Skin cancer incidence in transgender individuals receiving gender-affirming hormone treatment: a nationwide cohort study in the Netherlands.
Development of skin cancer, in particular melanoma, has been linked to sex hormones. We aimed to determine the incidence of skin cancer in transgender individuals receiving gender-affirming hormone treatment (GAHT). In this nationwide retrospective cohort study, clinical information of participants who visited our clinic between (the years) 1972 and 2018 and received GAHT was integrated with national pathology and cancer statistics data in order to assess skin cancer incidence. Standardized incidence ratios (SIRs) were calculated. The cohort consisted of 2,436 trans women and 1,444 trans men. The median age at the start of GAHT was 31 years (IQR 24-42) in trans women and 24 years (IQR 20-32) in trans men. The median follow-up time for trans women was 8 years (IQR 3-18) with a total follow-up time of 29,152 years and 4 years (IQR 2-12) with a total follow-up time of 12,469 years for trans men. Eight trans women were diagnosed with melanoma (SIR 1.80 [95% CI 0.83-3.41] vs. all men; SIR 1.40 [0.65-2.65] vs. all women), and seven developed squamous cell carcinoma (SIR 0.78 [0.34-1.55] vs. all men; SIR 1.15 [0.50-2.27] vs. all women). Two trans men developed melanoma (SIR 1.05 [0.18-3.47] vs. all men; SIR 0.77 [0.14-2.70] vs. all women). GAHT did not appear to affect skin cancer incidence in this large cohort of transgender individuals. As skin cancer incidence increases with age and the proportion of elderly subjects is currently limited in this cohort, it will be worthwhile to repeat this analysis in the future.


The exon 4 variations of Tim-1 gene are associated with rheumatoid arthritis in a Korean population.
The family of T-cell immunoglobulin domain and mucin domain (TIM) proteins is identified to be expressed on T cells. A member of Tim family, TIM-1, is considered as a membrane protein that is associated with the development of Th2 biased immune responses and selectively expressed on Th2 cells. In the present study, we analyzed the association of genotype and allele frequencies between rheumatoid arthritis (RA) patients and the controls without RA using large samples size at 5383_5397del and 5509_5511delCAA variations of Tim-1 gene. We further investigated the relationships among these variations to C-reactive protein (CRP) and rheumatoid factor (RF) levels in RA patients. Although these factors were not associated with exon 4 variations in RA patients, the genotype and allele frequencies of 5383_5397del variation site (P = 0.015 and 0.014, respectively) as well as 5509_5511delCAA variation site (P = 0.0002 and 0.0001, respectively) in RA patients were significantly different from those in the non-RA controls. Our results strongly suggest that the variations of Tim-1 exon 4 might be associated with the susceptibility to RA.


Assessing asthma severity based on claims data: a systematic review.
Asthma is one of the most common chronic diseases in Germany. Substantial economic evaluation of asthma cost requires knowledge of asthma severity, which is in general not part of claims data. Algorithms need to be defined to use this data source. The aim of this study was to systematically review the international literature to identify algorithms for the stratification of asthma patients according to disease severity based on available information in claims data. A systematic literature review was conducted in September 2015 using the DIMDI SmartSearch, a meta search engine including several databases with a national and international scope, e.g. BIOSIS, MEDLINE, and EMBASE. Claims data based studies that categorize asthma patients according to their disease severity were identified. The systematic research yielded 54 publications assessing asthma severity based on claims data. Thirty-nine studies used a standardized algorithm such as HEDIS, Leidy, the GINA based approach or CACQ. Sixteen publications applied a variety of different criteria for the severity categorisation such as asthma diagnoses, asthma-related drug prescriptions, emergency department visits, and hospitalisations. There is no best practice method for the categorisation of asthma severity with claims data. Rather, a combination of algorithms seems to be a pragmatic approach. A transfer to the German context is not entirely possible without considering particular conditions associated with German claims data.


Cap-assisted colonoscopy (CAC) significantly extends visualization in the right colon.
Although colonoscopy is the standard procedure in the diagnosis of colorectal neoplasia, a significant number of clinically relevant lesions may be missed even by experienced endoscopists using current technology. Particular problems may occur with blind spots behind the semilunar folds and within the right colon. A transparent cap mounted at the tip of a colonoscope may be an easy way to extend the visual field during colonoscopy and may improve the detection rate of mucosal lesions. However, data in the literature are controversial and the quantity of the potential extension of visualization by a transparent cap has not been reported yet. The significance of cap-assisted colonoscopy (CAC) to increase visualization within different colonic segments (rectum, sigmoid colon, descending colon, transverse colon, ascending colon, cecum) was quantitatively analyzed by randomized back-to-back colonoscopies with and without cap. The investigations were performed in a colonic training model by 5 investigators. The inner colonic surface was stained by a raster of dots and the number of dots counted during colonoscopy served as a measure for the visible surface area of each segment. The time to advance the colonoscope to the respective colonic segments and the overall time to reach the cecum were not significantly different between conventional and CAC. In contrast, overall withdrawal time and withdrawal times for the cecum, ascending colon, descending colon and rectum were significantly longer for CAC, but not for the transverse and sigmoid colon. Visualization of the colonic surface was significantly increased during CAC. Overall, 59.76 ± 2.70 % of the maximal countable dots were visualized without cap and 85.36 ± 9.62 % with cap. The improvement of visualization was only significant for the right colon, but not for the rectum, sigmoid or descending colon. The finding of the present study suggests that the extension of visualization by CAC may be of particular value for the right colon.


Effects of adenosine receptor overexpression and silencing in neurons and glial cells on lifespan, fitness, and sleep of Drosophila melanogaster.
A single adenosine receptor gene (dAdoR) has been detected in Drosophila melanogaster. However, its function in different cell types of the nervous system is mostly unknown. Therefore, we overexpressed or silenced the dAdoR gene in eye photoreceptors, all neurons, or glial cells and examined the fitness of flies, the amount and daily pattern of sleep, and the influence of dAdoR silencing on Bruchpilot (BRP) presynaptic protein. Furthermore, we examined the dAdoR and brp gene expression in young and old flies. We found that a higher level of dAdoR in the retina photoreceptors, all neurons, and glial cells negatively influenced the survival rate and lifespan of male and female Drosophila in a cell-dependent manner and to a different extent depending on the age of the flies. In old flies, expression of both dAdoR and brp was higher than in young ones. An excess of dAdoR in neurons improved climbing in older individuals. It also influenced sleep by lengthening nighttime sleep and siesta. In turn, silencing of dAdoR decreased the lifespan of flies, although it increased the survival rate of young flies. It hindered the climbing of older males and females, but did not change sleep. Silencing also affected the daily pattern of BRP abundance, especially when dAdoR expression was decreased in glial cells. The obtained results indicate the role of adenosine and dAdoR in the regulation of fitness in flies that is based on communication between neurons and glial cells, and the effect of glial cells on synapses.


TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus: a phase 2, randomised, double-blind, placebo-controlled trial.
Activation of free fatty acid receptor 1 (FFAR1; also known as G-protein-coupled receptor 40) by fatty acids stimulated glucose-dependent β-cell insulin secretion in preclinical models. We aimed to assess whether selective pharmacological activation of this receptor by TAK-875 in patients with type 2 diabetes mellitus improved glycaemic control without hypoglycaemia risk. We undertook a phase 2, randomised, double-blind, and placebo-controlled and active-comparator-controlled trial in outpatients with type 2 diabetes who had not responded to diet or metformin treatment. Patients were randomly assigned equally to receive placebo, TAK-875 (6·25, 25, 50, 100, or 200 mg), or glimepiride (4 mg) once daily for 12 weeks. Patients and investigators were masked to treatment assignment. The primary outcome was change in haemoglobin A(1c) (HbA(1c)) from baseline. Analysis included all patients randomly assigned to treatment groups who received at least one dose of double-blind study drug. The trial is registered at ClinicalTrials.gov, NCT01007097. 426 patients were randomly assigned to TAK-875 (n=303), placebo (n=61), and glimepiride (n=62). At week 12, significant least-squares mean reductions in HbA(1c) from baseline occurred in all TAK-875 (ranging from -1·12% [SE 0·113] with 50 mg to -0·65% [0·114] with 6·25 mg) and glimepiride (-1·05% [SE 0·111]) groups versus placebo (-0·13% [SE 0·115]; p value range 0·001 to <0·0001). Treatment-emergent hypoglycaemic events were similar in the TAK-875 and placebo groups (2% [n=7, all TAK-875 groups] vs 3% [n=2]); significantly higher rates were reported in the glimepiride group (19% [n=12]; p value range 0·010-0·002 vs all TAK-875 groups). Incidence of treatment-emergent adverse events was similar in the TAK-875 overall (49%; n=147, all TAK-875 groups) and placebo groups (48%, n=29) and was lower than in the glimepiride group (61%, n=38). TAK-875 significantly improved glycaemic control in patients with type 2 diabetes with minimum risk of hypoglycaemia. The results show that activation of FFAR1 is a viable therapeutic target for treatment of type 2 diabetes. Takeda Global Research and Development.


Factors associated with peptide-based formula prescription in a pediatric intensive care unit.
There is no evidence-based consensus on the use of peptide-based formulas for critically ill children. The present study aimed to identify the factors associated with the choice of peptide-based formulas in the first enteral nutrition prescription for critically ill children and to compare the direct costs of the enteral formulas used in a pediatric intensive care unit. In a prospective study, children admitted to the intensive care unit and receiving tube feeding for ≥48 hours were evaluated. The potential exposure variables for the use of peptide-based formulas as the first nutrition prescription were age, sex, malnutrition, sepsis/septic shock, fasting period >2 days, use of α-adrenergic drugs before initiating first diet, and the revised Pediatric Index of Mortality score. A direct cost comparison of prescribed formulas was performed. Of 291 patients included, 85 (29.2%) were given peptide-based formulas in the first nutrition prescription. This choice was independently associated with malnutrition (odds ratio [OR] 2.94; 95% confidence interval [CI] 1.60%-5.39%; P < 0.01), fasting period >2 days (OR 3.46; 95% CI 1.93%-6.20%; P < 0.01), and use of α-adrenergic drugs (OR 2.32; 95% CI 1.24%-4.31%; P < 0.01). Peptide-based formula costs were up to 10 times higher than standard polymeric formula costs. The choice of peptide-based formula as the first enteral nutrition prescription is associated with the greater severity of patients' clinical status-patients receiving α-adrenergic drugs, those who are malnourished, and those with longer fasting periods. These prescriptions engender costs higher than those associated with standard polymeric formula.


Survival outcomes for postoperative chemoradiation in intermediate-risk oral tongue cancers.
The survival outcomes for surgery + postoperative radiotherapy (S+RT) or surgery + postoperative chemoradiation (S+CRT) was compared in patients having oral tongue cancers with intermediate-risk pathological features. Using the National Cancer Database (NCDB), overall survival (OS) for S+RT or S+CRT was estimated using the Kaplan-Meier methods and Cox proportional hazard models in the entire population (n = 2803) and in a propensity-matched cohort (n = 1136). The 3-year OS was 73.3% for S+CRT versus 66.7% for S+RT (P = .02). The S+CRT improved the 3-year OS for patients with 2 or more involved metastatic lymph nodes (≥2 MLNs; P = .01) but not for patients with <2 MLNs (P = .73). Undergoing S+CRT improved the 3-year OS for patients with pathologic T classification (pT) pT3-pT4 disease (P = .01) but not for patients with pT1-pT2 disease (P = .18). Undergoing S+CRT was associated with improved survival for patients with tongue cancers with ≥2 MLNs and/or pT3-pT4 suggesting that specific intermediate-risk pathological features benefit from treatment intensification.


Thiol-Michael addition based conjugate for glutathione activation and release.
Glutathione (GSH) level has long been recognized as a valuable tumor biomarker. GSH-mediated activation and release systems have been extensively developed for cancer diagnosis and treatment, but mainly focused on disulfide-based conjugate. We reported here a new thiol-Michael addition based GSH response conjugate TC6, which consists of a unique tricyclic structure containing α, β-unsaturated ketone responsive groups. The conjugate was easily synthesized and showed good selectivity to glutathione with certain stability. The camptothecin delivery experiment of TC6 showed improved anti-tumor ability in cells and tumor-bearing mice. TC6 could be used for the development of antibody or small molecule conjugated drugs.


Genetic and Genomic Mechanisms of Primary Aldosteronism.
Aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia are the main cause of primary aldosteronism (PA), the most frequent form of secondary hypertension. Mutations in ion channels and ATPases have been identified in APA and inherited forms of PA, highlighting the central role of calcium signaling in PA development. Different somatic mutations are also found in aldosterone-producing cell clusters in adrenal glands from healthy individuals and from patients with unilateral and bilateral PA, suggesting additional pathogenic mechanisms. Recent mouse models have also contributed to a better understanding of PA. Application of genetic screening in familial PA, development of surrogate biomarkers for somatic mutations in APA, and use of targeted treatment directed at mutated proteins may allow improved management of patients.


Streptococcus pneumoniae meningitis in a child with idiopathic nephrotic syndrome: a case report.
Children with nephrotic syndrome are at increased risk of infections, including bacterial peritonitis, pneumonia, and cellulitis. However, bacterial meningitis, a potentially life-threatening complication, has not been highlighted as an infectious complication of nephrotic syndrome in recent reviews. We report a very subtle and unusual presentation of bacterial meningitis in a child with nephrotic syndrome, which without a high index of suspicion, would have been missed. A 9-year-old African-American male with a history of steroid-dependent nephrotic syndrome presented to the nephrology clinic for routine follow-up. His medications included mycophenolate mofetil and alternate-day steroids. His only complaint was neck pain and stiffness that the mother attributed to muscle tightness relieved by massage. There was no history of fever, vomiting, headache, photophobia, or altered mental status. On physical examination, he was afebrile (99 °F), but had mild periorbital swelling and edema on lower extremities. He appeared ill and exhibited neck rigidity, and demonstrated reflex knee flexion when the neck was bent. Laboratory evaluation revealed leukocytosis, elevated C-reactive protein, hypoalbuminemia, and proteinuria. Cerebrospinal fluid suggested bacterial meningitis. The patient was treated with ceftriaxone and vancomycin. Both cerebrospinal and blood cultures grew Streptococcus pneumoniae; vancomycin was discontinued. The child completed a 2-week course of ceftriaxone and was discharged home. A high index of suspicion is necessary in children with nephrotic syndrome treated with corticosteroids, as symptoms may be masked, and thus, a life-threatening disease be missed. Bacterial meningitis should be highlighted as a serious infection complication in children with nephrotic syndrome.


Repeatability and reliability of GABA measurements with magnetic resonance spectroscopy in healthy young adults.
Gamma-aminobutyric acid (GABA) abnormalities have been implicated in a range of neuropsychiatric disorders. Despite substantial interest in probing GABA in vivo, human imaging studies relying on magnetic resonance spectroscopy (MRS) have generally been hindered by technical challenges, including GABA's relatively low concentration and spectral overlap with other metabolites. Although past studies have shown moderate-to-strong test-retest repeatability and reliability of GABA within certain brain regions, many of these studies have been limited by small sample sizes. GABA+ (macromolecular-contaminated) test-retest reliability and repeatability were assessed via a Meshcher-Garwood point resolved spectroscopy (MEGA-PRESS) MRS sequence in the rostral anterior cingulate cortex (rACC; n = 21) and dorsolateral prefrontal cortex (dlPFC; n = 20) in healthy young adults. Data were collected on a 3T scanner (Siemens Prisma, Siemens Healthcare, Erlangen, Germany) and GABA+ results were reported in reference to both total creatine (GABA+/tCr) and water (GABA+/water). Results showed strong test-retest repeatability (mean GABA+/tCr coefficient of variation [CV] = 4.6%; mean GABA+/water CV = 4.0%) and reliability (GABA+/tCr intraclass correlation coefficient [ICC] = 0.77; GABA+/water ICC = 0.87) in the dlPFC. The rACC showed acceptable (but comparatively lower) repeatability (mean GABA+/tCr CV = 8.0%; mean GABA+/water CV = 7.5%), yet low-moderate reliability (GABA+/tCr ICC = 0.40; GABA+/water ICC = 0.44). The present study found excellent GABA+ MRS repeatability and reliability in the dlPFC. The rACC showed inferior results, possibly because of a combination of shimming impedance and measurement error. These data suggest that MEGA-PRESS can be utilized to reliably distinguish participants based on dlPFC GABA+ levels, whereas the mixed results in the rACC merit further investigation.


Identification and characterization of calyceal diverticula with MR urography (MRU) in children.
To determine the MRU imaging findings of calyceal diverticula in a large cohort of children and to compare the frequency of calyceal diverticula in our cohort with what has been previously reported. This was a HIPAA-compliant, IRB-approved retrospective study of all patients with suspected CD based on their medical records. All patients in this study underwent MRU at our institution between 2010 and 2017. Two pediatric radiologists reviewed each MRU blinded to clinical information and other urologic imaging regarding the presence, size, location, and morphology of the cyst and presence/absence of contrast within it. The time when contrast first appeared within the cystic mass was recorded, and a χ2 test was used to determine significance on differences between the different characteristics of renal cysts and diverticula. Fifty children (29 girls and 21 boys; median age of 11.5 years, IQR 7-16) with a total of 66 individual cystic masses were included. 21 (21/66, 31.8%) Cystic masses demonstrated contrast filling and were characterized as diverticula, resulting in a frequency of 26.6 cases per 1000 patients (21/787). The remaining 45 cystic masses (45/66, 68.1%) were cysts. The median diameter of CD was 2.5 cm (IQR 1.5-3.7). Contrast was observed within the cystic mass on average at 4.6 min (SD ± 2.4; range 1.5-13 min). The agreement between both radiologists was 91% (k = 0.78). 6 Cysts and 18 CD were confirmed surgically, MRU demonstrated accurate diagnosis in 100% of those cases. Magnetic resonance urography is reliable in differentiating calyceal diverticula from renal cysts. On MRU, all diverticula were identified within 15 min of contrast administration; hence longer delays in imaging are unnecessary.


Adaptive event-triggered extended dissipative synchronization of delayed reaction-diffusion neural networks under deception attacks.
Under spatially averaged measurements (SAMs) and deception attacks, this article mainly studies the problem of extended dissipativity output synchronization of delayed reaction-diffusion neural networks via an adaptive event-triggered sampled-data (AETSD) control strategy. Compared with the existing ETSD control methods with constant thresholds, our scheme can be adaptively adjusted according to the current sampling and latest transmitted signals and is realized based on limited sensors and actuators. Firstly, an AETSD control scheme is proposed to save the limited transmission channel. Secondly, some synchronization criteria under SAMs and deception attacks are established by utilizing Lyapunov-Krasovskii functional and inequality techniques. Then, by solving linear matrix inequalities (LMIs), we obtain the desired AETSD controller, which can satisfy the specified level of extended dissipativity behaviors. Lastly, one numerical example is given to demonstrate the validity of the proposed method.


Evidence for endorphin-mediated cross-tolerance between chronic stress and the behavioral effects of ionizing radiation.
C57BL/6J mice exhibit a naloxone-reversible locomotor hyperactivity after exposure to ionizing radiation. These data implicate endogenous opiates in this radiogenic behavioral change. Similarly, endorphins mediate analgesia produced by chronic stress (e.g., foot shock or restraint) and levels of plasma Beta-endorphin are elevated following exposure to acute stress. Therefore, the present study sought to determine if behavioral cross-tolerance could be obtained between endorphin-producing stressors and radiation exposure. Repeated pretreatment with foot shock or restraint subsequently inhibited the locomotor-activating effects of radiation. These data are consistent with the hypothesis that cross-tolerance developed between the effects of stress-induced endogenous opiate release and the radiation-induced release of endorphins.


Chromosomal assignment of the gene encoding the human 58-kDa inhibitor (PRKRI) of the interferon-induced dsRNA-activated protein kinase to chromosome 13q32.
The 58-kDa inhibitor (p58) of the interferon-induced dsRNA-activated protein kinase (PKR) is a cellular protein recruited by the influenza virus to down-regulate the activity of PKR during virus infection. The inhibitor also appears to play a role in the regulation of cellular gene expression in the absence of viral infection and has oncogenic properties when overexpressed. Using fluorescence in situ hybridization, we have mapped the p58 gene (PRKRI) to human chromosome 13 band q32. Aberrations in the structure or number of chromosome 13 have been identified in a variety of human cancers, particularly in acute leukemia.


Tumor necrosis factor-alpha generates reactive oxygen species via a cytosolic phospholipase A2-linked cascade.
Reactive oxygen species (ROS) are important regulatory molecules implicated in the signaling cascade triggered by tumor necrosis factor (TNF)-alpha, although the events through which TNF-alpha induces ROS generation are not yet well characterized. We therefore investigated selected candidates likely to mediate TNF-alpha-induced ROS generation. Consistent with the role of Rac in that process, stable expression of Rac(Asn-17), a dominant negative Rac1 mutant, completely blocked TNF-alpha-induced ROS generation. To understand better the mediators downstream of Rac, we investigated the involvement of cytosolic phospholipase A(2) (cPLA(2)) activation and metabolism of the resultant arachidonic acid (AA) by 5-lipoxygenase (5-LO). TNF-alpha-induced ROS generation was blocked by inhibition of cPLA(2) or 5-LO, but not cyclooxygenase, suggesting that TNF-alpha-induced ROS generation is dependent on synthesis of AA and its subsequent metabolism to leukotrienes. Consistent with that hypothesis, TNF-alpha Rac-dependently stimulated endogenous production of leukotriene B(4) (LTB(4)), while exogenous application of LTB(4) increased levels of ROS. In contrast, application of leukotrienes C(4), D(4), and E(4) or prostaglandin E(2) had little effect. Our findings suggest that LTB(4) production by 5-LO is situated downstream of the Rac-cPLA(2) cascade, and we conclude that Rac, cPLA(2), and LTB(4) play pivotal roles in the ROS-generating cascade triggered by TNF-alpha.


Clinical evaluation comparing the fit of all-ceramic crowns obtained from silicone and digital intraoral impressions.
The aim of this study is to compare the fit of all-ceramic crowns fabricated from conventional silicone impressions with the fit of all-ceramic crowns fabricated from intraoral digital impressions. Twenty patients with 26 posterior teeth with a prosthetic demand were selected for the study. Two crowns (Straumann-Zerion) were made for each preparation. One crown was fabricated from an intraoral digital impression system (IDI group; Cadent-iTero), and the other crown was fabricated from a conventional one-step silicone impression (CI group; Express Penta Putty and Body Light). To replicate the interface between the crown and the preparation, each crown was cemented on its corresponding clinical preparation with ultra-flow silicone (Express Ultra Light Body). Each crown was embedded in resin to stabilize the registered interface, cut in 2-mm-thick slices in a buco-lingual orientation. Internal misfit was measured in microns using stereomicroscopy with a magnification of ×40. Measurements were taken at different landmarks: margin, chamfer angle, axial, crest, and occlusal fosse. After checking for normality, data was analyzed using paired Student's t test (α = 0.05). Fit values were significantly affected by the impression technique (p = 0.000). Mean internal misfit and mean marginal misfit were 111.40 μm (SD = 54.04)/80.29 μm (SD = 26.24) for the crowns of the IDI group and 173.00 μm (SD = 92.65)/133.51 μm (SD = 48.78) for the CI group. All-ceramic crowns fabricated from intraoral digital impressions with parallel confocal technology demonstrated a clinically acceptable internal and marginal fit as conventional impression. Intraoral digital impressions as initial step to the digital workflow could further improve the marginal adaptation of all ceramic single crowns. http://www.isrctn.com/ISRCTN16111844.


Diagnosis-linked antibiotic prescribing in Swedish primary care - a comparison between in-hours and out-of-hours.
The rise in antibiotic resistance is a global public health concern, and antibiotic overuse needs to be reduced. Earlier studies of out-of-hours care have indicated that antibiotic prescribing is less appropriate than that of in-hours care. However, no study has compared the out-of-hours treatment of infections to in-hours treatment within the same population. This retrospective, descriptive study was based on data retrieved from the Kronoberg Infection Database in Primary Care (KIDPC), which consists of all visits to primary care with an infection diagnosis or prescription of antibiotics during 2006-2014. The purpose was to study the trends in antibiotic prescribing and to compare consultations and prescriptions between in-hours and out-of-hours. The visit rate for all infections was 434 visits per 1000 inhabitants per year. The visit rate was stable during the study period, but the antibiotic prescribing rate decreased from 266 prescriptions per 1000 inhabitants in 2006 to 194 prescriptions in 2014 (mean annual change - 8.5 [95% CI - 11.9 to - 5.2]). For the out-of-hours visits (12% of the total visits), a similar reduction in antibiotic prescribing was seen. The decrease was most apparent among children and in respiratory tract infections. When antibiotic prescribing during out-of-hours was compared to in-hours, the unadjusted relative risk of antibiotic prescribing was 1.37 (95% CI 1.36 to 1.38), but when adjusted for age, sex, and diagnosis, the relative risk of antibiotic prescribing was 1.09 (95% CI 1.08 to 1.10). The reduction after adjustment was largely explained by a higher visit rate during out-of-hours for infections requiring antibiotics (acute otitis media, pharyngotonsillitis, and lower urinary tract infection). The choices of antibiotics used for common diagnoses were similar. Although the infection visit rate was unchanged over the study period, there was a significant reduction in antibiotic prescribing, especially to children and for respiratory tract infections. The higher antibiotic prescribing rate during out-of-hours was small when adjusted for age, sex, and diagnosis. No excess prescription of broad-spectrum antibiotics was seen. Therefore, interventions selectively aiming at out-of-hours centres seem to be unmotivated in a low-prescribing context.


Is there a relationship between occupational activities and low back pain in obese, middle-aged women?
Although low back pain and obesity are major health issues for women, our understanding of the relationship between these conditions is limited. This study aimed to investigate the relationship between occupational activities and low back pain and disability in obese and non-obese, middle-aged females. Eighty-nine obese and 56 non-obese participants were recruited for a community-based study of musculoskeletal health. Low back pain intensity and disability were examined using the Chronic Pain Grade Questionnaire and participants were asked about their involvement in occupational activities. More manual activity and heavy lifting, bending or squatting were found to be associated with low back pain intensity in obese females (odds ratio (OR) 1.83, 95% confidence interval (CI) 1.14-2.94; OR 3.02, 95% CI 1.24-7.37, respectively), but not in non-obese females (OR 0.83, 95% CI 0.42-1.63; OR 0.81, 95% CI 0.25-2.6, respectively), after adjusting for age and recreational activity. Similarly, there were also relationships between performance of more manual activity and heavy lifting, bending or squatting and low back disability in the obese (OR 1.68, 95% CI 1.07-2.63; OR 2.79, 95% CI 1.21-6.46, respectively), but not in the non-obese (OR 0.88, 95% CI 0.36-2.13; OR 1.78, 95% CI 0.39-8.22, respectively). Obese females who perform predominately manual activity or heavy lifting, bending or squatting at work have high levels of low back pain and disability, independent of their recreational activity. This was not the case for non-obese, female workers. Although longitudinal investigation is needed, these findings highlight the role of obesity in low back pain and disability for middle-aged females in occupational settings.


Sugar-responsive Pickering emulsions mediated by switching hydrophobicity in microgels.
Pickering emulsions stabilized by soft and responsive microgels can demulsify on demand upon microgel collapse. The concept has been explored with simple model microgels such as poly(N-isopropylacrylamide) (pNIPAM) and their derivatives, but the role of functionalization is largely unexplored. Saccharide-responsive phenylboronic-modified microgels are used as Pickering emulsion stabilizers. Emulsion stability and microgel organization at drop surface are studied as a function of saccharide concentration. Better insight into their behavior at interfaces is gained through adsorption kinetics and Langmuir film studies at air-water interface. The functionalization of water-swollen microgels by phenylboronic functions imparts some hydrophobicity to the structure, at the origin of additional internal cross-links analogous which rigidify the structure compared to non-functionalized microgels, as proved by their slow adsorption kinetics and poor interfacial compressibility. Upon boronate ester formation with diol groups of the saccharide, the hydrophobic character of the phenylboronic acid decreases, increasing the adsorption kinetics and their interfacial compressibility. Emulsions are stable in the presence of saccharide, given the high deformability of the yet-hydrophilic microgels, and mechanically unstable with less deformable particles in low saccharide concentration. The hydrophobic-hydrophilic switch acts as a trigger to tune the microgel stabilizing properties.


Development of a STAT3 reporter prostate cancer cell line for high throughput screening of STAT3 activators and inhibitors.
STAT3 is constitutively activated in several cancers, including prostate cancer, and is therefore, a potential target for cancer therapy. DU-145 prostate cancer cells were stably co-transfected with STAT3 reporter and puromycin resistant plasmids to create a stable STAT3 reporter cell line that can be used for high throughput screening of STAT3 modulators. The applicability of this cell line was tested with two known activators and inhibitors of STAT3. As expected, EGF and IL-6 increased STAT3 reporter activity and enhanced the nuclear localization of phosphorylated STAT3 (pSTAT3); whereas Cucurbitacin I and AG490 decreased STAT3 reporter activity dose and time-dependently and reduced the localization of pSTAT3 in the nuclei of prostate cancer cells. Given the importance of STAT3 in cancer initiation and progression, the development of a stable STAT3 reporter cell line in prostate cancer cells provides a rapid, sensitive, and cost effective method for the screening of potential STAT3 modulators.


Positively selected sites in the Arabidopsis receptor-like kinase gene family.
We analyze members of the receptor-like kinase (RLK) gene family in Arabidopsis thaliana for positive selection. Likelihood analyses find evidence for positive selection in 12 of the 52 RLK family sequences groups. These 12 groups represent 97 of the 403 sequences analyzed. The majority of genes in groups subject to positive selection have not been functionally characterized, but sites under selection are predominantly located in the extracellular region. The pattern of selection in the extracellular leucine-rich repeat (LRR) motif of groups 14 and 51 is similar to previous studies where positively selected positions are located in a solvent exposed beta-strand that may determine disease specificity, raising the possibility that some RLK genes function in a similar role.


Triple helix stabilization properties of oligonucleotides containing 8-amino-2'-deoxyguanosine.
Analysis of the Hoogsteen base pairs of guanine and 8-aminoguanine with cytosine in the gase phase shows a strong stabilization of the 8-aminoguanine.cytosine base pair due to the formation of an extra H-bond. Melting profiles of oligonucleotides carrying 8-amino-2'-deoxyguanosine confirm the triple helix stabilization properties of 8-aminoguanine.


Packaging colour research by tobacco companies: the pack as a product characteristic.
Tobacco companies use colour on cigarette packaging and labelling to communicate brand imagery, diminish health concerns, and as a replacement for prohibited descriptive words ('light' and 'mild') to make misleading claims about reduced risks. We analysed previously secret tobacco industry documents to identify additional ways in which cigarette companies tested and manipulated pack colours to affect consumers' perceptions of the cigarettes' flavour and strength. Cigarette companies' approach to package design is based on 'sensation transference' in which consumers transfer sensations they derive from the packaging to the product itself. Companies manipulate consumers' perceptions of the taste and strength of cigarettes by changing the colour of the packaging. For example, even without changes to the tobacco blends, flavourings or additives, consumers perceive the taste of cigarettes in packages with red and darker colours to be fuller flavoured and stronger, and cigarettes in packs with more white and lighter colours are perceived to taste lighter and be less harmful. Companies use pack colours to manipulate consumers' perceptions of the taste, strength and health impacts of the cigarettes inside the packs, thereby altering their characteristics and effectively creating new products. In countries that do not require standardised packaging, regulators should consider colour equivalently to other changes in cigarette characteristics (eg, physical characteristics, ingredients, additives and flavourings) when making determinations about whether or not to permit new products on the market.


Characterization of fish myofibrillar protein film incorporated with catechin-Kradon extract.
This study investigates the properties of films made from fish myofibrillar protein (FMP) incorporated with combinations of catechin-Kradon extract (C/K) (20%, w/w) at different ratios. The experimental films were compared to a polyvinyl chloride (PVC). The thickness and the transparency of the films were in the range of 0.014-0.015mm and 3.65-3.77, respectively. Significant decreases were observed in elongation at break (35-122%), water vapor permeability (0.54-1.26×10-10gm-1s-1Pa-1) properties, and a gradual decrease in L* value was pronounced when the proportions of catechins were increased (P<0.05). FMP films incorporated with C/K demonstrated to have very good barrier properties to UV light and also enhanced the thermal stability of the developed FMP films. All film samples had a smooth surface; however coarser surfaces were observed when the amounts of catechins were increased. Furthermore, the developed FMP films showed high antioxidant capability. However, no significant antimicrobial activity was observed in this film. It is determined that FMP films enriched with C/K can be used for food packaging, with particular potential for active packaging. However, as compared with the PVC, the FMP films need further development, especially in terms of their mechanical and water barrier properties.


Fatigue after colorectal surgery and its relationship to patient expectations.
Feelings of fatigue are pronounced even after uncomplicated abdominal surgery. Patient expectations are associated with a variety of postsurgical outcomes, but few data about fatigue prevalence, nature, and time frame are available for patients and health professionals. Therefore, this study sought to investigate the effect of patient expectations on fatigue experiences following major colorectal surgery. Based on the common sense model of illness self-regulation, prior to surgery 51 patients were asked to complete questionnaires assessing their perceptions of likely time frame and ability to control their return to normal functioning after surgery, using subset of questions from the Revised Illness Perceptions Questionnaire. Experience of fatigue and impact of fatigue were also assessed for 2 mo postsurgery using the Identity-Consequences Fatigue Scale. Using mixed model linear regression, baseline depression scores exerted significant main effects on both Fatigue Experiences and Fatigue Impacts scores of the patients. Further, after controlling for depression, there remained significant expectation interactions with both Fatigue Experiences and Fatigue Impacts scores. Postsurgical fatigue is multidimensional and this should be considered in studies investigating this phenomenon. Patients who before surgery reported shorter expected fatigue resolution time lines and a higher degree of expected control, experienced more persistent fatigue following surgery.


Predominant Antibody Deficiency and Risk of Microscopic Colitis: a Nationwide Case-Control Study in Sweden.
PURPOSE : Predominant antibody deficiency (PAD) disorders, including common variable immunodeficiency (CVID), have been linked to increased risk of gastrointestinal infections and inflammatory bowel diseases. However, there are limited data on the relationship between PAD, specifically CVID, and risk of microscopic colitis (MC). We performed a nationwide case-control study of Swedish adults with MC diagnosed between 1997 and 2017 (n = 13,651). Data on biopsy-verified MC were retrieved from all of Sweden's pathology departments through the Epidemiology Strengthened by histoPathology Reports in Sweden (ESPRESSO) study. We defined predominant antibody deficiency using International Union of Immunologic Societies (IUIS) phenotypic classification. Individuals with MC were matched to population controls by age, sex, calendar year, and county. We used logistic regression to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). The prevalence of PAD in MC was 0.4% as compared to 0.05% in controls. After adjustment for potential confounders, this corresponded to an aOR of 7.29 (95%CI 4.64-11.63). The magnitude of the association was higher for CVID (aOR 21.01, 95% 5.48-137.44) compared to other antibody deficiencies (aOR 6.16, 95% CI 3.79-10.14). In exploratory analyses, the association between PAD and MC was particularly strong among males (aOR 31.73, 95% CI 10.82-135.04). In this population-based study, predominant antibody deficiency was associated with increased risk of MC, particularly among males. Clinicians who encounter these patients should consider a detailed infectious history and screening for antibody deficiency.


Umbilical cord haematoma as a complication of intrauterine intravascular blood transfusion.
Between October 1985 and February 1989, 49 ultrasound-guided intravascular fetal blood transfusions were performed in 16 patients (14 with rhesus (Rh) isoimmunization, 2 with non-immunologic hydrops fetalis (NIHF)). As an intra-operative complication, perivascular haematoma of the cord occurred in three patients (7 per cent). In two cases, fetal bradycardia necessitated delivery by Caesarean section at 30 and 32 weeks' gestation, respectively. In the third case, fetal bradycardia developed during transfusion, at 31 weeks' gestation, but normalized within 3 min. The baby was delivered as planned at 36 weeks of gestation, after another transfusion at 34 weeks. Dislodgement of the needle tip into perivascular tissue, caused by sudden fetal or maternal movements, is the reason for this complication. The haematoma develops as a result of delayed recognition and continuous transfusion into Wharton's jelly. Cord haematoma may be diagnosed in time by continuous ultrasound imaging, as illustrated in case 3. To minimize the risk of needle dislodgement during transfusion, sedation of the mother and complete immobilization of the fetus by injecting a short-acting muscle relaxant into the umbilical vessel are recommended.


Phorbol esters and cAMP differentially regulate the expression of CD4 and CD8 in human thymocytes.
Intrathymic development and selection of the T lymphocyte repertoire is restricted by the interactions of the T cell antigen receptor and CD4 or CD8 co-receptors with self major histocompatibility complex molecules. Positive or negative selection depends on a tight regulatory control of CD4 and CD8 expression. Determining the intracellular signals that differentially regulate the expression of CD4 and CD8 is important to understand the mechanisms that are implicated in selection of single positive CD4+CD8- or CD4-CD8+. The present study shows that stimulation of human thymocytes by phorbol esters or cAMP result in a differential regulation of CD4 and CD8 expression, both at the mRNA and cell surface glycoprotein level. The differential regulation of CD4 and CD8 gene expression suggests that the selective activation of protein kinase C (PKC) and cAMP-dependent protein kinases (PKA) may be required for the selection of single positive CD4+CD8- and CD4-CD8+ cells during Intrathymic differentiation.


[Development of an Integrated Community-Based Prevention Strategy in Freiham (Munich) from the Perspective of the Steering Group: A Qualitative Interview Study with Social Network Analysis].
The City of Munich is planning and implementing a "Prevention Chain" as an integrated community-based prevention strategy in the new district of "Freiham" in Munich. This is taking place while the district is being built. The "Prevention Chain Freiham" aims to create an environment that enables a healthy upbringing of all children and adolescents right from the start. In order to guide this project, an interdepartmental working group was formed within the City of Munich's administration. This study analyses the working group's structures, processes and its collaboration with a variety of stakeholders. We conducted a multimethod study comprising qualitative interviews and social network analysis. Between March and April 2018, we conducted semi-structured interviews with members of the working group. The study participants also generated ego-centred social network maps. The transcripts were analysed using qualitative content analysis as described by Schreier. The network maps were also analysed using qualitative content analysis and the results were visualized. Our preliminary findings were interpreted, discussed and validated in a workshop in June 2018 with study participants. Ten members of the working group participated in the study. The interdepartmental, multiprofessional collaboration in the working group was perceived as beneficial for the process of developing and implementing the Prevention Chain. The external coordination by MAGs and the scientific expertise provided by the LMU Munich were considered highly supportive. Barriers to the planning and implementation of the Prevention Chain were mainly located at administration level. Most facilitators were attributed to the collaborative processes within the working group. After having mapped all stakeholders currently involved in the Prevention Chain (mainly actors within the City of Munich's administration), additional relevant stakeholders were identified by the members of the working group. The organizational form of the working group as a formalized association of representatives of various departments that are jointly responsible for the Prevention Chain is considered beneficial for the success of the Prevention Chain. This is further supported by the external coordination and academic support. Advancing the development and implementation of the Prevention Chain will require support from all relevant departments across sectors and hierarchies.


HiBiT Cellular Thermal Shift Assay (HiBiT CETSA).
Cellular thermal shift assay (CETSA) is based on the thermal stabilization of the protein target by a compound binding. Thus, CETSA can be used to measure a compound's cellular target engagement and permeability. HiBiT CETSA method is quantitative and has higher throughput compared to the traditional Western-based CETSA. Here, we describe the protocol for a HiBiT CETSA, which utilizes a HiBiT tag derived from the NanoLuciferase (NanoLuc) that upon complementation by LgBiT NanoLuc tag produces a bright signal enabling tracking of the effects of increasing temperature on the stability of a protein-of-interest in the presence/absence of various compounds. Exposure of a HiBiT-tagged protein to increasing temperatures induces protein denaturation and thus decreased LgBiT complementation and NanoLuc signal. As the stability of proteins at higher temperatures can be influenced by the compound binding, this method enables screening for target engagement in living or permeabilized cells.


Improved breast cytology results with near patient FNA diagnosis.
To examine the impact of a cytopathologist using near patient fine needle aspiration diagnosis (NPFD) for breast diagnosis. The cytology results of all palpable solid breast lesions undergoing fine needle aspiration (FNA) during a two-year period were prospectively audited and categorized as definitely benign or malignant (definite), probably benign, indeterminate or suspicious (indefinite) or unsatisfactory. The final diagnosis (benign or malignant) was determined from a review of patients' charts and a survey of patients' family physicians. Aspirates were performed by surgical staffand reported either later (non-NPFD) or by NPFD. Of 720 FNAs, 230 were by NPFD and 490 by non-NPFD. NPFD was associated with a significantly greater proportion of definite reports (91.9% versus 82.4%). NPFD of discrete breast lumps was associated with higher specificity (89.1% versus 67.5%) and a lower unsatisfactory rate (9.4% versus 19.6%) than non-NPFD. NPFD did not improve the unsatisfactory rate of FNAs from diffuse breast thickenings. FNA by a dedicated specialist and immediate reporting should be an integral part of a breast diagnostic service.


Influence of the protocol used for fibroin extraction on the mechanical properties and fiber sizes of electrospun silk mats.
Silk fibroin (SF) was regenerated using three of the most common protocols described in the bibliography for the dissolution of raw SF (LiBr 9.3M, CaCl2 50 wt.% or CaCl2:EtOH:H2O 1:2:8 in molar ratio). The integrity of regenerated SF in aqueous solution was analyzed by SDS-PAGE and different profiles of degradation were observed depending on the protocol used. This fact was found to affect also the aqueous solubility of the freeze dried protein. These different SFs were used to produce electrospun mats using SF solutions of SF 17 wt.% in 1,1,1,1',1',1'-hexafluoro-2-propanol (HFIP) and significant differences in fiber sizes, elongation and ultimate strength values were found. This work provides a global overview of the manner that different methods of SF extraction can affect the properties of electrospun SF-mats and consequently it should be considered depending on the use they are going to be made for.


Postoperative Complication Impact on Quality of Life after Postmastectomy Breast Reconstruction.
Although the overall psychosocial benefits and body image gains of postmastectomy breast reconstruction are well-established, there is limited information on how postoperative complications affect patient quality of life (QOL). A single-institution cross-sectional survey analysis was performed on patients who underwent postmastectomy breast reconstruction between 2008 and 2020. QOL was assessed using the BREAST-Q and the Was It Worth It questionnaires. The results were compared among patients who had major complications, minor complications, and no complications. Responses were compared using 1-way ANOVA and chi-square tests as appropriate. A total of 568 patients met inclusion criteria, and 244 patients responded (43% response rate). Most patients did not have any complications (n = 128; 52%), 41 had minor complications (17%), and 75 had major complications (31%). There were no differences in any of the BREAST-Q well-being metrics based on degree of complication. Across all 3 groups, patients reported that surgery was worthwhile (n = 212; 88%), they would choose reconstruction again (n = 203; 85%), and they would recommend it to a friend (n = 196; 82%). Overall, 77% reported that their overall experience either met or exceeded expectations, and 88% of patients had unchanged or improved overall QOL. Our study demonstrates that QOL and well-being are not negatively impacted by postoperative complications. Although patients who had no complications had an overall more positive experience, nearly two-thirds of all patients, no matter the degree of complication, stated that their overall experience either met or exceeded their expectations.


Spontaneous release of acetylcholine from Torpedo synaptosomes: effect of cetiedil and its analogue MR 16728.
The effects of cetiedil and its analogue MR 16728 were examined on spontaneous acetylcholine release measured with a chemiluminescent assay using choline oxidase in a synaptosomal suspension obtained from Torpedo marmorata electric organ. Evoked acetylcholine release is inhibited by cetiedil, whereas this drug enhances spontaneous extracellular Ca(2+)-independent acetylcholine release (up to 340%). This effect was examined as a function of cetiedil concentration and incubation time. On the other hand, the analogue MR 16728, which enhances A23187-evoked acetylcholine release, also enhances spontaneous Ca(2+)-independent acetylcholine release. Cetiedil and MR 16728 effects on spontaneous acetylcholine release were also examined in the presence of Ca2+. Addition of Ca2+ enhanced spontaneous acetylcholine release by 75%, and cetiedil and MR 16728 stimulation was maintained but with different levels of enhancement. Thus, these results show that the processes responsible for evoked and spontaneous acetylcholine release are sensitive but in different ways to drugs of the cetiedil family.


Analysis of endoplasmic reticulum stress-related gene signature for the prognosis and pattern in diffuse large B cell lymphoma.
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults. This study aimed to determine the prognostic significance of endoplasmic reticulum (ER) stress-related genes in DLBCL. ER stress-related genes were obtained from the molecular signatures database. Gene expression data and clinical outcomes from the gene expression omnibus and TCGA datasets were collected, and differentially expressed genes (DEGs) were screened out. Gene ontology enrichment analysis, the kyoto encyclopaedia of genes and genomes pathway analysis, and geneset enrichment analysis were used to analyse the possible biological function of ER stress-related DEGs in DLBCL. Protein-protein interaction network construction using the STRING online and hub genes were identified by cytoHubba on Cytoscape software. The significant prognosis-related genes were screened, and the differential expression was validated. The immune microenvironment assessment of significant genes were evaluated. Next, the nomogram was built using univariate and multivariate Cox regression analysis. 26 ER stress-related DEGs were screened. Functional enrichment analysis showed them to be involved in the regulation of the endoplasmic reticulum mainly. NUPR1 and TRIB3 were identified as the most significant prognostic-related genes by comparison with the GSE10846, GSE11318, and TCGA datasets. NUPR1 was correlated with a good prognosis and immune infiltration in DLBCL; on the other hand, high expression of TRIB3 significantly correlated with a poor prognosis, which was an independent prognostic factor for DLBCL. In summary, we identified NUPR1 and TRIB3 as critical ER stress-related genes in DLBCL. NUPR1 might be involved in immune infiltration in DLBCL, and TRIB3 might serve as a potential therapeutic target and prognostic factor in DLBCL.


Introduction: Development, Young People, and the Social Production of Aspirations.
In this editorial introduction to the Special Issue Youth, Aspirations and the Life Course: Development and the social production of aspirations in young people's lives, we put the work presented in this collection in conversation with the wider literature on development, youth and aspirations. Aspiration we define as an orientation towards a desired future. We elaborate on our conceptualisation of aspirations as socially produced and reflect on the methodological challenges in researching young people's aspirations in development. While mindful of the various critiques of aspiration research we argue that aspirations constitute fertile terrain for theorising the temporal dynamics of being young and growing up in contexts of development.


Pathways of ascending evoked spinal cord potentials of dogs.
Pathways of the ascending evoked potentials (AEPs) of the spinal cord of the dog were investigated by stimulating rear leg nerves and recording at thoracic levels before and after making selective partial or complete transections of topographic regions of the spinal cord in the L-1 segment: hemisection; ventral quadrant (VQ); dorsal quadrant (DQ); dorsolateral fasciculus (DLF); dorsal columns (DCs). The AEPs were found to be propagated in all topographic areas of the spinal cord. The contribution by the DQ ipsilateral to the stimulated nerve appeared to be the largest. Within the DQ, both the DLF and the DC participated in the AEP but the DLF contribution tended to predominate in the earliest parts while the DC contribution tended to lag somewhat behind that of DLF. The predominance of DLF activity in early phases of the AEP probably reflected the influence of high conduction velocities in muscle afferents and in postsynaptic DLF axons having connections with muscle afferents or with cutaneous afferents. The VQ contribution to the AEP appeared to arise from both crossed and uncrossed pathways but was not otherwise defined. Based on the results and on data in the literature, important considerations in interpretation of AEPs are: the relative numbers of muscle or cutaneous afferent fibers in the stimulated nerves; temporal dispersion of action potentials associated with differences in conduction velocities; conduction distances in the stimulated primary afferent axons and in postsynaptic spinal cord axons.


Rapid platelet turnover in WASP(-) mice correlates with increased ex vivo phagocytosis of opsonized WASP(-) platelets.
Our objective was to determine a mechanism for the thrombocytopenia of murine Wiskott-Aldrich syndrome (WAS). Consumption rates of WAS protein (WASP)(-) and wild-type (WT) platelets were measured by injection of 5-chloromethylfluorescein diacetate (CMFDA)-labeled platelets into WT or WASP(-) recipients, and by in vivo biotinylation. Platelet and reticulated platelet counts were performed using quantitative flow cytometry. Bone marrow megakaryocyte number and ploidy was assessed by flow cytometry. Phagocytosis of CMFDA-labeled, opsonized platelets was assessed using bone marrow-derived macrophages. Serum antiplatelet antibodies were assayed via their binding to WT platelets. CMFDA-labeled WASP(-) platelets are consumed more rapidly than WT platelets in either WT or WASP(-) recipients. In vivo biotinylation studies corroborate these findings and show a normal consumption rate for WASP(-) reticulated platelets. The number of reticulated platelets is reduced in WASP(-) mice, but a significant number of the mice show an increased proportion of reticulated platelets and more severe thrombocytopenia. Sera from some of the latter group contain antiplatelet antibodies. Compared to WT platelets, WASP(-) platelets opsonized with anti-CD61 or 6A6 antibody are taken up more rapidly by bone marrow-derived macrophages. In vivo consumption rates of WASP(-) platelets are more accelerated by opsonization than are those of WT platelets. Both rapid clearance and impaired production contribute to the thrombocytopenia of murine WAS. Increased susceptibility of opsonized WASP(-) platelets to phagocytosis leads to increased in vivo clearance. This correlates with a higher incidence of individuals with an elevated fraction of reticulated platelets, a more severe thrombocytopenia, and antiplatelet antibodies.


Concentrations of unconjugated 5 alpha-androstane-3 alpha, 17 beta-diol and 5 alpha-androstane-3 beta, 17 beta-diol and their precursor in human testicular tissue. Comparison with testosterone, 5 alpha-dihydrotestosterone, estradiol-17 beta, and with steroid concentrations in human epididymis.
The concentrations of testosterone and its tissular metabolites were determined in testicular and epididymal tissue obtained from eleven male subjects (aged 65-85 years) after orchiectomy for prostatic cancer. The steroids were measured in different tissular compartments, i.e. testis, caput, corpus and cauda epididymis. The values (mean +/- SD; ng/g wet weight) were: Testosterone 724.0 +/- 286.0, 32.08 +/- 2.56, 41.45 +/- 1.77 and 32.24 +/- 2.14; 5 alpha-dihydrotestosterone 6.95 +/- 1.99, 9.76 +/- 2.33, 16.87 +/- 0.21 and 15.79 +/- 2.67; 5 alpha-androstane-3 alpha, 17 beta-diol 6.07 +/- 2.33, 2.17 +/- 0.24, 1.93 +/- 0.02 and 1.17 +/- 0.20; 5 alpha-androstane-3 beta, 17 beta-diol 56.66 +/- 20.97, 3.55 +/- 0.19, 2.21 +/- 0.27 and 3.34 +/- 0.32; estradiol-17 beta 5.36 +/- 3.0, 1.08 +/- 0.014, 1.44 +/- 0.038 and 1.47 +/- 0.03, respectively. Incubation of human testicular tissue with [3H]androst-5-ene-3 beta, 17 beta-diol or [3H]dihydrotestosterone showed that both androstane-diols were exclusively formed from dihydrotestosterone. Since high concentrations of 5 alpha-androstane-3 beta, 17 beta-diol are found in testicular tissue it is suggested that this steroid may be an index of seminiferous tubular function.


Analysis of risk factors for high postoperative D-dimer levels: A single-center nurse-observational study.
As an elevated D-dimer level is directly proportional to the degrees of trauma and coagulation, it is often used to assess the severity of the trauma as well as the risk of thrombosis. This study aimed to investigate the risk factors for a high postoperative D-dimer level. A total of 623 patients undergoing radical mastectomy were included. The association between various clinicopathological factors and D-dimer variation was examined. Age, neoadjuvant chemotherapy, diabetes, and elevated neutrophil count were significant risk factors for D-dimer variation, after adjusting for other factors. This study has identified the characteristics of patients who are likely to experience considerable postoperative increases in the D-dimer level. The development of effective nursing interventions for these patients is the focus of future studies.


Surgical management of the unruptured cerebral aneurysm accompanied by ischemic cerebrovascular disease.
Unruptured cerebral aneurysms accompanied by ischemic CVD in 16 patients were analyzed and their managements are discussed. Unruptured aneurysms of 8 patients with mild or no clinical symptoms and small low density areas on CT were treated surgically. There was no operative mortality, but postoperative complication occurred in two patients. Both were operated on through the ipsilateral side of ischemic lesions shortly after the onset of ischemic symptoms. Eight patients who had severe neurological deficits due to ischemic lesions and large low density areas on CT did not receive aneurysmal operation. When unruptured aneurysms are accompanied by ischemic CVD, the treatment should be determined by the severity of neurological deficits caused by ischemic CVD. If an unruptured aneurysm was the source of emboli resulting in the ischemic lesion, it should be operated. Careful manipulation is required during surgery, especially from the ipsilateral side of ischemic lesion.


Macroautophagy and the proteasome are differently involved in the degradation of alpha-synuclein wild type and mutated A30P in an in vitro inducible model (PC12/TetOn).
Many data suggest that alpha synuclein (α-syn) aggregation is involved in Parkinson's disease (PD) neurotoxicity and is accelerated by the pathogenetic point mutation A30P. The triplication of α-syn gene has been linked to early-onset familial PD, suggesting that the cellular dosage of α-syn is an important modulator of its toxicity. To verify this point, we developed an inducible model of α-syn expression (both wild type [WT] and mutated A30P) in rat PC12/TetOn cells. At low expression level, both α-syn(WT) and (A30P) did not aggregate, were not toxic, and displayed a protective action against oxidative stress triggered by hydrogen peroxide (H(2)O(2)). By increasing α-syn expression, its antioxidant function was no longer detectable as for the A30P form, but again no aggregation and cell death were present both for the WT and the mutated protein. To clarify why α-syn did not accumulate at high expression level, we inhibited macroautophagy by 3-methyladenine (3-MA) and the proteasome by MG132. In presence of 3-MA, α-syn(WT) accumulated, A11 anti-oligomer antibody-positive aggregates were detectable, and cell toxicity was evident, while proteasome inhibition did not increase α-syn(WT) accumulation. Macroautophagy or proteasome inhibition slightly increased α-syn(A30P) toxicity, with no detectable aggregation. This model can provide useful details about α-syn function, aggregation, and degradation pathways.


stevor and rif are Plasmodium falciparum multicopy gene families which potentially encode variant antigens.
Several multicopy gene families have been described in Plasmodium falciparum, including the var genes that code for the variant surface antigen PfEMP1, the stevor family of subtelomeric open reading frames and the rif interspersed repetitive elements. This report documents the chromosomal location of stevor genes, their transcription and characteristics of the deduced protein. On 14 chromosomes, 34 stevor copies were identified from the Dd2 parasite line. Most are in subtelomeric regions within 50 kb of the telomere. stevor genes are located close to var genes and rij. All stevor genes sequenced had two exons: a short exon 1 encoding a start codon and a transmembrane domain; exon 2 encoding for the remainder of the approximately 30 kDa protein and including two more transmembrane segments. A similar structure was found for copies of rif and its predicted protein. In both STEVOR and RIF proteins, a highly polymorphic region is predicted to be a loop on the outer side of the membrane. We propose that stevor and rif are members of a larger superfamily. The number of copies of stevor and rif, their location close to the var genes, their extreme polymorphism and the predicted structure of the proteins suggest that stevor and rif code for variant surface antigens.


The Genetic, Pharmacogenomic, and Immune Landscapes Associated with Protein Expression across Human Cancers.
Proteomics is a powerful approach that can rapidly enhance our understanding of cancer development. Detailed characterization of the genetic, pharmacogenomic, and immune landscape in relation to protein expression in patients with cancer could provide new insights into the functional roles of proteins in cancer. By taking advantage of the genotype data from The Cancer Genome Atlas and protein expression data from The Cancer Proteome Atlas, we characterized the effects of genetic variants on protein expression across 31 cancer types and identified approximately 100,000 protein quantitative trait loci (pQTL). Among these, over 8000 pQTLs were associated with patient overall survival. Furthermore, characterization of the impact of protein expression on more than 350 imputed anticancer drug responses in patients revealed nearly 230,000 significant associations. In addition, approximately 21,000 significant associations were identified between protein expression and immune cell abundance. Finally, a user-friendly data portal, GPIP (https://hanlaboratory.com/GPIP), was developed featuring multiple modules that enable researchers to explore, visualize, and browse multidimensional data. This detailed analysis reveals the associations between the proteomic landscape and genetic variation, patient outcome, the immune microenvironment, and drug response across cancer types, providing a resource that may offer valuable clinical insights and encourage further functional investigations of proteins in cancer. Comprehensive characterization of the relationship between protein expression and the genetic, pharmacogenomic, and immune landscape of tumors across cancer types provides a foundation for investigating the role of protein expression in cancer development and treatment.


PIAS1 mediates TGFbeta-induced SM alpha-actin gene expression through inhibition of KLF4 function-expression by protein sumoylation.
TGFbeta and proliferation/phenotypic switching of smooth muscle cells (SMCs) play a pivotal role in pathogenesis of atherosclerotic and restenotic lesions after angioplasty. We have previously shown that the protein inhibitor of activated STAT (PIAS)1 activates expression of SMC differentiation marker genes including smooth muscle (SM) alpha-actin by interacting with serum response factor (SRF) and class I bHLH proteins. Here, we tested the hypothesis that TGFbeta activates SM alpha-actin through PIAS1. An siRNA specific for PIAS1 and ubc9, an E2-ligase for sumoylation, inhibited TGFbeta-induced expression of SM alpha-actin in cultured SMCs as determined by real-time RT-PCR. Overexpression of PIAS1 increased SM alpha-actin promoter activity in a TGFbeta control element (TCE)-dependent manner. Because the TCE within the SM alpha-actin promoter could mediate repression through interaction with KLF4, we tested whether PIAS1 regulates the function of KLF4 for SMC gene expression. PIAS1 interacted with KLF4 in mammalian two-hybrid and coimmunoprecipitation assays, and overexpression of PIAS1 inhibited KLF4-repression of SM alpha-actin promoter activity. Moreover, PIAS1 promoted degradation of KLF4 through sumoylation. These results provide evidence that PIAS1 promotes TGFbeta-induced activation of SM alpha-actin gene expression at least in part by promoting sumoylation and degradation of the TCE repressor protein, KLF4.


NLRX1 knockout aggravates lipopolysaccharide (LPS)-induced heart injury and attenuates the anti-LPS cardioprotective effect of CYP2J2/11,12-EET by enhancing activation of NF-κB and NLRP3 inflammasome.
NLRX1 weakens lipopolysaccharide (LPS)-induced NF-κB activation on immune cells. Cytochrome P450 epoxygenase 2J2 (CYP2J2) attenuates LPS-induced cardiac injury by inhibiting NF-κB activation. However, it is still unclear whether NLRX1 could reduce LPS-induced heart damage and whether it is involved in the anti-LPS cardioprotective effect of CYP2J2. In this study, we found that NLRX1 knockout further exacerbated LPS-induced heart injury and up-regulated the proinflammatory cytokines in serum and heart tissue, and weakened the inhibitory effect of CYP2J2 on the harmful effects caused by LPS. We also found that LPS treatment induced ubiquitination of NLRX1 and promoted its binding to IKKα/β in myocardial tissue, which should theoretically inhibit NF-κB activation. However, LPS eventually leads to activation of NF-κB and NLRP3 inflammasome. Under the action of LPS, CYP2J2 further promoted the ubiquitination of NLRX1 and its binding to IKKα/β, impaired NF-κB activation and NLRP3 inflammasome activation. NLRX1 knockout notably aggravated LPS-induced NF-κB activation and NLRP3 inflammasome activation, and attenuated the inhibitory effects of CYP2J2 on NF-κB signal and NLRP3 inflammasome. More, CYP2J2 reduced LPS-induced reactive oxygen species (ROS) production and mitochondrial depolarization in heart cells, thereby inhibiting NLRP3 inflammasome activation. NLRX1 knockdown aggravated mitochondrial depolarization induced by LPS and weakened the protective effect of CYP2J2 on mitochondrial potential, although it had no significant effect on reactive oxygen species production. Together, these findings demonstrated that NLRX1 knockout aggravated LPS-induced heart injury and weakened the anti-LPS cardioprotective effect of CYP2J2 by enhancing activation of NF-κB and NLRP3 inflammasome.


Clinical relevance of B7H3 expression in retinoblastoma.
Retinoblastoma (RB) is the most common paediatric intraocular tumour. Currently, chemotherapy is widely used to reduce the chance of metastasis as well as for vision salvage. The limitations of chemotherapy for RB include chemoresistance and cytotoxicity. Recently, immunotherapy is considered for treating chemoresistant cancers. Although, several molecular targets are available for immunotherapy in different cancers, we were interested in B7H3, as it was differentially expressed between retinoblastoma and retina in our earlier proteomics study. Hence, in this study we validated the previous finding by Western blotting and immunohistochemistry on primary RB tumor samples. The results suggest significantly increased expression of B7H3 in RB tumor samples compared to retina by western blotting. Immunohistochemistry revealed spatial, inter and intratumoral heterogeneity in the primary RB tumor sections. Correlation of the B7H3 expression with clinical and histopathological data revealed significantly increased expression of B7H3 in poorly differentiated, non-neural invasive tumors and lower expression in neural invasion and severe anaplastic areas of the tumors. B7H3 expression did not significantly vary between low-risk and high-risk tumors. The study also revealed considerably reduced infiltration of T lymphocytes in RB. We conclude that B7H3 is prominently expressed in primary RB tumors and could be used for targeted therapy.


The influence of the total flavonoids of Hedysarum polybotry on the proliferation, cell cycle, and expressions of p21Ras and proliferating cell nuclear antigen gene in erythroleukemia cell line K562.
To investigate the effect of total flavonoids of Hedysarum polybotry on the proliferation, cell cycle, and expressions of p21(Ras) and proliferating cell nuclear antigen (PCNA) gene in erythroleukemia cell line K562. The effect of total flavonoids of Hedysarum polybotry on K562 cell line survival was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) reduction assay. The time- and dose-dependent manner was also observed. The cell cycle and apoptosis were analyzed with flow cytometry (FCM). The immunocytochemistry method was applied to quantitatively analyze the effects of flavonoids of Hedysarum polybotry on changes p21(Ras) and PCNA gene expressions. Flavonoids of Hedysarum polybotry (20-100 μg/mL) significantly inhibited the proliferation of K562 cells in a time- and dose-dependent manner. After K562 cells were cultured for 48 h, total flavonoids of Hedysarum polybotry had no significant effect on the apoptosis of K562 cells but showed significantly inhibition (P<0.01), indicating that total flavonoids of Hedysarum polybotry could induce K562 cells arrested at G(0)/G(1) and G(2)/M phases. Compared with the control group, p21(Ras) and PCNA gene expressions were decreased significantly in K562 cells treated with total flavonoids of Hedysarum polybotry (40 and 80 μg/mL, respectively) for 48 h. The inhibitory effect on proliferation of K562 cells was observed in the groups treated with flavonoids of Hedysarum polybotry, which might be related to cells arresting.


The role of contrast radiography in presumed bowel obstruction.
A retrospective review of 229 patients with a final diagnosis of small-bowel obstruction was undertaken to evaluate the role of contrast radiography in the management of their conditions. In 84 patients (37%) the clinical findings and plain abdominal roentgenograms were sufficient for diagnosis and subsequent management. Of the remaining 145 patients with equivocal findings, 27% had an upper gastrointestinal series, 29% a barium enema, and 44% had both. Useful information (complete obstruction, unobstructed passage of contrast, or diagnosis other than adhesional obstruction) was obtained from 86% of the radiographic studies. Three patients had negative contrast studies yet eventually underwent adhesiolysis (enterolysis) and were classified as false-negative. Two patients had evidence of high-grade obstruction yet had nonoperative resolution and were classified as false-positive. The mortality in the contrast group (7%) was not statistically different than that in the no-contrast group (7%). Contrast radiography is a safe and effective means of increasing diagnostic accuracy in patients with presumed small-bowel obstruction.


The asynchronous discrete coding model: further tests with single-attribute stimuli.
Two experiments using a probe-RT paradigm showed that partial information about the size of a stimulus can influence response processes before complete size information is available. Contrary to the asynchronous discrete coding model, these results suggest that the perceptual system may transmit to the response system information that only partially specifies a single stimulus attribute. In combination with previous findings, these results also suggest that there are at least two dissociable forms of selective preparation for a given response.


High-performance liquid chromatographic resolution of synthetic opiate and "anti-opiate" peptides from human plasma.
An assay system using reversed-phase high-performance liquid chromatographic (HPLC) resolution of synthetic anti-opioid peptides (AOPs) and opioid peptides (OPs) was developed. Samples were diluted with trifluoroacetic acid, loaded onto Sep-Pak C18 cartridges, eluted, dried, and redissolved in ethanol-acetic acid-water. Retention-time consistency was established, and high levels of synthetic AOP and OP recovery, generally higher than 80%, were achieved. In a single HPLC run synthetic enkephalins, dynorphins, and beta-endorphins were separated even when extracted from human plasma using a volatile mobile phase which yielded fractions totally compatible with quantitation by radioimmunoassay. Combining the resolution of HPLC with the sensitivity of radioimmunoassay (RIA) may facilitate simultaneous measurement of numerous neuropeptides in body fluids such as plasma and cerebrospinal fluid.


A novel method to calculate pressure on the twin-tunnel in layered strata.
Tunnel pressure from the surrounding rocks plays a critical role for the safety of tunnel. The existing methods for calculate twin-tunnel pressure supposed that the tunnel is buried in a uniform soil layer. This work presents detailed equations of an analytical method to calculate the twin-tunnel pressure in layered strata, which can consider the effects from soil layers. The proposed method is applied to analyse the pressure of the metro twin-tunnels in Chongqing. To demonstrate the efficiency of the proposed analytical method, both the tunnel pressure in layered strata and single strata were calculated. The method article is a companion paper with the original article [1]. • Analyses of the soil parameters; • Determine the failure pattern A/B; • Calculate the vertical and horizontal pressure.


Intimate partner violence resource materials: assessment of information distribution.
To determine the educational impact of placing partner violence resource information in a medical setting. A cross-sectional study with a structured interview. Emergency department (ED) in an urban academic medical center. adult patients and visitors. Educational materials and community resource information. 51 patients and 71 visitors (N = 122) met the inclusion criteria and consented to enrollment during a 2-week study period. Of the participants, 71% were female and 29% were male. Sixty-five (53%) of the participants noticed the literature or cards. Ten (8%) read the materials. Seven (6%) retained a copy of the literature. Nineteen (16%) of the participants acknowledged knowing someone who could benefit from the information. Nine (7%) revealed that some of the information was new to them. Placing intimate partner violence resource pamphlets and cards in a medical setting is one means of educating the community and promoting violence prevention.


Immunosuppression in murine malaria. II. The primary response to bovine serum albumin.
The primary antibody response to alumadsorbed bovine serum albumin was depressed in CBA mice infected with Plasmodium yoelii yoelii. Responses initiated within approximately 3 weeks of this malaria infection were reduced in quantity, but not in avidity. Responses initated later were normal. A depressed primary response was also seen in infected compared to control splenectomized mice; this was accompanied by impaired priming for a secondary response.


The immune response is affected for at least three weeks after extensive surgery for ovarian cancer.
The treatment of women with ovarian cancer in advanced stages consists of extensive surgery followed by chemotherapy initiated three weeks after surgery. In this study, selected immune parameters were investigated to elucidate when the immune system is normalised following the operation. Ten women undergoing extensive surgery for ovarian cancer were compared with a control group of ten women undergoing abdominal hysterectomy for a benign diagnosis. Blood samples were collected over a period of 21 days post-operatively. The levels of interleukin-6, interleukin-8, interleukin-10 and the activity and total frequency of natural killer cells were measured. Interleukin-6 and interleukin-10 were significantly elevated immediately after the operation and also after 21 days. The total population of natural killercells and the total activity were reduced. The total activity of natural killer-cells did not normalise within 21 days. The level of the cytokines interleukin-6 and interleukin-10 is increased 21 days after the operation, and the function of natural killer cells is not normalised at 21 days after surgery. The study received funding from Odense University Hospital Free Research Fund. not relevant.


Burning Mouth Syndrome.
Burning mouth syndrome (BMS) is a rare chronic neuropathic pain condition characterized by recurring burning pain or dysesthesia in the absence of any local or systemic causes of symptoms. The exact pathophysiology of BMS is unknown, but recent research suggests a medley of neuropathic, endocrinological, and psychosocial elements. This article presents a case history and reviews the epidemiology, diagnostic criteria, clinical features, diagnostic investigations, pathophysiology, and management of BMS.


Assessment of GP management of symptoms of dying patients in an Australian community hospice by chart audit.
With specialist palliative care services becoming widespread, and the place of the GP in palliative care being examined, audit of patient care delivered by GPs is required in order to ensure adequate standards of care. We aimed to evaluate symptomatic care delivered to palliative care patients by GPs in an Australian community hospice with a developed quality assurance programme. The study was set in a newly established community-based, GP-run hospice in a provincial city in Queensland, Australia. A chart audit was carried out of the first 20 patients admitted to a community-based hospice, in order to establish (i) whether attempts were made by the treating doctor to find the direct cause of symptoms before initiating management; and (ii) whether management accorded with developed consensus-based guidelines. Twenty patients were treated by 14 GPs; 135 new symptoms were identified in the records of these patients. Of the 125 symptoms for which guidelines could be identified in the literature, in 87 (70%) an attempt by the treating GP to find a direct cause could be demonstrated. Of the 114 symptoms with treatments defined in the guidelines, 107 (90%) treatments conformed to the guidelines. Constipation, nausea/vomiting, anorexia and back pain were the conditions for which there were the fewest attempts at establishing a direct cause before treatment. In most cases these conditions were treated in accordance with the guidelines. Quality assurance mechanisms present in an in-patient palliative care setting appear to be associated with high-quality care by GPs.


Experimental evaluation on the influence of autoclave sterilization on the cyclic fatigue of new nickel-titanium rotary instruments.
The purpose of this study was to evaluate the effect of autoclave sterilization on cyclic fatigue resistance of rotary endodontic instruments made of traditional and new nickel-titanium (NiTi) alloys. Four NiTi rotary endodontic instruments of the same size (tip diameter 0.40 mm and constant .04 taper) were selected: K3, Mtwo, Vortex, and K3 XF prototypes. Each group was then divided into 2 subgroups, unsterilized instruments and sterilized instruments. The sterilized instruments were subjected to 10 cycles of autoclave sterilization. Twelve files from each different subgroup were tested for cyclic fatigue resistance. Means and standard deviations of number of cycles to failure (NCF) and fragment length of the fractured tip were calculated for each group, and data were statistically analyzed (P < .05). Comparing the results between unsterilized and sterilized instruments for each type of file, differences were statistically significant (P < .05) only between sterilized and unsterilized K3XF files (762 versus 651 NCF). The other instruments did not show significant differences (P > .05) in the mean NCF as a result of sterilization cycles (K3, 424 versus 439 NCF; Mtwo, 409 versus 419 NCF; Vortex, 454 versus 480 NCF). Comparing the results among the different groups, K3 XF (either sterilized or not) showed a mean NCF significantly higher than all other files (P < .05). Repeated cycles of autoclave sterilization do not seem to influence the mechanical properties of NiTi endodontic instruments except for the K3 XF prototypes of rotary instruments that demonstrated a significant increase of cyclic fatigue resistance.


Association between atherosclerosis and gastric biomarkers concerning Helicobacter pylori infection in a Chinese healthy population.
Studies have suggested that Helicobacter pylori (Hp) infection is associated with atherosclerotic process, while the relationship between pepsinogens, gastrin and atherosclerosis is unknown. The aim of the study was to observe association of Hp infection on atherosclerotic parameters and blood pressure, and explore the relationship between atherosclerotic parameters, blood pressure and gastric biomarkers in a healthy population. 395 subjects were chosen and received physical examinations, carotid artery ultrasound, peripheral atherosclerosis measurement, and testing of serum pepsinogen (PG) I and II, Hp antibody, and gastrin-17 (G-17) levels. Analyses were conducted by Student's t-test, ANOVA, Pearson correlation, multiple linear regression and binary logistic regression. In Hp-infected subjects, right carotid intima media thickness (R-CIMT) were higher (P = 0.027) and left ankle brachial index were higher in 45-64 years compared to 35-44 years group (P = 0.039, P = 0.016). Hp-IgG, PGI and G-17 respectively positively correlated with CIMT, pulse wave velocity and systolic blood pressure (P = 0.044, P = 0.013, P = 0.021). The unadjusted OR in subjects with elevated CIMT for quartile IV of PGI was 3.542 (95% CI, 1.491-8.411), the adjusted OR was 2.916 (95% CI, 1.035-8.216). The unadjusted OR in subjects with elevated CIMT for quartile III of G-17 was 4.351 (95% CI, 1.670-11.336) and for quartile IV was 3.108 (95% CI, 1.149-8.406), the adjusted OR for quartile III was 4.962 (95% CI, 1.515-16.258). Hp infection, higher levels of PGI and G-17 may contribute to atherosclerotic process by influencing atherosclerotic parameters and blood pressure in a healthy population, the influence on CIMT was most significant.


Regional groundwater flow system characterization of volcanic aquifers in upper Awash using multiple approaches, central Ethiopia.
ABSTRACTCharacterization of the groundwater flow systems is important for sustainable water resource management decision-making. We have used vertical profiles of electrical conductivity (EC) and water temperature taken at 2 m intervals during drilling of 109 boreholes, and samples for stable isotope analysis (δ18O, δ2H) taken from 47 boreholes to characterize groundwater recharge, flow and discharge. 222Rn measurements and piezometric evidence were used to complement results from the EC and stable isotopes. The converging evidence shows that groundwater in the study area is characterized by a mix of two different groundwater flow systems: i) the deep groundwater systems are connected to the regional groundwater flow originating from the highlands, outside the surface water basin, ii) the shallow groundwater systems get recharge from local rains. The local recharge zones are located in highly urbanized and industrialized zones posing risk to recharge reduction and pollution. Therefore, attention should be given to protect groundwater resources from contamination and increase groundwater resilience to climate change.


Preclinical PET imaging study of lung cancer with 64CuCl2.
Human copper transporter 1 (CTR1) has been proven to be overexpressed in many types of cancer cells, and copper (II)-64 chloride (64CuCl2) has been used as an effective tracer for positron emission tomography (PET) imaging in tumor-bearing animal models. Thus, this study aimed to investigate the potential application of 64CuCl2 in PET imaging of lung cancer through targeting CTR1. The expression of CTR1 in a series of lung cancer cell lines was identified by quantitative real-time polymerase chain reaction (Q-PCR), western blot, enzyme-linked immunosorbnent assay (ELISA), and immunofluorescent staining. Then in vitro cell uptake assay of 64CuCl2 was investigated in human lung cancer cell lines with different levels of CTR1 expression. Small animal PET imaging and quantitative analysis were performed in human lung cancer tumor-bearing mice after intravenous injection of 64CuCl2, respectively. The CTR1 expression in multiple human lung cancer cells was identified and confirmed, and H1299 cell lines with high CTR1 expression, H460 with moderate CTR1, and H1703 with low CTR1 were selected for further experiments. In vitro cellular uptake assay displayed that the 64CuCl2 uptake by these three kinds of cells was positively correlated with their CTR1 expressed levels. The blocking experiments testified the specificity of 64CuCl2 to target CTR1. Moreover, small animal PET imaging and quantitative results showed that 64CuCl2 accumulation in H1299, H460, and H1703 tumor-bearing mice were consistent with CTR1 levels and cell uptake experiments. The expression of CTR1 in human lung cancer xenograft model could be successfully visualized by 64CuCl2 PET examination. With the expected growth of PET/CT examination to be an essential strategy in clinical lung cancer management, 64CuCl2 has the potential to be a promising PET imaging agent of lung cancer.


Caspase-1 has a critical role in blood-brain barrier injury and its inhibition contributes to multifaceted repair.
Excessive inflammation might activate and injure the blood-brain barrier (BBB), a common feature of many central nervous system (CNS) disorders. We previously developed an in vitro BBB injury model in which the organophosphate paraoxon (PX) affects the BBB endothelium by attenuating junctional protein expression leading to weakened barrier integrity. The objective of this study was to investigate the inflammatory cellular response at the BBB to elucidate critical pathways that might lead to effective treatment in CNS pathologies in which the BBB is compromised. We hypothesized that caspase-1, a core component of the inflammasome complex, might have important role in BBB function since accumulating evidence indicates its involvement in brain inflammation and pathophysiology. An in vitro human BBB model was employed to investigate BBB functions related to inflammation, primarily adhesion and transmigration of peripheral blood mononuclear cells (PBMCs). Caspase-1 pathway was studied by measurements of its activation state and its role in PBMCs adhesion, transmigration, and BBB permeability were investigated using the specific caspase-1 inhibitor, VX-765. Expression level of adhesion and junctional molecules and the secretion of pro-inflammatory cytokines were measured in vitro and in vivo at the BBB endothelium after exposure to PX. The potential repair effect of blocking caspase-1 and downstream molecules was evaluated by immunocytochemistry, ELISA, and Nanostring technology. PX affected the BBB in vitro by elevating the expression of the adhesion molecules E-selectin and ICAM-1 leading to increased adhesion of PBMCs to endothelial monolayer, followed by elevated transendothelial-migration which was ICAM-1 and LFA-1 dependent. Blocking caspase-8 and 9 rescued the viability of the endothelial cells but not the elevated transmigration of PBMCs. Inhibition of caspase-1, on the other hand, robustly restored all of barrier insults tested including PBMCs adhesion and transmigration, permeability, and VE-cadherin protein levels. The in vitro inflammatory response induced by PX and the role of caspase-1 in BBB injury were corroborated in vivo in isolated blood vessels from hippocampi of mice exposed to PX and treated with VX-765. These results shed light on the important role of caspase-1 in BBB insult in general and specifically in the inflamed endothelium, and suggest therapeutic potential for various CNS disorders, by targeting caspase-1 in the injured BBB.


Velopharyngeal insufficiency and secondary palatal management. A new look at an old problem.
The main objective of primary palatoplasty is to achieve adequate velopharyngeal (VP) function and normal oral-nasal resonance. Many children, however, who undergo cleft palate repair fail to develop normal VP function. Symptoms of velopharyngeal insufficiency (VPI), such as hypernasality and audible nasal air emission, may have a variety of causes, which underscores the need for comprehensive evaluation. This article focuses on the problem of VPI and emphasizes the need for differential diagnosis at the most critical step in management planning. The challenge of the future is to implement the team approach, integrating the expertise of speech scientists and plastic surgeons, so that differential diagnosis can and will lead to differential management.


The Role of NRF2/KEAP1 Pathway in Glioblastoma: Pharmacological Implications.
Glioblastoma multiforme (GBM) grade IV glioma is the most frequent and deadly intracranial cancer. This tumor is determined by unrestrained progression, uncontroled angiogenesis, high infiltration and weak response to treatment, which is chiefly because of abnormal signaling pathways in the tumor. A member related to the Cap 'n' collar family of keypart-leucine zipper transcription agents-the transcription factor NF-E2-related factor 2 (Nrf2)-regulates adaptive protection answers by organized upregulation of many genes that produce the cytoprotective factors. In reply to cellular pressures types such as stresses, Nrf2 escapes Kelch-like ECH-related protein 1 (Keap1)-facilitated suppression, moves from the cytoplasm towards the nucleus and performs upregulation of gene expression of antioxidant responsive element (ARE). Nrf2 function is related tocontrolling many types of diseases in the human specially GBM tumor.Thus, we will review the epigeneticalregulatory actions on the Nrf2/Keap1 signaling pathway and potential therapeutic options in GBM by aiming the stimulation of Nrf2.


Pincer nail deformity associated with systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is an autoimmune disorder with various systemic and cutaneous manifestations. Nail abnormalities, including onycholysis, red lunulae, pitting, and ridging, have been seen in patients with the disorder. To our knowledge, however, pincer nail deformity has yet to be reported coincident with the onset of SLE. We report a case of pincer nail deformity subsequent to the development of SLE and describe surgical treatment of the deformed nails. This is followed by a review of the literature. Acquired pincer nail is a dystrophy with numerous reported causative associations, including psoriasis, tumors of the nail apparatus, tinea ungium, ss-blocker usage, and now SLE. Pain from the resulting constriction can interfere greatly with daily activities and can be debilitating to the extent of requiring therapy.


[Bile salt induces apoptosis of hepatocytes: the mechanism of hepatic function injury during obstructive jaundice].
To determine if the bile salt induces hepatocyte apoptosis in vitro. Hepatocytes were isolated by in situ collagenase perfusion and plated in 6 well flat bottom with DMEM/F12, 0.5 micro/ml insulin. Two hours later, glycochenodeoxcholate (GCDC) 25, 50, 100, 200, 300 micromol was added and cells evaluated by DNA-PI staining FACS and terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) 3, 6, 9, 12, 18, 20, 24 hours later. Agarose gel electrophoresis of DNA extracted from hepatocytes after incubation with GCDC using various experimental conditions. The hepatocytes treated with GCDC have a high apoptotic rate as compared with the controls. 100 micromol GCDC treated 24 hours, nearly 61.81% of hepatocytes were apoptotic by FACS evaluation. The TUNEL showed that apoptotic hepatocytes had less cell volume and stained with brown by Biotin-11-dUTP. DNA ladder of bile-salt treated hepatocytes were shown in agarose gel electrophoresis. The mechanism of hepatic injury during obstructive jaundice is related to bile salt caused hepatocyte apoptosis.


Effects of tropospheric ozone on loblolly pine seedlings inoculated with root infecting ophiostomatoid fungi.
Seedlings from four loblolly pine (Pinus taeda L.) families were exposed in open-top chambers to charcoal-filtered air (CF), non-filtered air (NF) or air amended with ozone to 2 times ambient (2×). Two of the families used were selected for their tolerance to fungi associated with Southern Pine Decline while two were selected for their susceptibility. Seedlings were treated with five inoculation treatments: no wound (NW), wound only (W), wound + media (WM), Grosmannia huntii (GH) and Leptographium terebrantis (LT). After 118 days of exposure (AOT40 = 31 ppm-hr(-1) for 2× ozone) seedling volume, dry matter, chlorophyll content, water potential and lesions were measured and analyzed using ANOVA procedures. Our results indicate that seedlings selected for their susceptibility to root infecting ophiostomatoid fungi were also more sensitive to ozone. Overall lesion length was greater on seedlings exposed to elevated ozone concentrations but was not specific to either root infecting ophiostomatoid fungi.