the relative importance of, and interactions among, multiple drivers joint analyses of resurvey data from many regions spanning large environmental gradients are needed. In this paper we illustrate how combining resurvey data from multiple regions can increase the likelihood of driver-orthogonality within the design and show that repeatedly surveying across multiple regions provides higher representativeness and comprehensiveness, allowing us to answer more completely a broader range of questions. We provide general guidelines to aid implementation of multi-region resurvey databases. In so doing, we aim to encourage resurvey database development across other community types and biomes to advance global environmental change research.


Increased variability of the coupling interval of premature ventricular contractions as a predictor of cardiac mortality in patients with left ventricular dysfunction.
The characteristics and prognostic value of the variability of premature ventricular contraction (PVC) coupling intervals (CIs) for cardiac mortality are not yet decisive. In 133 consecutive patients (58±14 years old, 53 women) who had left ventricular dysfunction (LVD: ejection fraction <50%) and frequent PVCs (≥10/h) who underwent 24-h ambulatory electrocardiography (AECG) recording and (123)I-metaiodobenzylguanidine myocardial single-photon emission computed tomography simultaneously, the heart rate turbulence onset, slope, and T-wave alternans were analyzed from the 24-h AECG. The CI of the PVCs (MEANNV), standard deviation of the CI of the PVCs (SDNV) as an index of the variability of the PVC CI, and their ratio to the preceding N-N intervals (SDNV/SDNN) were calculated from constructed Poincaré plots using the annotated 24-h AECG QRS data. The primary endpoint was cardiac mortality. The mean follow-up period was 63 months. Among 133 patients, 114 survived (group 1) and 19 (14%, group 2) died during the follow-up. The MEANNVand SDNVwere higher in group 2 (539±104 vs. 599±114 ms, P=0.021; 64±34 vs. 83±37 ms, P=0.022, respectively). The SDNV, PVC count, and delayed heart/mediastinum ratio remained as significant predictors of cardiac mortality in the binary logistic regression analysis. These results suggest that the SDNVcould be another adjunctive parameter for predicting cardiac mortality in LVD.


Properties of subsequent induction of long-term potentiation and/or depression in one synaptic input in apical dendrites of hippocampal CA1 neurons in vitro.
The hippocampus is a prominent structure to study mechanisms of learning and memory at the cellular level. Long-term potentiation (LTP) as well as long-term depression (LTD) are the major cellular models which could underlie learning and memory formation. LTP and LTD consist of at least two phases, an early protein synthesis-independent transient stage (<4 h; E-LTP, E-LTD) as well as a prolonged phase (>4 h; L-LTP, L-LTD) requiring the synthesis of new proteins. It is known that during E-LTP the further induction of longer lasting LTP is precluded. However, if E-LTP is transformed into L-LTP, the same synapses now allow the induction of LTP again. We reproduced the LTP-results first and then investigated whether hippocampal LTP or LTD also prevents the establishment of subsequent LTD-induction in the same synaptic input. We show that the prior induction of LTP or LTD does not prevent a short-term depression (STD) but occludes LTD in apical dendrites of CA1 neurons in hippocampal slices in vitro during the early phase of LTP or LTD. However, LTD can again be induced in addition to STD after the establishment of L-LTP or L-LTD, that is about 4 h after the induction of the first event in the same synaptic input. We suggest that the neuronal input preserves the capacity for STD immediately after an initial potentiation or depression, but for the onset of additional longer lasting LTD in the same synaptic input, the establishment of the late plasticity form of the preceding event is critical.


Pulmonary sclerosing pneumocytoma and mortality risk.
Surgical resection is usually recommended for the treatment of pulmonary sclerosing pneumocytoma (PSP). However, no comparative study has demonstrated that surgical resection leads to improved outcomes. We aimed to compare all-cause mortality between patients with PSP who underwent surgery or did not and those without PSP. Participants aged ≥18 years who had pathologically diagnosed PSP between 2001 to 2018, at 3 hospitals were included. Randomly selected (up to 1:5) age-, sex-, and smoking status-matched controls without PSP who were randomly selected from those who underwent health checkups including chest CT were included. Mortality was compared using Kaplan-Meier estimates and Cox proportional hazards regression models. Literature review of studies reporting PSP was also conducted. This study included 107 patients with PSP (surgery:non-surgery, 80:27) and 520 matched controls. There were no cases of lymph node or distant metastasis, recurrence, or mortality from PSP. No significant difference in all-cause mortality risk was observed between the PSP surgery, PSP non-surgery, and non-PSP groups (log rank test P = 0.78) (PSP surgery vs. non-PSP: adjusted hazards ratio [aHR], 1.80; 95% confidence interval [CI], 0.22-14.6; PSP non-surgery vs. non-PSP: aHR, 0.77; 95% CI, 0.15-3.86; PSP surgery vs. PSP non-surgery: aHR, 2.35; 95% CI, 0.20-28.2). In the literature review, we identified 3469 patients with PSP from 355 studies. Only 1.33% of these patients reported metastasis, recurrence, or death. All-cause mortality did not differ between patients with PSP and those without, irrespective of undergoing surgery. Our study and the literature review suggest that PSP has less impact on increased mortality risk.


Automation of the patient history--evaluation of ergonomic aspects.
In this study it was investigated in quantitative terms how patient reactions were on automated history-taking. The study is part of a comprehensive project, in which also physicians participated in the validation of such computerized medical records. In total 99 patients, visiting the outpatient clinic of Internal Medicine for the first time, took part in this in-depth study, in which they could express themselves via an interactive and modified terminal and keyboard. The questionnaire that was used in the system contains 28 different screens. Patient complaints are entered together with data on frequency, severity, onset, and duration. The patient may indicate his physical complaints on a stylized picture of the human body. Of the 99 patients, 67 answered the full questionnaire, and another 16 the main part. On the average, 66 min were needed. Younger patients do complete the history in a significantly shorter time than older patients, resulting in relatively more completed histories for the younger group. Quick patients answered on the average 3.5 questions per minute, the slow patients only 2.5. This was strongly correlated with patient familiarization, that has also been investigated: patients who had a quick familiarization were able to finish within 50 min. Patients who needed no help at all in using the system had even answering rates of 3.9/min.


Stress views in the radiography of scapholunate instability.
On the suspected carpal instabilities stress views are recommended but not often used. The present study evaluates the reliability of the dorsal and volar stress radiographs on patients with posttraumatic wrist pain. Stress radiographs of the wrists were examined in 22 patients with chronic wrist pain and the results were compared with scaphoid shift test and standard and positional views. The stress examination consists of applying to the wrist dorsal and volar stresses on the hand. Static scapholunate instability was diagnosed in 4 patients in whom 3 of them had positive scaphoid shift test sign as well. There were, however, 18 patients with dynamic scapholunate instability in whom the standard films were normal but dorsal stress radiography showed gap greater than 3mm between the scaphoid and lunate. Stress tests may provide considerable information in the evaluation of a patient who has a painful wrist in whom routine and special views do not demonstrate scapholunate dissociation.


Creating and Implementing a Professional Development Program to Improve Organizational Capacity for Health Analytics in a Public Health Setting.
The implementation of an Electronic Medical Record (EMR) in the public healthcare system of Buenos Aires City began in June 2016. AGISE is a government department that assists in health decision-making processes by providing timely and quality data. In this study we designed a professional development program to improve organizational capacities for health analytics.


Enhancement of mammographic density measures in breast cancer risk prediction.
Mammographic density is a strong risk factor for breast cancer. We present a novel approach to enhance area density measures that takes advantage of the relative density of the pectoral muscle that appears in lateral mammographic views. We hypothesized that the grey scale of film mammograms is normalized to volume breast density but not pectoral density and thus pectoral density becomes an independent marker of volumetric density. From analysis of data from a Swedish case-control study (1,286 breast cancer cases and 1,391 control subjects, ages 50-75 years), we found that the mean intensity of the pectoral muscle (MIP) was highly associated with breast cancer risk [per SD: OR = 0.82; 95% confidence interval (CI), 0.75-0.88; P = 6 × 10(-7)] after adjusting for a validated computer-assisted measure of percent density (PD), Cumulus. The area under curve (AUC) changed from 0.600 to 0.618 due to using PD with the pectoral muscle as reference instead of a standard area-based PD measure. We showed that MIP is associated with a genetic variant known to be associated with mammographic density and breast cancer risk, rs10995190, in a subset of women with genetic data. We further replicated the association between MIP and rs10995190 in an additional cohort of 2,655 breast cancer cases (combined P = 0.0002). MIP is a marker of volumetric density that can be used to complement area PD in mammographic density studies and breast cancer risk assessment. Inclusion of MIP in risk models should be considered for studies using area PD from analog films.


Conduction-block induced by capsaicin in crayfish giant axon.
The effects of capsaicin on the crayfish giant axon were examined by using microelectrode and double sucrose gap-voltage clamp methods. Capsaicin (1-3 X 10(-4) M), when applied externally, had no effect on the resting membrane potential but gradually suppressed the action potential. The rate of rise of the action potential was simultaneously decreased. Voltage clamp experiments revealed the following: capsaicin (10(-4) M) reduced more effectively the transient sodium current than the steady-state potassium current. Inhibition of the sodium current was derived from a decrease in maximum sodium conductance, as the equilibrium potential remained much the same. The inhibitory effects of capsaicin on action potentials and membrane ionic currents were slowly reversible after removal of capsaicin. These results indicate that capsaicin seems to produce a conduction block in the crayfish giant axon due to an inhibition of sodium channels. The significance of these findings is discussed in relation to the sensory neurone-blocking action of capsaicin.


The influence of a two-step leaching pretreatment on the steam gasification properties of cornstalk waste.
Knowing the effect of specific alkali and alkali earth metals forms is vital for the high-efficient gasification of biomass. This work developed a two-step leaching method to pretreat cornstalk, dividing the inorganic metals into water-soluble (K+, 74 wt%), acid-soluble (Al3+, Ca2+, Fe2+, etc) and insoluble (Si4+) substances. The water-soluble K+ was mainly in KCl form, the acid-soluble metals were removed in phosphates and sulfates forms. The rapid gasification properties of raw material, water leaching residue and acid leaching residue indicated that KCl was the key factor to enhance the hydrogen yield and gasification efficiency. Apart from K+, the alkali earth metals (Ca2+, Mg2+) also had a little catalytic effect on producing hydrogen. When the feedstock was out of metal cations, the syngas was mainly composed of CO. The basic ions to acid ions ratio was linearly related to the syngas quality, which could conduct the flux additives.


The effect of Need for Cognition on the stability of prejudiced attitudes toward South American immigrants.
The purpose of this study was to examine the role of thinking in reducing prejudice toward stigmatized groups. Participants received a persuasive message composed of strong arguments in favor of South American immigrants or a control message. In order to distinguish high- from low-elaboration individuals, participants were asked to complete the Need for Cognition Scale (NC). As expected, attitude change was equivalent for individuals with relatively high and low NC. Importantly, although both high- and low-NC participants showed a reduction in the extremity of prejudiced attitudes, the stability of these changes was different. Two days later, the changes produced in participants with high NC were found to be more persistent than equivalent changes produced in participants with low NC. An understanding of the processes through which prejudiced attitudes are modified can provide information about the long-term stability of such changes.


Photoaffinity labeling of rhodopsin and bacteriorhodopsin.
Photoaffinity labeling with bovine rhodopsin using a retinal with a fixed 11-cis-ene cross-linked exclusively to Trp-265/Leu-266 in helix F, showing that the beta-ionone C-3 is close to helix F. Moreover, since these labeled amino acids are in the middle of helix F, while the Schiff-base linkage to Lys-296 at the other terminus of the chromophore is also in the middle of helix G, the chromophore lies horizontally near the center of the lipid bilayer. In bacteriorhodopsin, photoaffinity studies using a retinal with a C-10 tritiated phenylazide appended through a 13 A spacer cross-linked to Arg-175/Asn-176 on the cytoplasmic side of helix F; this indicates that 9-Me points toward the extracellular space. This result agrees with our earlier studies with 9-sulfate analogs but is opposite to that deduced by biophysical measurements.


Biomarkers of lipid peroxidation in the aqueous humor of primary open-angle glaucoma patients.
To investigate the lipid peroxidation (PEROX) processes in primary open-angle glaucoma (POAG) patients, and whether this mechanism may be related to disease progression. A prospective, observational, cross-sectional, non-experimental, and analytical study was conducted on a case and a comparison group, consisting of 175 surgical patients divided into: 1) POAG group (GG; n=88) and 2) comparison group of patients with cataracts (CG; n=87). Demographic data, patient characteristics, lifestyle data, as well as ophthalmological examination were registered in an Excel spreadsheet. Biochemical data were obtained by processing the aqueous humor collected at the beginning of surgery. Determination of malondialdehyde/thiobarbituric acid reactive substances (MDA/TBARS) and total antioxidant activity (AAO) was assayed using enzymatic-colorimetric methods in the aqueous humor samples. Statistical analysis was performed using SPSS 15.0 software. Aqueous humor MDA/TBARS levels were significantly higher (P<.001) and the AAO significantly lower (P<.001) in the GG than in the GC. The MDA/TBARS directly correlated with intraocular pressure (IOP) values and the cup-to-disc ratio (CDR). Decreased AAO activity correlated inversely with IOP and CDR. Differences between groups were noticeably higher in the GG as regards obesity, alcohol consumption, anxiety, depression, and sedentary lifestyle. In the multivariate analysis, the variables that showed a better predictive ability were: MDA/TBARS, PIO, AAO, CDR, and depression. The POAG patients have a PEROX background that is reflected in the aqueous humor by variations in MDA/TBARS and AAO. Moreover, both the MDA/TBARS and AAO correlated with IOP values and the CDR. We propose that determination of MDA/TBARS and AAO in the aqueous humor of POAG patients can be used as biomarkers for monitoring the disease, as well the changes in lifestyle and other related risk factors.


Right anterior theta connectivity predicts autistic social traits in typically developing children.
Growing evidence supports functional network alterations in autism spectrum disorder, however much less is known about the neural mechanisms underlying autistic traits in typically developing children. Using resting-state electroencephalographic (EEG) recordings, we examined whether functional connectivity could predict autistic trait expression in 127 children aged between 4 and 12 years. Regression models showed that right anterior theta connectivity was a significant predictor of autistic traits (p = 0.013), with increased connectivity in this region associated with greater autistic trait expression. These results corroborate similar recent findings in adults, extending this observation to a cohort of children spanning early-to-middle childhood. These findings further highlight EEG-derived functional connectivity as a sensitive physiological correlate of autistic trait expression in typically developing children.


Does suckling offer protection to the lamb against Teladorsagia circumcincta infection?
This study tested the hypothesis that milk has a direct effect on the establishment of infection with Teladorsagia circumcincta, and provides information on the effects of suckling on resilience to infection in young lambs. Of 46 six-week-old twin-born lambs, one from each twin was allowed to continue suckling (S-) and its twin-weaned (W-) while both were concurrently infected with an average of either 0 (-0; n=7/group), 250 (-250; n=8/group) or 1000 (-1000; n=8/group) third stage infective larvae (L3) of T. circumcincta per day, providing six treatment groups. All groups grazed minimally contaminated pasture, and after 42 days were slaughtered for necropsy. Low pasture larval contamination was confirmed in W0 and S0 lambs by faecal egg counts (FEC) of less than 30 eggs per gram (EPG) and burdens of less than 140 worms. There was no difference in FEC between weaned and suckled lambs. Within infection regime, total worm burdens were 55-60% greater in the weaned compared with their suckled counterparts (P=0.05), and represented 27 and 17%, respectively, net establishment of larvae. The greater worm burdens of both groups of weaned animals, which compared with their suckled counterparts, and of those infected with 1000 compared with 250 larvae per day, were associated with shorter female adults that had fewer eggs in utero, perhaps indicating intra-worm population regulation, but highlighting the limitation of FEC in assessing nematode burdens of such young lambs. There was no effect of infection on live weight gain of either weaned or suckled groups and the possibility was raised that, in such young lambs, immune unresponsiveness may be responsible. The major benefit of continued milk consumption appears to lie more in providing nutrients for enhanced growth rather than in improving resilience of the lambs to infection.


When should intensive care be provided for the extremely preterm infants born at the margin of viability? A survey of Australasian parents and clinicians.
This study aimed to explore clinician and parent opinions of risk limits on resuscitation and intensive care (IC) for extremely premature infants born at the margin of viability. Two anonymous on-line surveys were conducted from August 2016 to January 2017. Survey participants were: (i) clinicians affiliated with neonatal intensive care units in Australia; and (ii) parents or individuals who expressed interest in premature babies through the Facebook page of Miracle Babies Foundation. A total of 961 responses were received. Among 204 clinicians, 52% were neonatologists, 22% obstetricians, 20% neonatal intensive care unit nurses and 4% were midwives. Among 757 parents, 98% had a premature baby. Only 75% of clinicians responded to the risk limits questions. Median mortality risk above which they would not recommend resuscitation/IC was 70% (interquartile range (IQR) 50-80%); major disability risk in survivors 60% (IQR 50-75%); and composite risk of mortality and major disability 70% (IQR 50-80%). All parents answered the risk limit questions. The median mortality risk for not planning resuscitation was 90% (IQR 60-90%); major disability risk in survivors 50% (IQR 30-90%); and composite risk 90% (IQR 50-90%). Most clinicians (82%) stated that decisions should be guided by parent opinions if there are uncertainties. Parents had varying perception of previous counselling, and 57% stated that both their viewpoint and doctor's predicted risk influenced their decision-making. Clinicians and parents had different views on mortality and major disability risks when deciding on resuscitation/neonatal IC treatment. When there was uncertainty, both agreed on working together.


[Demonstration by immunofluorescence and immunoperoxidase of an antigen of the measles type in the osteoclasts of Paget's disease of bone].
The intra nuclear and intra cytoplasmic inclusions described in osteoclasts in PAGET's bone disease are morphologically similar to those observed in subacute sclerosing panencephalitis. Immunological techniques using different specific immune sera demonstrate the presence of an antigenic structure of viral origin in osteoclasts in PAGET's bone disease. A measles or a measles like virus is most likely to be involved and may play a role in the etiology of the disease.


In silico identification of potential inhibitors against main protease of SARS-CoV-2 6LU7 from Andrographis panniculata via molecular docking, binding energy calculations and molecular dynamics simulation studies.
The ongoing global outbreak of new corona virus (SARS-CoV-2) has been recognized as global public health concern since it causes high morbidity and mortality every day. Due to the rapid spreading and re-emerging, we need to find a potent drug against SARS-CoV-2. Synthetic drugs, such as hydroxychloroquine, remdisivir have paid more attention and the effects of these drugs are still under investigation, due to their severe side effects. Therefore, the aim of the present study was performed to identify the potential inhibitor against main protease SARS-CoV-2 6LU7. In this study, RO5, ADME properties, molecular dynamic simulations and free binding energy prediction were mainly investigated. The molecular docking study findings revealed that andrographolide had higher binding affinity among the selected natural diterpenoids compared to co-crystal native ligand inhibitor N3. The persistent inhibition of Ki for diterpenoids was analogous. Furthermore, the simulations of molecular dynamics and free binding energy findings have shown that andrographolide possesses a large amount of dynamic properties such as stability, flexibility and binding energy. In conclusion, findings of the current study suggest that selected diterpenoids were predicted to be the significant phytonutrient-based inhibitor against SARS-CoV-2 6LU7 (Mpro). However, preclinical and clinical trials are needed for the further scientific validation before use.


Sweet potato cysteine proteases SPAE and SPCP2 participate in sporamin degradation during storage root sprouting.
Sweet potato sporamins are trypsin inhibitors and exhibit strong resistance to digestion by pepsin, trypsin and chymotrypsin. In addition, they constitute the major storage proteins in the sweet potato and, after degradation, provide nitrogen as a nutrient for seedling regrowth in sprouting storage roots. In this report, four cysteine proteases-one asparaginyl endopeptidase (SPAE), two papain-like cysteine proteases (SPCP1 and SPCP2), and one granulin-containing cysteine protease (SPCP3)-were studied to determine their association with sporamin degradation in sprouting storage roots. Sporamin degradation became significant in the flesh of storage roots starting from week 4 after sprouting and this correlated with expression levels of SPAE and SPCP2, but not of SPCP1 and SPCP3. In the outer flesh near the skin, sporamin degradation was more evident and occurred earlier than in the inner flesh of storage roots. Degradation of sporamins in the outer flesh was inversely correlated with the distance of the storage root from the sprout. Exogenous application of SPAE and SPCP2, but not SPCP3, fusion proteins to crude extracts of the outer flesh (i.e., extracted from a depth of 0.3cm and within 2cm of one-week-old sprouts) promoted in vitro sporamin degradation in a dose-dependent manner. Pre-treatment of SPAE and SPCP2 fusion proteins at 95°C for 5min prior to their application to the crude extracts reduced sporamin degradation. These data show that sweet potato asparaginyl endopeptidase SPAE and papain-like cysteine protease SPCP2 participate in sporamin degradation during storage root sprouting.


Quality Improvement Initiative in the NICU for Improved Practice of Cuff Blood Pressure Measurements.
Extreme preterm infants face lengthy hospitalizations and are often subjected to painful stimuli. These stimuli may be related to routine caregiving that may negatively impact long-term developmental outcomes. Frequently obtained cuff blood pressure (BP) measurements are an example of a potentially noxious stimulus to preterm infants that may have a cumulating impact on development. The primary aim was to explore the frequency of cuff BP measurements obtained in hemodynamically stable extreme preterm infants in the neonatal intensive care unit (NICU). Our secondary aim was to reduce the number of cuff BP measurements obtained in hemodynamically stable extreme preterm infants in the NICU. Quality improvement methodologies per the Institute for Healthcare Improvement were used combined with a multidisciplinary approach. Participants were infants born less than 27 weeks of gestation and discharged home. The baseline period was 2015 through Q2-2018 and the intervention period was Q3-2018 through Q1-2020. The electronic medical record was used to collect data and Minitab Statistical Software was used for data analysis. A baseline of 5.0% of eligible patients received the desired number of cuff BP measurements and increased to 63.2% after the intervention period. Findings demonstrate that using quality improvement methodology can improve clinical care. Findings suggest the feasibility and safety of reducing the number of cuff BP measurements obtained on hemodynamically stable infants in the NICU. Future endeavors should aim to reduce the quantity of painful stimuli in the NICU. Long-term developmental outcomes should be correlated in these patients.


Devolution and public perceptions and experience of health services in Pakistan: linked cross sectional surveys in 2002 and 2004.
The government of Pakistan introduced devolution in 2001. Responsibility for delivery of most health services passed from provincial to district governments. Two national surveys examined public opinions, use, and experience of health services in 2001 and 2004, to assess the impact of devolution on these services from the point of view of the public. A stratified random cluster sample drawn in 2001 and revisited in 2004 included households in all districts. Field teams administered a questionnaire covering views about available health services, use of government and private health services, and experience and satisfaction with the service. Focus groups in each community discussed reasons behind the findings, and district nazims (elected mayors) and administrators commented about implementation of devolution. Multivariate analysis, with an adjustment for clustering, examined changes over time, and associations with use and satisfaction with services in 2004. Few of 57,321 households interviewed in 2002 were satisfied with available government health services (23%), with a similar satisfaction (27%) among 53,960 households in 2004. Less households used government health services in 2004 (24%) than in 2002 (29%); the decrease was significant in the most populous province. In 2004, households were more likely to use government services if they were satisfied with the services, poorer, or less educated. The majority of users of government health services were satisfied; the increase from 63% to 67% between 2002 and 2004 was significant in two provinces. Satisfaction in 2004 was higher among users of private services (87%) or private unqualified practitioners (78%). Users of government services who received all medicines from the facility or who were given an explanation of their condition were more likely to be satisfied. Focus groups explained that people avoid government health services particularly because of bad treatment from staff, and unavailable or poor quality medicines. District nazims and administrators cited problems with implementation of devolution, especially with transfer of funds. Under devolution, the public did not experience improved government health services, but devolution was not fully implemented as intended. An ongoing social audit process could provide a basis for local and national accountability of health services.


Chromosomal rearrangement-A rare cause of complement factor I associated atypical haemolytic uraemic syndrome.
Chromosomal rearrangements affecting the genes encoding complement factor H and the factor H related proteins have been described in aHUS patients. To date such disorders have not been described in other aHUS associated genes. We describe here a heterozygous 875,324bp deletion encompassing the gene (CFI) encoding complement factor I and ten other genes. The index case presented with aHUS and did not recover renal function. No abnormalities were detected on Sanger sequencing of CFI but a low factor I level led to a multiplex ligation-dependent probe amplification assay being undertaken. This showed a complete heterozygous deletion of CFI. The extent of the deletion and the breakpoint was defined. In the Newcastle aHUS cohort we have identified and report here 32 different CFI variants in 56 patients but to date this is the only deletion that we have identified. This finding although rare does suggest that screening for chromosomal rearrangements affecting CFI should be undertaken in all aHUS patients particularly if the factor I level is unexplainably low.


Prior cognitive activity implicitly modulates subsequent emotional responses to subliminally presented emotional stimuli.
It has been reported that engagement in several kinds of cognitive activity can successfully inhibit unpleasant emotions. In this study, we tried to replicate the previous finding that cognitive activity can modulate subsequent psychological and physiological emotional processes and to investigate whether prior cognitive activity can attenuate implicit emotional processes triggered by subliminal emotional stimuli. Sixty students were randomly divided into three groups (cognitive task group, noncognitive task group, control group). The cognitive task group was asked to engage in an n-back task, while the control group was asked to stay calm. The noncognitive task group was asked to do a handgrip-squeezing task. All participants then engaged in a version of a subliminal affective priming task where they were unconsciously exposed to affectively negative pictures. The cognitive task group showed lower negative experiences after the subliminal affective priming task and a substantial reduction in their heart rate responses, as compared with the other groups. These results provide evidence that engagement in cognitive activity can attenuate emotional processes in an automatic and unconscious manner.


Technique for measurement of inert gases in liquids by gas chromatography.
A method for quantitative analysis of inert gases in liquids by gas chromatography is described. The technique comprises an equilibration system for partial extraction of dissolved gases from liquids and a gas chromatograph equipped with helium ionization detector. The method is particularly devised for determination of solubility coefficients of gases in liquid materials, e.g. water, aqueous solutions, blood, tissue homogenates, and for simultaneous measurement of several inert gases dissolved in liquids. Coefficients of variation for serial analyses of individual samples were less than or equal to 3%. The method is applicable to studies of blood-tissue transfer of respiratory and inert gases.


Membrane tension may define the deadliest virus infection.
This manuscript describes the potentially significant role of interfacial tension in viral infection. Our hypothesis is based on evidence from drop coalescence hydrodynamics. A change in membrane tension can trigger fusion between the vesicle and cell such that genetic material, like viral RNA, can subsequently be transported to the cell interior. In other cases, RNA may reside near the cell membrane inside the cell, which could make their removal energetically unfavorable because of hydrodynamic interactions between membrane and RNA. Interfacial tension of the virus membrane can be modulated by temperature, among many other factors, of the mucosa layer. We discuss our hypothesis within the scope of recent SARS-CoV-2 studies where temperature-dependent membrane surface tension could be impacted through different atmospheric conditions, air conditioning systems, and the use of masks.


Screening for biliary atresia.
Early diagnosis followed by proper KP is essential for the improvement of long-term prognosis for patients with BA. It is increasingly accepted that KP at ≤ 30 days of age significantly improves native liver survival rate. Published analyses in English and Japanese indicate that screening by SCC and DB/CB is potentially feasible. Screening with SCC has been implemented in Tochigi Prefecture, Japan, since 1994. The concept of SCC was introduced from Japan to Taiwan and resulted in nationwide screening with SCC for the first time in Taiwan in 2004, followed by Japan in 2012. Home-based screening using SCC is easy and cost-effective; however, it may cause some difficulties for families in case of stools with intermediate colors. Laboratory-based screening using DB/CB may detect the suspected cases earlier, resulting in an increase in the number of patients with BA who undergo KP at ≤ 30 days of age; however, the recall rate is 1% and may be beyond an acceptable range. Further studies are needed to assess the feasibility and cost-effectiveness of both home-based (SCC) and laboratory-based (DB/CB) screening for BA.


Differential expression of alternate forms of a Drosophila src protein during embryonic and larval tissue differentiation.
The Dsrc28C gene encodes two major proteins, p66 and p55, each of which contains a tyrosine kinase domain. Using monoclonal antibodies we have completed a detailed investigation of the spatial expression of Dsrc28C proteins during embryonic and larval development. Differentiation of a number of embryonic tissues is accompanied by the induction of Dsrc28C expression. With the exception of the developing salivary glands which express high levels of p66, developing tissues express the p55 form of Dsrc28C. Notable examples are cells of the and peripheral nervous systems which express p55 from the early stages of neurogenesis through the remainder of embryogenesis and pole cells which transiently express p55 during portions of embryonic stages 10 and 11. Nervous system expression includes the cell bodies and neuronal fibers of the central nervous system, the anterior sensory organs, and the peripheral sensory neurons. During larval development, p55 levels within the central nervous system remain high but substantial changes in the pattern of expression take place. p55 gradually disappears from the neuronal fibers of the central nervous system and from embryonic cell bodies. During the third larval instar, the birth of immature neuroblasts within the ventral and midbrain ganglia, but not within the optic ganglia, is marked by a transient high level of p55 expression. All imaginal cells that have been observed within the larva express the p66 protein. The patterns of expression that we have noted suggest that expression of the p55 form of Dsrc28C protein is an early event in the differentiation of neuronal cells, while expression of the p66 form is characteristic of cells committed to ectodermal cell differentiation.


Bayesian global regression model relating product characteristics of intermediate moisture food products to heat inactivation parameters for Salmonella Napoli and Eurotium herbariorum mould spores.
Thermal inactivation of pathogenic and spoilage organisms in low and intermediate moisture foods is of critical importance for guaranteeing microbiological safety and stability of these products. Producers tendentially reduce salt in low and intermediate moisture foods because of nutritional health considerations, but it is unclear how this affects microbial inactivation rates during pasteurization. In this study we predict the time to achieve a pre-defined 6-log reduction for Salmonella enterica subsp. enterica serovar Napoli (hereafter: S. Napoli) and Eurotium herbariorum mould spores (hereafter: E. herbariorum spores) and the relationship with product characteristics. We tested 31 design products for heat inactivation of S. Napoli and 29 design products for heat inactivation of E. herbariorum spores. We used a global Bayesian regression combining primary Weibull models with a secondary regression model to relate pasteurization temperature and product characteristics (water activity (aw), pH, and fractions of sodium chloride, sucrose and oil on product) to microbial counts. With this model, we predict the time to 6-log reduction. Thermal inactivation rates were much higher for vegetative S. Napoli than for E. herbariorum spores. Also, inactivation curves were non-linear for many experiments. There were significant associations between the Weibull model parameters and temperature, and pH and aw for S. Napoli and E. herbariorum spores, respectively. We parameterized an inactivation model for S. Napoli and E. herbariorum spores using design products with a broad range of characteristics and showed how the simplified approach of using D-values does not accurately describe the non-linearity of thermal inactivation for both types of organism. Results of our model can be used to produce accurate heat inactivation predictions as input for the pasteurization process in factories where intermediate moisture foods are manufactured.


The fluorosolvatochromism of Brooker's merocyanine in pure and in mixed solvents.
The fluorescence-based solvatochromism (fluorosolvatochromism) of 4-[(1-methyl-4(1H)-pyridinylidene)-ethylidene]-2,5-cyclohexadien-1-one (Brooker's merocyanine) was studied. The results revealed that the fluorescence emission band of the dye was dependent on the medium (lambda(fl)(max)= 573 nm in water and lambda(fl)(max)=622 nm in DMF). The fluorescence quantum yields (phi (f)) were calculated for the dye in the solvents investigated. Low phi (f) values ( < 10%) were obtained for the dye and in order to better comprehend the radiative and nonradiative decay processes of this dye, its fluorescence lifetime in methanol was measured and was found to be very short (230 ps). The results suggest that the dye in the excited state decays rapidly through nonradiative processes. The behavior of the probe in binary mixtures including a hydrogen-bond accepting solvent (acetonitrile, N,N-dimethylformamide, and dimethylsulfoxide) and a hydroxylic solvent (water, methanol, ethanol, propan-2-ol, and butan-1-ol) was also investigated. All data were successfully fitted to a model based on solvent exchange equilibria, which allowed the separation of the different contributions of the solvent species in the solvation shell of the dye. The data obtained for the mixed solvents were explained based on solute-solvent and solvent-solvent interactions.


Randomized clinical trial of omega-3 fatty acid-supplemented enteral nutrition versus standard enteral nutrition in patients undergoing oesophagogastric cancer surgery.
Oesophagogastric cancer surgery is immunosuppressive. This may be modulated by omega-3 fatty acids (O-3FAs). The aim of this study was to assess the effect of perioperative O-3FAs on clinical outcome and immune function after oesophagogastric cancer surgery. Patients undergoing subtotal oesophagectomy and total gastrectomy were recruited and allocated randomly to an O-3FA enteral immunoenhancing diet (IED) or standard enteral nutrition (SEN) for 7 days before and after surgery, or to postoperative supplementation alone (control group). Clinical outcome, fatty acid concentrations, and HLA-DR expression on monocytes and activated T lymphocytes were determined before and after operation. Of 221 patients recruited, 26 were excluded. Groups (IED, 66; SEN, 63; control, 66) were matched for age, malnutrition and co-morbidity. There were no differences in morbidity (P = 0·646), mortality (P = 1·000) or hospital stay (P = 0·701) between the groups. O-3FA concentrations were higher in the IED group after supplementation (P < 0·001). The ratio of omega-6 fatty acid to O-3FA was 1·9:1, 4·1:1 and 4·8:1 on the day before surgery in the IED, SEN and control groups (P < 0·001). There were no differences between the groups in HLA-DR expression in either monocytes (P = 0·538) or activated T lymphocytes (P = 0·204). Despite a significant increase in plasma concentrations of O-3FA, immunonutrition with O-3FA did not affect overall HLA-DR expression on leucocytes or clinical outcome following oesophagogastric cancer surgery. ISRCTN43730758 (http://www.controlled-trials.com).


Lys-Arg mutation improved the thermostability of Bacillus cereus neutral protease through increased residue interactions.
Neutral proteases have broad application as additives in modern laundry detergents and therefore, thermostability is an integral parameter for effective production of protein crystals. To improve thermostability, the contribution of individual residues of Bacillus cereus neutral protease was examined by site-directed mutagenesis. The Lys11Arg and Lys211Arg mutants clearly possessed improved thermostabilities (Tm were 63 and 61 °C respectively) compared to the wild-type (Tm was 60 °C). MD simulations further revealed that the mutants had low RMSD and RMSF values compared to wild-type BCN indicating increased stability of the protein structure. Lys11Arg mutant particularly possessed the lowest RMSD values due to increased residue interactions, which resulted in enhanced thermostability. The mutants also displayed strong stability to most inhibitors, organic solvents and surfactants after incubation for 1 h. This study demonstrated Lys-Arg mutation enhanced thermostability of BCN and thus provides insight for engineering stabilizing mutations with improved thermostability for related proteins.


Demographic Composition of Select Oncologic New Molecular Entities Approved by the FDA Between 2008 and 2017.
Race, ethnicity, sex, and age are demographic factors that can influence drug exposure and/or response, and can consequently affect treatment outcome. We evaluated demographic subgroup enrollment patterns in new therapeutic products approved by the US Food and Drug Administration (FDA) for the treatment of select cancers-breast, colorectal, lung, and prostate-that have comparative differences in morbidity and/or mortality among some demographic subgroups. In submissions of products approved between 2008 and 2013, participants (n = 22,481) were white (80%), from outside the United States (74%), between 17 and 64 years old (59%), and men (56% and 53%, including and excluding sex-specific indications, respectively). In pivotal trials of products approved between2014 and 2017, participants (n = 3,612) were white (71%), between 17 and 64 years old (61%), and men (48% and 63%, including and excluding sex-specific indications, respectively). The US-relevant minority populations were under-represented. A broader representation of patient subgroups in clinical trials may contribute to better understanding of exposure and/or response variability, and consequently help personalize drug therapy.


Pseudoaneurysm formation of segmental artery with retroperitoneal hematoma after percutaneous transpedicular screws insertion.
Vascular injury is one of the potential complications of percutaneous transpedicular screws fixation. Carefully review the vascular anatomy preoperatively is important. Once unexpected low blood pressure or anemia occurs, vascular injury should be taken into consideration.


Aqueous synthesis of LiFePO4 with Fractal Granularity.
Lithium iron phosphate (LiFePO4) electrodes with fractal granularity are reported. They were made from a starting material prepared in water by a low cost, easy and environmentally friendly hydrothermal method, thus avoiding the use of organic solvents. Our method leads to pure olivine phase, free of the impurities commonly found after other water-based syntheses. The fractal structures consisted of nanoparticles grown into larger micro-sized formations which in turn agglomerate leading to high tap density electrodes, which is beneficial for energy density. These intricate structures could be easily and effectively coated with a thin and uniform carbon layer for increased conductivity, as it is well established for simpler microstructures. Materials and electrodes were studied by means of XRD, SEM, TEM, SAED, XPS, Raman and TGA. Last but not least, lithium transport through fractal LiFePO4 electrodes was investigated based upon fractal theory. These water-made fractal electrodes lead to high-performance lithium cells (even at high rates) tested by CV and galvanostatic charge-discharge, their performance is comparable to state of the art (but less environmentally friendly) electrodes.


Microtubule associated protein 1B (MAP1B) promotes efficient tubulin polymerisation in vitro.
The effect of MAP1B on tubulin polymerisation has been examined in reconstitution experiments using purified tubulin and MAP1B. Under the assembly conditions used, tubulin alone was incapable of polymerising, but addition of MAP1B resulted in rapid assembly into microtubules. The kinetics of MAP1B-promoted microtubule assembly examined using pseudo-first-order plots show that assembly is described by a single reaction rate. The calculated association rate constant for MAP1B was about 200 x 1096) M-1.s-1 and this constant was one order of magnitude higher when compared with that for MAP2-promoted assembly.


An approach to the treatment of malocclusion caused by bone expanding lesions.
A case is described in which fixed orthodontic appliances were used to correct a malocclusion complicated by the local effects of a dentigerous cyst.


Frameless stereotactic image-guided C1-C2 transarticular screw fixation for atlantoaxial instability: review of 20 patients.
We retrospectively studied 20 adults who underwent C1-C2 transarticular screw (TAS) fixation utilizing frameless stereotaxy. The study group comprised 13 men and 7 women, with a mean age of 63 years (range 12-87 years). All patients demonstrated clinical and radiographic evidence of C1-C2 instability. The cause of the instability was trauma in 11 patients, rheumatoid arthritis in 6 patients, failed prior surgery in 2 patients, and congenital malformation in 1 patient. All patients underwent stabilization with C1-C2 TASs using image-guided frameless stereotaxy. There were no new or worsening neurologic symptoms reported at 18-month follow-up. Motor weakness improved in seven of nine patients, myelopathy in seven of seven, and gait in three of six patients in whom these deficits were present preoperatively. Postoperative complications included one surgical site abscess, one cutaneous pressure ulcer, and one iliac crest donor site infection. Of 36 screws placed, 33 (92%) were well positioned. Normal C1-C2 alignment was achieved in 17 of 20 (85%) patients. In 4 of 20 cases, screw implant, which was thought to be anatomically difficult, if not impossible, on the basis of routine magnetic resonance or computed tomography imaging, was actually accomplished successfully using surgical navigation. C1-C2 TAS placement is a safe and accurate surgical technique that may improve neurologic function. Use of intraoperative navigation can facilitate achieving difficult surgical trajectories that match the patient's anatomy, thus allowing TAS implant in patients who otherwise would not be candidates for this type of internal fixation.


Sphenoidotomy.
Because of the complex anatomic relations of the sphenoid, the surgical approach to this sinus was only introduced 100 years ago. There are three approaches to the sphenoid sinus: transethmoidal, transseptal, and transpalatal. We present a case report, and discuss surgical anatomy, with attention to the important anatomic relationship of the cavernous sinus and its contents. A variant of the classical, sublabial, transseptal approach is described as follows: a window is created in the face of the sphenoid. This approach is particularly applicable to the surgery of mucoceles and allows easy postoperative inspection of the sphenoid sinus.


What is the risk of sham surgery in Parkinson disease clinical trials? A review of published reports.
Placebo, or sham surgery, as a control condition in surgical clinical trials in Parkinson disease (PD) remains controversial. The authors reviewed the adverse effects reported in double blind, placebo surgery controlled trials for PD. Placebo surgeries were generally safe and well tolerated but the number of subjects receiving the procedure was small. Harm occurred more frequently in subjects randomized to the experimental intervention.


Midbrain dopamine neurons regulate preprotachykinin-A mRNA expression in the rat forebrain during development.
Intracerebroventricular 6-hydroxydopamine injections were performed at postnatal days 3 and 6 in animals pretreated with the norepinephrine uptakeblocker desimipramine in order to generate a selective lesion of dopamine neurons. In situ hybridization was then used to analyze preprotachykinin-A (PPT-A) mRNA expression in the lesioned as well as in saline-injected control animals. The midbrain dopaminergic lesion caused a 22-25% increase in the level of PPT-A mRNA in cingulate cortex and frontoparietal cortex when analysed at 2 weeks of age, compared to saline-injected control animals. In contrast, the lesion caused no change in PPT-A mRNA expression in the neonatal caudate-putamen. These results indicate that dopamine neurons downregulate the expression of PPT-A mRNA specifically in cingulate cortex and frontoparietal cortex during early postnatal brain development. In the adult rat forebrain, lesioned at P3 and P6, no change in the level of PPT-A mRNA was seen in cingulate cortex and frontoparietal cortex. However, a 29% decrease in PPT-A mRNA was seen in the lateral caudate-putamen with no significant change in neurons of medial caudate-putamen. Thus, dopamine neurons appears to exert a region specific influence on PPT-A mRNA expression during brain development.


Maternal distress, HPA activity, and antenatal interventions: A systematic review.
Elevated antenatal distress has been associated with negative outcomes for both mothers and, as a result, their infants. One mechanism hypothesised to underlie these associations is the maternal hypothalamic pituitary adrenal (HPA) axis. Though research has examined whether biopsychosocial antenatal interventions can reduce maternal HPA activity, only one review has summarized the nature of findings to date. The present study examined randomised control trials (RCTs) specifically; our primary aim was to assess the effectiveness of antenatal interventions in reducing HPA activity in pregnant women, our secondary aim was to examine whether antenatal interventions reduced maternal self-report of depression and/or anxiety. This study systematically reviewed RCTs that evaluated biopsychosocial interventions that reported subjective and objective markers of maternal distress in pregnant women within the clinical population. Eight studies met inclusion criteria and women were in their second or third trimester. HPA-activity was primarily assessed through salivary cortisol (n = 7) and self-reported maternal distress was assessed using a variety of validated screening measures. Included trials demonstrated significant methodological heterogeneity and small sample sizes, poor treatment adherence, and poor reliability in cortisol measurement indicated low methodological quality. Due to the high heterogeneity across studies, small sample sizes, and unreliable sampling methods, firm conclusions about the efficacy and effectiveness of antenatal interventions cannot be drawn. Despite this, interventions which targeted pregnancy-specific influencers of maternal mood were more likely to result in reduced depression and anxiety symptomatology as reported by mothers.


Biological challenges of phage therapy and proposed solutions: a literature review.
Introduction: In light of the emergence of antibiotic-resistant bacteria, phage (bacteriophage) therapy has been recognized as a potential alternative or addition to antibiotics in Western medicine for use in humans.Areas covered: This review assessed the scientific literature on phage therapy published between 1 January 2007 and 21 October 2019, with a focus on the successes and challenges of this prospective therapeutic.Expert opinion: Efficacy has been shown in animal models and experimental findings suggest promise for the safety of human phagotherapy. Significant challenges remain to be addressed prior to the standardization of phage therapy in the West, including the development of phage-resistant bacteria; the pharmacokinetic complexities of phage; and any potential human immune response incited by phagotherapy.


Overexpression of phosphorylated-STAT3 correlated with the invasion and metastasis of cutaneous squamous cell carcinoma.
In order to evaluate the possible effects of STAT3 phosphorylation and expression of E-cadherin on metastasis of some human epidermal non-melanoma cutaneous tumors, the expression of phosphorylated STAT3 (p-STAT3) and E-cadherin were analyzed by immunohistochemistry staining in formalin-fixed, paraffin-embedded tissue sections of human cutaneous squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and seborrhoeic keratosis (SK). An immunohistochemistry staining technique was employed to measure the expression of p-STAT3 and E-cadherin protein in 30 cases of cutaneous SCC, 20 cases of BCC, 20 cases of SK, and 20 specimens of normal skin. The results were as follows: 1) p-STAT3 protein was abnormally increased in SCC as compared to normal skin and SK (p<0.001). Expression of p-STAT3 in SCC was also significantly higher than in BCC (p<0.05). 2) Expression of p-STAT3 was higher in poorly-differentiated SCC than in well-differentiated ones (p<0.05). The positive rate of the expression of p-STAT3 correlated well with the depth of tumor invasion and with metastasis (p<0.05), but there was no correlation between the positive rate and tumor size. 3) E-cadherin was strongly expressed on the cell membranes of normal skin and SK, especially on basal cells. E-cadherin was weakly expressed on cell membranes of SCC and BCC (p<0.001), whereas its expression was significantly lower in SCC than in BCC (p<0.05). In SCC, the intensity of E-cadherin expression was correlated with the extent of tumor differentiation, but there was no correlation between the expression intensity and the depth of tumor invasion or tumor size. 4) There was a negative correlation between the expression intensity of p-STAT3 and E-cadherin in SCC (rs=-0.372, p<0.05). We concluded that the overexpression of p-STAT3 may have an important role in the development of epidermal tumors. Abnormal activation of STAT3 may be related to metastasis potential in SCC and the simultaneous detection of p-STAT3 and E-cadherin may contribute to predicating the prognosis in SCC.


The metabolic and hormonal effects of continuous subcutaneous insulin infusion therapy in diabetic children.
To find out whether the concurrent metabolic and hormonal abnormalities are corrected when normoglycaemia is achieved, two groups of diabetic children (newly-diagnosed and chronically-treated) were treated with insulin pumps. Fasting levels of metabolites, lipids and hormones were measured before and after 8 to 10 days of pump treatment and the immediate postprandial hormonal and metabolic changes after a test-meal were also measured. Restoration of normoglycaemia was accompanied by correction of multiple metabolic abnormalities including the normalisation of fasting plasma free insulin, growth hormone, free fatty acid, triglyceride and total cholesterol levels. Plasma glucagon, however, decreased below normal, and significant hypoketonaemia developed in newly-diagnosed diabetic children. The fall in (VLDL + LDL)-cholesterol levels was accompanied by a substantial increase in HDL2-cholesterol concentration in newly-diagnosed diabetic children, whereas pump-treatment resulted in a decrease of the HDL3-cholesterol subfraction in chronically-treated diabetic children. The postprandial blood glucose and free insulin profiles were similar to that of control subjects, but there was an "abnormal" postmeal fall in plasma glucagon and free fatty acid levels. These changes together with the fasting hypoglucagonaemia and hypoketonaemia indirectly suggest that optimal glycaemic control is only achievable at the expense of "increased insulin action" despite the failure to detect peripheral hyperinsulinaemia. Furthermore, the restoration of normoglycaemia and the simultaneous normalisation of the metabolic and endocrine milieu is not entirely possible with this mode of therapy.


Alzheimer's disease tau is a prominent pathology in LRRK2 Parkinson's disease.
Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). While the clinical presentation of LRRK2 mutation carriers is similar to that of idiopathic PD (iPD) patients, the neuropathology of LRRK2 PD is less clearly defined. Lewy bodies (LBs) composed of α-synuclein are a major feature of iPD, but are not present in all LRRK2 PD cases. There is some evidence that tau may act as a neuropathological substrate in LB-negative LRRK2 PD, but this has not been examined systematically. In the current study, we examined α-synuclein, tau, and amyloid β (Aβ) pathologies in 12 LRRK2 mutation carriers. We find that α-synuclein pathology is present in 63.6% of LRRK2 mutation carriers, but tau pathology can be found in 100% of carriers and is abundant in 91% of carriers. We further use an antibody which selectively binds Alzheimer's disease (AD)-type tau and use quantitative analysis of tau pathology to demonstrate that AD tau is the prominent type of tau present in LRRK2 mutation carriers. Abundant Aβ pathology can also be found in LRRK2 mutation carriers and is consistent with comorbid AD pathology. Finally, we assessed the association of neuropathology with clinical features in LRRK2 mutation carriers and idiopathic individuals and find that LRRK2 PD shares clinical and pathological features of idiopathic PD. The prevalence of AD-type tau pathology in LRRK2 PD is an important consideration for understanding PD pathogenesis and refining clinical trial inclusion and progression criterion.


Lipoprotein(a) and inflammation in human coronary atheroma: association with the severity of clinical presentation.
The purpose of this study was the investigation of the in vivo role of lipoprotein(a) [Lp(a)] and inflammatory infiltrates in the human coronary atherosclerotic plaque and their correlation with the clinical syndrome of presentation. Lipoprotein(a) is an atherogenic and thrombogenic lipoprotein, and has been implicated in the pathogenesis of acute coronary syndromes. Lipoprotein(a) induces monocyte chemoattraction and smooth muscle cell activation in vitro. Macrophage infiltration is considered one of the mechanisms of plaque rupture. This study of atherectomy specimens investigated the in vivo role of Lp(a) at different stages of the atherogenic process, and its relationship with macrophage infiltration. We examined coronary atheroma removed from 72 patients with stable or unstable angina. Specimens were stained with antibodies specific for Lp(a), macrophages (KP-1), and smooth muscle cells (alpha-actin). Morphometric analysis was used to quantify the plaque areas occupied by each of the three antigens, and their colocalization. All specimens had localized Lp(a) staining; the mean fractional area was 58.2%. Ninety percent of the macrophage areas colocalized with Lp(a) positive areas, whereas 31.3% of the smooth muscle cell areas colocalized with Lp(a) positive areas. Patients with unstable angina (n = 46) had specimens with larger mean plaque Lp(a) areas than specimens from stable angina patients (n = 26): 64.4% versus 47.7% (p = 0.004). Unstable angina patients with rest pain (n = 28) had greater mean plaque Lp(a) area than unstable angina patients with crescendo exertional pain (n = 18): 71.1% versus 52.4% (p < 0.001). Mean KP-1 area was 31.2% in unstable rest angina versus 18.3% in stable angina (p = 0.05); alpha-actin area was greater in stable (48.5%) and crescendo exertional angina (48.8%) than in rest angina (30.4%). The strongest correlation between plaque KP-1 and Lp(a) area was in unstable rest angina (r = 0.88, p < 0.001), and between alpha-actin and Lp(a) areas in the crescendo exertional angina (r = 0.62, p < 0.01). Lipoprotein(a) is ubiquitous in human coronary atheroma. It is detected in larger amounts in tissue from culprit lesions in patients with unstable compared to stable syndromes, and has significant colocalization with plaque macrophages. A correlation of plaque alpha-actin and Lp(a) area suggests a role of Lp(a) in plaque growth.


The DEAD-box RNA helicase eIF4A1 interacts with the SWI2/SNF2-related chromatin remodelling ATPase DDM1 in the moss Physcomitrella.
eIF4A is a DEAD box containing RNA helicase that plays crucial roles in regulating translation initiation, growth and abiotic stress tolerance in plants. It also functions as an ATP-dependent RNA binding protein to curb granule formation by limiting RNA-RNA interactions that promote RNA condensation and formation of ribonucleoprotein particles in vivo. Helicase activity of eIF4A is known to be dictated by its binding partners. Proteins interacting with eIF4A have been identified across land plants. In monocots a close link between eIF4A regulated processes and DNA methylation in epigenetic regulation of plant development is inferred from interaction between OseIF4A and the de novo methyltransferase OsDRM2 and loss-of-function studies of these genes in Oryza sativa and Brachypodium distachyon. In the moss Physcomitrella patens, eIF4A1 encoded by Pp3c6_1080V3.1 interacts with the heterogeneous nuclear ribonucleoprotein (hnRNP) PpLIF2L1, homolog of which in Arabidopsis regulates transcription of stress-responsive genes. In this study, using different protein-protein interaction methods, targeted gene knockout strategy and quantitative expression analysis we show genetic interaction between PpeIF4A1 and the putative nucleosome remodeler protein PpDDM1 and between PpDDM1 and PpLIF2L1 in vivo. Stress-induced co-expression of PpeIF4A1, PpDDM1 and PpLIF2L1, their roles in salt stress tolerance and differences in subnuclear distribution of PpLIF2L1 in ppeif4a1 cells in comparison to wild type suggest existence of a regulatory network comprising of RNA helicases, chromatin remodelling proteins and hnRNP active in stress-responsive biological processes in P. patens.


Contrast-enhanced high-resolution magnetic resonance imaging of autologous cartilage implants of the knee joint.
Over the past decade, a number of interventions for durable cartilage repair have emerged. Magnetic resonance (MR) tomography is an excellent noninvasive method for monitoring cartilage repair tissues throughout the postsurgical period. However, evaluating cartilage morphology after matrix-based autologous cartilage implantation (ACI) with MR imaging (MRI) still remains a challenge. In this study, we combined a high-resolution cartilage-sensitive fast-spin echo (FSE) sequence with intravenous application of a contrast agent for enhancing synovial fluid. Two independent musculoskeletal radiologists interpreted the pictures for the thickness, length and surface of the cartilage implants. A multivariate two-way analysis of variance with two repeated measures was performed and showed that evaluation of cartilage implant morphology was significantly improved after the application of gadodiamide on proton density FSE images. Contrast-enhanced MRI of articular cartilages is a promising technique in the postoperative follow-up of patients after ACI.


From extraocular photoreception to pigment movement regulation: a new control mechanism of the lanternshark luminescence.
The velvet belly lanternshark, Etmopterus spinax, uses counterillumination to disappear in the surrounding blue light of its marine environment. This shark displays hormonally controlled bioluminescence in which melatonin (MT) and prolactin (PRL) trigger light emission, while α-melanocyte-stimulating hormone (α-MSH) and adrenocorticotropic hormone (ACTH) play an inhibitory role. The extraocular encephalopsin (Es-Opn3) was also hypothesized to act as a luminescence regulator. The majority of these compounds (MT, α-MSH, ACTH, opsin) are members of the rapid physiological colour change that regulates the pigment motion within chromatophores in metazoans. Interestingly, the lanternshark photophore comprises a specific iris-like structure (ILS), partially composed of melanophore-like cells, serving as a photophore shutter. Here, we investigated the role of (i) Es-Opn3 and (ii) actors involved in both MT and α-MSH/ACTH pathways on the shark bioluminescence and ILS cell pigment motions. Our results reveal the implication of Es-Opn3, MT, inositol triphosphate (IP3), intracellular calcium, calcium-dependent calmodulin and dynein in the ILS cell pigment aggregation. Conversely, our results highlighted the implication of the α-MSH/ACTH pathway, involving kinesin, in the dispersion of the ILS cell pigment. The lanternshark luminescence then appears to be controlled by the balanced bidirectional motion of ILS cell pigments within the photophore. This suggests a functional link between photoreception and photoemission in the photogenic tissue of lanternsharks and gives precious insights into the bioluminescence control of these organisms.


Associations of liver fat content with cardiometabolic phenotypes and outcomes in a multi-ethnic population: Results from the Dallas Heart Study.
To evaluate the associations between liver fat content and cardiometabolic parameters to explore potential threshold values that define metabolically healthy liver fat content, and to examine the association of liver fat content with cardiovascular events as well as its longitudinal progression. Participants in the Dallas Heart Study underwent clinical evaluation, including laboratory testing, and liver fat quantification by magnetic resonance spectroscopy (MRS) at baseline (N = 2287) and at follow-up (N = 343) after a mean of 7.3 years. Cardiovascular events were adjudicated (>12 years). The mean age at study entry was 44 years, 47% of participants were men, and 48% were African American. The following cardiometabolic biomarkers worsened across liver fat quintiles (P < 0.0001): body mass index (BMI); waist circumference; prevalence of hypertension; prevalence of diabetes; cholesterol, triglyceride, high-sensitivity C-reactive protein (CRP), leptin and fasting glucose levels; homeostatic model assessment of insulin resistance index (HOMA-IR); coronary artery calcium score; visceral adipose tissue; abdominal subcutaneous adipose tissue; and lower body subcutaneous adipose tissue. Cardiovascular events were comparable across groups defined by tertile of baseline liver fat content. Change in BMI (R = 0.40), waist circumference (R = 0.35), CRP (R = 0.31), alanine aminotransferase (R = 0.27), HOMA-IR (R = 0.26), aspartate transaminase (R = 0.15) and triglycerides (R = 0.12) significantly correlated with change in liver fat content (P < 0.01 for all). Clinically relevant metabolic abnormalities were higher across quintiles of liver fat, with increases noted well within normal liver fat ranges, but cardiovascular events were not associated with liver fat content. Longitudinal changes in metabolic parameters, especially adiposity-related parameters, were correlated with change in liver fat content.


Determination of nitroaromatic explosives in water samples by direct ultrasound-assisted dispersive liquid-liquid microextraction followed by gas chromatography-mass spectrometry.
A fast, simple, inexpensive, sensitive, efficient and environmental friendly direct ultrasound-assisted dispersive liquid-liquid microextraction (DUSA-DLLME) procedure has been developed to concentrate five nitroaromatic explosives from water samples prior to quantification by gas chromatography-mass spectrometry (GC-MS). An efficient ultrasonic probe has been used to radiate directly the samples producing very fine emulsions from immiscible liquids. A D-optimal design was used for optimizing the factors and to evaluate their influential upon extraction. The optimum experimental conditions were: sample volume, 10 mL; extraction time, 60s; cycles, 0.6s(s(-1)); power of ultrasound energy, 40% (70 W); and, extractant solvent (chlorobenzene) volume, 20 μL. Under the optimized experimental conditions the method presents good level of repeatability with coefficients of variation under 6% (n=8; spiking level 10 μg L(-1)). Calculated calibration curves gave high level of linearity with correlation coefficient values between 0.9949 and 0.9992. Limits of detection were ranged between 0.03 and 0.91 μg L(-1). Finally, the proposed method was applied to the analysis of two types of water samples, reservoir and effluent wastewater. The samples were previously analysed and confirmed free of target analytes. At 5 μg L(-1) spiking level recovery values ranged between 75 and 96% for reservoir water sample showing that the matrix had a negligible effect upon extraction. However, a noticeable matrix effect (around 50% recovery) was observed for effluent wastewater sample. In order to alleviate this matrix effect, the standard addition calibration method was used for quantitative determination. This calibration method supplied recovery values ranged between 71 and 79%. The same conclusions have been obtained from an uncertainty budget evaluation study.


Classical and alloimmune anaphylactic degranulation of isolated single mast cells.
Viable mast cells, directly isolated by micromanipulation from a mouse peritoneal cell suspension, were deposited on the bottom of microtiter-plate wells and submitted to histamine release. Conventional antigen-induced anaphylactic degranulation as well as direct allogeneic anaphylactic degranulation were strongly inhibited when these mast cells were settled on normal tissue culture plastic surfaces. Nevertheless, normal degranulation could be recovered by pretreatment of the experimental surface with a multipositive charged molecule (poly-L-lysine). Under these conditions, we demonstrate that the degranulation of one isolated mast cell is possible and consequently, as regards the direct allogeneic anaphylactic degranulation, confirm the "self-triggering mechanism" in which the recognition of histocompatibility antigens on the membrane of the mast cell itself is the trigger to the secretory response. The technique of monocellular degranulation described in this paper provides a new tool which leads us to think that the problem of detection of anaphylactic antibody-secreting cells can be solved.


Drug-coated balloon in the treatment of coronary bifurcation lesions: A hope or hype?
When compared to non-bifurcation lesions, percutaneous coronary intervention in coronary bifurcation lesions is technically demanding and has historically been limited by lower procedural success rates and inferior clinical results. Following the development of drug-eluting stents, dramatically better results have been demonstrated. In most of the bifurcation lesions, the provisional technique of implanting a single stent in the main branch (MB) remains the default approach. However, some cases require more complex two-stent techniques which carry the risk of side branch (SB) restenosis. The concept of leaving no permanent implant behind is appealing because of the complexity of bifurcation anatomy with significant size mismatch between proximal and distal MB which may drive rates of in-stent restenosis and the potential impact of MB stenting affecting SB coronary flow dynamics. With the perspective of leaving lower metallic burden, a drug-coated balloon (DCB) has been utilized to treat bifurcations in both the MB and SB. The author gives an overview of the existing state of knowledge and prospects for the future for using DCB to treat bifurcation lesions.


Follow-up study of the first genome-wide association scan in alopecia areata: IL13 and KIAA0350 as susceptibility loci supported with genome-wide significance.
Recently, the first genome-wide association study (GWAS) of alopecia areata (AA) was conducted in a North-American sample, and this identified eight susceptibility loci surpassing genome-wide significance. The aim of the present follow-up association analysis was to confirm five of these eight loci (single-nucleotide polymorphisms (SNPs) from the CTLA4, IL-2RA, and HLA regions were not included due to previous own findings) and test 12 other loci from the GWAS, which did not surpass the threshold for genome-wide significance. Twenty-three SNPs from the 17 loci were investigated using a sample of 1,702 Central European AA patients and 1,723 controls. Of the five loci with previously reported genome-wide significance, association was confirmed for all of these: ULBP3/ULBP6, PRDX5, IL-2/IL-21, STX17, and IKZF4/ERBB3 (P-value <0.05). To detect robust evidence for association among the 12 other loci, a meta-analysis of the present association data and the data of the recent GWAS was performed. Genome-wide significant association was found for rs20541 (P(comb)=7.52 × 10(-10); odds ratio (OR)=1.30 (1.23-1.38)) and rs998592 (P(comb)=1.11 × 10(-11); OR=1.28 (1.21-1.36)), thus establishing IL-13 and KIAA0350/CLEC16A as susceptibility loci for AA. Interestingly, IL-13 and KIAA0350/CLEC16A are susceptibility loci for other autoimmune diseases, supporting the hypothesis of shared pathways of autoimmune susceptibility.


Long noncoding RNAs in viral infections.
Viral infections induce strong modifications in the cell transcriptome. Among the RNAs whose expression is altered by infection are long noncoding RNAs (lncRNAs). LncRNAs are transcripts with potential to function as RNA molecules. Infected cells may express viral lncRNAs, cellular lncRNAs and chimeric lncRNAs formed by viral and cellular sequences. Some viruses express viral lncRNAs whose function is essential for viral viability. They are transcribed by polymerase II or III and some of them can be processed by unique maturation steps performed by host cell machineries. Some viral lncRNAs control transcription, stability or translation of cellular and viral genes. Surprisingly, similar functions can be exerted by cellular lncRNAs induced by infection. Expression of cellular lncRNAs may be altered in response to viral replication or viral protein expression. However, many cellular lncRNAs respond to the antiviral pathways induced by infection. In fact, many lncRNAs function as positive or negative regulators of the innate antiviral response. Our current knowledge about the identity and function of lncRNAs in infected cells is very limited. However, research into this field has already helped in the identification of novel cellular pathways and may help in the development of therapeutic tools for the treatment of viral infections, autoimmune diseases, neurological disorders and cancer.


Innate immune defense of the nail unit by antimicrobial peptides.
The nail is susceptible to microbial invasion, yet is usually able to defend itself from infection. This occurs despite isolation from cell-mediated immunity. The aim of this study was to determine whether soluble innate immune molecules are present in the nail environment that can protect against microbial colonization. Chromatographic techniques were used to purify cationic antimicrobial molecules from porcine hoof extracts. Sections of human and mouse digits were immunostained with antibodies to each species' cathelicidin antimicrobial peptide. Liquid antimicrobial assays were used to determine the activity of these molecules against relevant pathogens. Human, porcine, and murine nails contain antimicrobial molecules, and the human cathelicidin LL-37 can kill Candida albicans. The presence of antimicrobial peptides in nails with activity against relevant nail pathogens may account for the ability of the nail unit to resist infection in the absence of direct access to the cellular immune system.


Characterizing the type 6 secretion system (T6SS) of E. cloacae SBP-8 and its role in pathogenesis and bacterial competition.
Despite the relevance of E. cloacae as an opportunistic pathogen, very little is known about its pathogenicity mechanism and the factors influencing its virulence. The mechanism of E. cloacae pathogenicity appears to be complex and multifactorial, with the presence of different putative virulence factors whose role is still not clear in the development of the disease. In this study, we systematically investigated the role of T6SS (type six secretion system) of E. cloacae SBP-8, an environmental isolate, in eukaryotic and bacterial cell interaction. Analysis of the genome sequence of E. cloacae SBP-8 revealed the presence of sets of genes coding for the expression of one complete T6SS cluster, which is similar to T6SS-1 cluster of E. cloacae ATCC 13047 (clinical isolates). In addition, an Hcp effector protein was detected in the secretome, and this secretion depended on ClpV, an Atpase of T6SS, confirming that strain SBP-8 produces functional T6SS. Deletion of T6SS-associated gene clpV did not induce any significant change in the life span and rate of colonization in C. elegans. No major significant change was observed in the expression profiling of antimicrobial genes (clec-60, clec-85, clec-87 and lys-1) and toll-like receptor (toll-1) gene, involved in stimulating an immune response against the pathogen. No difference in the ability to invade and proliferate in intestinal cells and phagocytosis by macrophages was observed. In addition, we demonstrated that the ability of E. cloacae SBP-8 to out-compete Escherichia coli was reliant upon its T6SS in contact-dependent manner. Our results show that T6SS of the environmental isolates is required for interbacterial competition but not for invasion and proliferation inside host cells.


Naturalism, tractability and the adaptive toolbox.
Many compelling examples have recently been provided in which people can achieve impressive epistemic success, e.g. draw highly accurate inferences, by using simple heuristics and very little information. This is possible by taking advantage of the features of the environment. The examples suggest an easy and appealing naturalization of rationality: on the one hand, people clearly can apply simple heuristics, and on the other hand, they intuitively ought do so when this brings them high accuracy at little cost.. The 'ought-can' principle is satisfied, and rationality is meaningfully normative. We show, however, that this naturalization program is endangered by a computational wrinkle in the adaptation process taken to be responsible for this heuristics-based ('ecological') rationality: for the adaptation process to guarantee even minimal rationality, it requires astronomical computational resources, making the problem intractable. We consider various plausible auxiliary assumptions in attempt to remove this obstacle, and show that they do not succeed; intractability is a robust property of adaptation. We discuss the implications of our findings for the project of naturalizing rationality.


DNA repair functional analyses of NBN hypomorphic variants associated with NBN-related infertility.
Nijmegen breakage syndrome caused by biallelic pathogenic variants of the DNA-damage response gene NBN, is characterized by severe microcephaly, cancer proneness, infertility, and karyotype abnormalities. We previously reported NBN variants in siblings suffering from fertility defects. Here, we identify a new founder NBN variant (c.442A>G, p.(Thr148Ala)) in Lebanese patients associated with isolated infertility. Functional analyses explored preserved or altered functions correlated with their remarkably mild phenotype. Transcript and protein analyses supported the use of an alternative transcript with in-frame skipping of exons 4-5, leading to p84-NBN protein with a preserved forkhead-associated (FHA) domain. The level of NBN was dramatically reduced and the MRN complex delocalized to the cytoplasm. Interestingly, ataxia-elangiectasia mutated (ATM) also shifted from the nucleus to the cytoplasm, suggesting some interaction between ATM and the MRN complex at a steady state. The ATM pathway activation, attenuated in typical patients with NBS, appeared normal under camptothecin treatment in these new NBN-related infertile patients. Cell cycle checkpoint defect was present in these atypical patients, although to a lesser extent than in typical patients with NBS. In conclusion, we report three new NBN-related infertile patients and we suggest that preserved FHA domain could be responsible for the mild phenotype and intermediate DNA-damage response defects.