Early life stress shapes female reproductive strategy through eggshell pigmentation in Japanese quail.
Physiological constraints on colouration have been widely reported; especially in birds, which trade-off antioxidant responses against colourful costly signals. One female extended phenotypic trait, which might also highlight important physiological trade-offs, is the pigmentation of their eggshells. In ground-nesting species, producing eggs that are visually undetectable by predators is the best camouflage strategy. However, the condition-dependence of eggshell pigmentation, and the pigments role in oxidative stress, may constrain females to trade-off between their antioxidant capacity and maximising the camouflage of their eggs when they deposit eggshell pigments. Developmental stress is one factor that influences female antioxidant capacity, and could lead to variations in eggshell pigmentation that might have crucial consequences on individual fitness if egg crypsis is compromised especially under stressful conditions. We investigated the interaction between developmental and breeding conditions with respect to eggshell pigmentation in Japanese quail. We studied 30 females that bred under both control and stressful conditions, and were exposed to pre- and/or post-natal stress, or neither. Pre- and post-natal stress independently influenced eggshell pigmentation strategies under stressful breeding conditions. Under stressful reproduction, eggshell protoporphyrin concentration and maculation were affected by pre-natal stress, whereas eggshell reflectance and biliverdin concentration were influenced by post-natal stress. These changes may reflect potential adaptive strategies shaped by developmental stress, but additional data on the benefit of egg crypsis in quail, combined with studies on the role of both pigments on chick survival, will help to clarify whether early life stress can enhance fitness through eggshell pigmentation when developmental and reproductive environments match.


Insights on the use of biosimilars in the treatment of inflammatory bowel disease.
Biologic therapy, such as those that target tumor necrosis factor (TNF) signaling, has proven to be an efficacious method of treatment for patients with inflammatory bowel disease (IBD) with regards to symptom management and mucosal healing. However, the rising prevalence of IBD worldwide and the ever-increasing burden of biologic pharmaceuticals in the health care industry is alarming for insurance companies, clinicians, and patients. The impending patent expiry and the relatively high costs of biologics, particularly anti-TNF agents, have paved the way for biosimilar development for IBD. The United States Food and Drug Administration defines a biosimilar as a biological product that is highly similar to its reference medicinal product, with no clinically meaningful differences in terms of safety, purity, and potency. The hope with biosimilars is that their entry into the market will be able to drive competition between pharmaceutical companies to reduce prices like that of the generic market, and that access to appropriate biologic treatments for IBD patients is increased in the long-term. Yet, there are challenging issues such as indication extrapolation and interchangeability that are still being debated in the field of IBD and must be addressed in future issued guidance. This review will discuss the issues and implications concerning the use of biosimilar therapy for IBD.


Heaping, secondary flows and broken symmetry in flows of elongated granular particles.
In this paper we report experiments where we shear granular rods in split-bottom geometries, and find that a significant heap of height of least 40% of the filling height can form at the particle surface. We show that heaping is caused by a significant secondary flow, absent for spherical particles. Flow reversal transiently reverses the secondary flow, leading to a quick collapse and slower regeneration of the heap. We present a symmetry argument and experimental data that show that the generation of the secondary flow is driven by a misalignment of the mean particle orientation with the streamlines of the flow. This general mechanism is expected to be important in all flows of sufficiently anisometric grains.


Trastuzumab increases the sensitivity of HER2-amplified human gastric cancer cells to oxaliplatin and cisplatin by affecting the expression of telomere-associated proteins.
HER2 amplification occurs in ~20% of gastric cancer (GC) cases; however, in gastric and gastroesophageal junction cancer with HER2 gene amplification, trastuzumab in combination with cisplatin (DDP)-based chemotherapy has been reported to improve the oncological outcome. The aim of the present study was to evaluate the combined antitumor efficacy of trastuzumab and various platinum agents in GC cells and to elucidate mechanisms that may be involved in the interaction between trastuzumab and the platinum agents. The in vitro chemosensitivity of the GC cells to platinum agents was evaluated using the CellTiter 96® AQueous One Solution Cell Proliferation Assay kit. Treatment with 1.0μg/ml trastuzumab for 48 h significantly increased the sensitivity of NCI-N87 cells with HER2 amplification to oxaliplatin (Oxa) and DDP. This chemosensitivity was most prominent in the NCI-N87 cells, in which the half maximal inhibitory concentration of Oxa and DDP was decreased to ~3.29 and 6.91 times, respectively. The apoptotic effect of the platinum agents was evaluated by double-staining the GC cells with Annexin V-fluorescein isothiocyanate and propodium iodide. Consistent with the chemosensitivity analysis, apoptotic analysis indicated that trastuzumab significantly increased Oxa- and DDP-induced apoptosis in the NCI-N87 cells. Furthermore, the mRNA expression levels of various telomere-associated genes was determined by performing quantitative reverse transcription-polymerase chain reactions in a number of GC cell lines, and revealed that trastuzumab (alone and in combination with DDP) may downregulate the mRNA expression levels of the TPP1, TRF1, TRF2, TRF2IP and POT1 genes. However, western blot analysis demonstrated that trastuzumab (alone and in combination with DDP) may significantly downregulate the protein expression levels of telomeric repeat binding factor 2, protection of telomere 1 and TPP1 (formerly known as TINT1, PTOP and PIP). The results of the present study indicate a potential role of low-dose trastuzumab administration for increasing Oxa and DDP sensitivity in HER2-amplified GC cells, possibly via the downregulation of telomere-associated gene expression.


Expression of placental leucine aminopeptidase is associated with a poor outcome in endometrial endometrioid adenocarcinoma.
Placental leucine aminopeptidase (P-LAP) is a cell surface aminopeptidase (oxytocinase). We cloned P-LAP cDNA and found a widespread tissue distribution of P-LAP. Since P-LAP can degrade several small peptide hormones such as oxytocin, this enzyme may affect many cellular functions of carcinoma cells as well as normal cells. This study investigated whether the expression of P-LAP correlates with clinicopathologic factors and prognosis in patients with endometrial endometrioid adenocarcinoma. Histologic sections of formalin-fixed, paraffin-embedded specimens from 99 primary endometrial carcinomas were stained for P-LAP using polyclonal P-LAP antibody. Disease-free survival and other clinicopathologic characteristics were analyzed according to the intensity of P-LAP staining. Of 99 cases, 69 (69.7%) showed specific P-LAP immunostaining. We found a positive correlation between the expression of P-LAP and histological grade (p < 0.01), surgical stage of the disease (p = 0.02), myometrial invasion (p = 0.01), lymph node involvement (p < 0.01), and vascular infiltration (p < 0.01). In patients who had strongly positive P-LAP staining, the disease-free interval was significantly lower than in patients who had negative or weakly positive P-LAP staining (p < 0.01). Multivariate analysis demonstrated that strongly immunoreactive P-LAP (odds ratio, 12.8; 95% confidence interval, 2.84-58.8; p < 0.01) and surgical stage (odds ratio, 8.78; 95% confidence interval, 2.77-27.8; p < 0.01) are independent prognostic factors. This study suggests P-LAP as an independent prognosticator of clinical outcome in patients with endometrial carcinoma. Therefore, assessment of the P-LAP status provides clinically useful prognostic information in patients with endometrial carcinoma.


DiOlistic labeling in fixed brain slices: phenotype, morphology, and dendritic spines.
Identifying neuronal morphology is a key component in understanding neuronal function. Several techniques have been developed to address this issue, including Golgi staining, electroporation of fluorescent dyes, and transfection of fluorescent constructs. Ballistic delivery of transgenic constructs has been a successful means of rapidly transfecting a nonbiased population of cells within tissue or culture. Recently, this technique was modified for the ballistic delivery of dye-coated gold or tungsten particles, enabling a nonbiased, rapid fluorescent membrane labeling of individual neurons in both fixed and nonfixed tissue. This unit outlines a step-by-step protocol for the ballistic method of dye delivery ("DiOlistic" labeling) to fixed tissue, including optimal tissue fixation conditions. In addition, a protocol for coupling "DiOlistic" labeling with other immunofluorescent methods is detailed, enabling the association of neuronal morphology with a specific cellular phenotype.


The altered DNA methylation pattern and its implications in liver cancer.
DNA methylation is the most intensively studied epigenetic phenomenon, disturbances of which result in changes in gene transcription, thus exerting drastic imparts onto biological behaviors of cancer. Both the global demethylation and the local hypermethylation have been widely reported in all types of tumors, providing both challenges and opportunities for a better understanding and eventually controlling of the malignance. However, we are still in the very early stage of information accumulation concerning the tumor associated changes in DNA methylation pattern. A number of excellent recent reviews have covered this issue in depth. Therefore, this review will summarize our recent data on DNA methylation profiling in cancers. Perspectives for the future direction in this dynamic and exciting field will also be given.


Adapted digital health literacy and health information seeking behavior among lower income groups in Malaysia during the COVID-19 pandemic.
Misinformation has had a negative impact upon the global COVID-19 vaccination program. High-income and middle-income earners typically have better access to technology and health facilities than those in lower-income groups. This creates a rich-poor divide in Digital Health Literacy (DHL), where low-income earners have low DHL resulting in higher COVID-19 vaccine hesitancy. Therefore, this cross-sectional study was undertaken to assess the impact of health information seeking behavior on digital health literacy related to COVID-19 among low-income earners in Selangor, Malaysia. A quantitative cross-sectional study was conducted conveniently among 381 individuals from the low-income group in Selangor, Malaysia. The remote data collection (RDC) method was used to gather data. Validated interviewer-rated questionnaires were used to collect data via phone call. Respondents included in the study were 18 years and older. A normality of numerical variables were assessed using Shapiro-Wilk test. Univariate analysis of all variables was performed, and results were presented as means, mean ranks, frequencies, and percentages. Mann-Whitney U test or Kruskal Wallis H test was applied for the comparison of DHL and health information seeking behavior with characteristics of the participants. Multivariate linear regression models were applied using DHL as dependent variable and health information seeking behavior as independent factors, adjusting for age, gender, marital status, educational status, employment status, and household income. The mean age of the study participants was 38.16 ± 14.40 years ranging from 18 to 84 years. The vast majority (94.6%) of participants stated that information seeking regarding COVID-19 was easy or very easy. Around 7 percent of the respondents cited reading information about COVID-19 on the internet as very difficult. The higher mean rank of DHL search, content, reliability, relevance, and privacy was found among participants who were widowed, had primary education, or unemployed. An inverse relationship was found between overall DHL and confidence in the accuracy of the information on the internet regarding COVID-19 (β = -2.01, 95% CI = -2.22 to -1.79). It is important to provide support to lower-income demographics to assist access to high-quality health information, including less educated, unemployed, and widowed populations. This can improve overall DHL.


How repetitive traumatic injury alters long-term brain function.
How recurrent traumatic brain injury (rTBI) alters brain function years after insult is largely unknown. This study aims to characterize the mechanistic cause for long-term brain deterioration following rTBI using a rat model. Eighteen Sprague-Dawley wild-type rats underwent bilateral rTBI using a direct skull impact device or sham treatment, once per week for 5 weeks, and were euthanized 56 weeks after the first injury. Weekly rotarod performance measured motor deficits. Beam walk and grip strength were also assessed. Brain tissue were stained and volume was computed using Stereo Investigator's Cavalieri Estimator. The L5 cortical layer proximal to the injury site was microdissected and submitted for sequencing with count analyzed using R "DESeq2" and "GOStats." Brain-derived neurotrophic factor (BDNF) levels were determined using enzyme-linked immunosorbent assay. Rotarod data demonstrated permanent deficits 1 year after rTBI. Decreased beam walk performance and grip strength was noted among rTBI rodents. Recurrent traumatic brain injury led to thinner cortex and thinner corpus callosum, enlarged ventricles, and differential expression of 72 genes (25 upregulated, 47 downregulated) including dysregulation of those associated with TBI (BDNF, NR4A1/2/3, Arc, and Egr) and downregulation in pathways associated with neuroprotection and neuroplasticity. Over the course of the study, BDNF levels decreased in both rTBI and sham rodents, and at each time point, the decrease in BDNF was more pronounced after rTBI. Recurrent traumatic brain injury causes significant long-term alteration in brain health leading to permanent motor deficits, cortical and corpus callosum thinning, and expansion of the lateral ventricles. Gene expression and BDNF analysis suggest a significant drop in pathways associated with neuroplasticity and neuroprotection. Although rTBI may not cause immediate neurological abnormalities, continued brain deterioration occurs after the initial trauma in part due to a decline in genes associated with neuroplasticity and neuroprotection.


Opioids and pituitary function: expert opinion.
Opioids are highly addictive potent analgesics and anti-allodynics whose use has dramatically increased in recent decades. The precipitous rise in opioid dependency and opioid use disorder is an important public health challenge given the risks for severely adverse health outcomes. The long-term opioid impact on hypothalamic-pituitary axes is particularly underappreciated among both endocrinologists and primary care physicians. We review the effects of opioids on hypothalamic-pituitary-target gland function and their implications for clinical practice. Experts in hypothalamic-pituitary disorders and opioid pharmacology reviewed recently published literature and considered strategies for diagnosing and managing these opioid-induced endocrine effects. Opioid suppression of hypothalamic-pituitary axes can lead to hypogonadotropic hypogonadism, central adrenal insufficiency, and hyperprolactinemia. These important clinical manifestations are often under-estimated, poorly evaluated, and typically either untreated or not optimally managed. Data on biochemical testing for diagnosis and on the effect of hormone replacement in these patients is limited and prospective randomized controlled studies for guiding clinical practice are lacking. Patients should be informed about risks for hypogonadism, adrenal insufficiency, and hyperprolactinemia, and encouraged to report associated symptoms. Based on currently available evidence, we recommend clinical and biochemical evaluation for potential central adrenal insufficiency, central hypogonadism, and/or hyperprolactinemia in patients chronically treated with opioids as well as the use of current expert guidelines for the diagnosis and treatment of these conditions.


[Influence of electroacupuncture intervention on hippocampal IL-1beta content and I kappa B kinase beta expression in focal cerebral ischemia/reperfusion rats].
To observe the effect of electroacupuncture (EA) of "Baihui" (GV 20) and left "Hegu" (LI 4)-"Taichong" (LR 3) on levels of hippocampal IL-1beta content and I kappa B kinase (IKK) beta protein in focal cerebral ischemia/reperfusion (CI/R) injury rats so as to reveal its mechanism underlying improvement of cerebral ischemia. One hundred and ninety-eight male SD rats were randomly divided into sham group (n = 54), model group (n = 72) and EA group (n = 72) which were further randomized into 12 h, 24 h and 48 h subgroups according to the duration of CI/R. The focal CI/R injury model was established by middle cerebral artery occlusion (MCAO) and reperfusion. EA (1 mA, 2 Hz/100 Hz) was applied to "Baihui" (GV 20) and the left "Hegu" (LI 4)-"Taichong" (LR 3) for 20 min, once every 12 h. The level of IL-1beta content in the right hippocampus tissue was detected by ELISA and the expression levels of hippocampal IKKbeta protein were detected by immunohistochemistry and Western blot, respectively. Compared with the 3 subgroups of the sham group, the levels of hippocampal IL-1beta contents at time-points of 12 h, 24 h and 48 h after MCAO were significantly increased in the model group (P < 0.01). In comparison with the model group, the contents of hippocampal IL-beta at the 3 corresponding time-points in the EA group were significantly reduced (P < 0.01). The expression levels of hippocampal IKKbeta protein at the 3 time-points after MCAO shown by immunohistochemistry and Western blot analysis were significantly higher in the model group than in the sham group (P < 0.05), and considerably lower in the EA group than in the model group (P < 0.05). EA of GV 20 and LI 4-LR 3 can obviously reduce CI/R injury induced increase of IL-1beta content and IKKbeta expression level in the hippocampus, which may be responsible for its effect in alleviating cerebral infarction by reducing inflammatory injury in the hippocampus.


Screening of radical scavengers in Scutellaria baicalensis using HPLC with diode array and chemiluminescence detection.
Scutellaria baicalensis Georgi is a well-known medical plant widely used as a famous traditional Chinese medicine. It has been reported that S. baicalensis can protect against oxidative stress and possess anti-inflammatory effect. In the present paper, an HPLC-diode array-chemiluminescence detection method for on-line detection was successfully developed to screen antioxidants in complex S. baicalensis extracts. Using the proposed approach, eight compounds in the S. baicalensis extracts were found to possess a potential antioxidant activity. Furthermore, the effects of purified compounds on protecting RAW 264.7 cells from hydrogen peroxide injury were also investigated in vitro to confirm the established method, which were consistent with the results of HPLC-diode array-chemiluminescence detection method. These results demonstrated that this method was a useful technique for rapidly screening and identifying bioactive components from complex herbal medicines.


Anion-templated synthesis of metallacages as a means for the colorimetric detection of chlorides.
In the presence of chloride or bromide in the appropriate mixture of solvents, 6 equiv of nickel(II) and 8 equiv of Hatu [Hatu=H2NC(=NH)NHC(=S)NH2] assemble to yield the metallacages [Ni6(atu)8X][ClO4]3 (atu=deprotonated form of Hatu; X=Cl, 5; Br, 6) where four "units" of the square-planar complex Ni(atu)2 are coordinated to two further nickel centers, forming an octahedral cage around an encapsulated chloride or bromide anion. Synthesis of the cages is highly dependent on the nature of the anions and the solvents used. In methanol, the cage only forms if chloride is present; in a mixture of acetone/methanol, the cage forms in the presence of either chloride or bromide. An interesting feature of the templation process is that there is a dramatic color change associated with assembly of the building blocks in the presence of the appropriate anion to yield the cages. This color change has been used as the basis for the colorimetric detection of chloride anions in methanol. The reaction of 4 equiv of nickel(II), 8 equiv of Hatu, and 2 equiv of platinum(II) has also been carried out, yielding the mixed-metal cage [Pt2Ni4(atu)8Cl][ClO4]3 (7a); the X-ray crystal structure of this compound is reported herein.


An Observational Study Quantifying the Disproportionate Impact of COVID-19 Among Immigrant Adults, 2021 California Health Interview Survey.
Substantial data on COVID-19-related morbidity and mortality among medically underserved populations are available, yet data on the social impact of the COVID-19 pandemic among immigrants in the United States are limited. We identified COVID-19-related health and social disparities among US immigrants. We analyzed predictors of COVID-19-related health and social outcomes (including ever had or thought had COVID-19, vaccine uptake, risk-reduction behaviors, job loss, childcare difficulties, and difficulty paying rent) during the pandemic by citizenship status, using data from the 2021 California Health Interview Survey. The overall sample size included 24 453 US-born citizens, naturalized citizens, and noncitizens aged ≥18 years. We examined relationships between sociodemographic variables, including immigration-related factors, and COVID-19-related health and social outcomes using descriptive, bivariate, and multivariate logistic regression analysis. When accounting for sociodemographic characteristics, noncitizens had higher odds than naturalized and US-born citizens of experiencing challenges during the COVID-19 pandemic, including difficulty paying rent (adjusted odds ratio [aOR] = 1.54; 95% CI, 1.47-2.42) and job loss (aOR = 1.43; 95%, CI, 1.14-1.79). At the bivariate level, noncitizens had the highest rate of ever had or thought had COVID-19 (24.7%) compared with US-born citizens (20.8%) and naturalized citizens (16.8%; all P < .001). Noncitizens also had a significantly higher likelihood of risk-reduction behaviors (eg, always wearing a face covering, getting vaccinated if available) than US-born citizens (P < .001). These findings reveal the disproportionate impact of the COVID-19 pandemic among noncitizens and reflect limited socioeconomic resources, limited access to health care, and precarious employment among noncitizens in California during the pandemic. Citizenship status should be considered a critical immigration-related factor when examining disparities among immigrant populations.


Reassortant rotaviruses containing structural proteins vp3 and vp7 from different parents induce antibodies protective against each parental serotype.
Genetic studies of reassortant rotaviruses have demonstrated that gene segments 4 and 9 each segregate with the serotype-specific neutralization phenotype in vitro. Reassortant rotaviruses derived by coinfection of MA-104 cells with the simian strain SA11 and the antigenically distinct bovine strain NCDV were used to determine which viral genes coded for proteins which induced a protective immune response in vivo. In addition, reassortant rotaviruses containing only the gene segment 4 or 9 protein products (vp3 and vp7, respectively) from SA11 or NCDV were used to determine the serotypic specificities of both vp3 and vp7 in several mammalian rotavirus strains. vp3 and vp7 from the murine strain Eb were shown to be indistinguishable from the corresponding proteins from strain SA11. Adult mice orally inoculated with strain Eb developed neutralizing antibodies to both vp3 and vp7. The two naturally occurring bovine rotavirus strains NCDV and UK were shown to contain antigenically similar vp7 but distinct vp3 proteins. Mouse dams orally immunized with a reassortant virus containing only gene 9 from NCDV passively protected their progeny against UK challenge, whereas mouse dams orally immunized with a reassortant virus containing only gene 4 from NCDV did not. Finally, we constructed reassortant viruses that immunized against rotaviruses of two distinct serotypes. SA11 X NCDV reassortants that contained vp3 and vp7 from different parents induced a protective immune response against both parental serotypes. vp3 and vp7 were independently capable of inducing a protective immune response after oral immunization. An understanding of the serotypic specificities of both vp3 and vp7 of human rotavirus isolates will be necessary for the development of successful strategies to protect infants against severe rotavirus infections.


Combining SPECT and Quantitative EEG Analysis for the Automated Differential Diagnosis of Disorders with Amnestic Symptoms.
Single photon emission computed tomography (SPECT) and Electroencephalography (EEG) have become established tools in routine diagnostics of dementia. We aimed to increase the diagnostic power by combining quantitative markers from SPECT and EEG for differential diagnosis of disorders with amnestic symptoms. We hypothesize that the combination of SPECT with measures of interaction (connectivity) in the EEG yields higher diagnostic accuracy than the single modalities. We examined 39 patients with Alzheimer's dementia (AD), 69 patients with depressive cognitive impairment (DCI), 71 patients with amnestic mild cognitive impairment (aMCI), and 41 patients with amnestic subjective cognitive complaints (aSCC). We calculated 14 measures of interaction from a standard clinical EEG-recording and derived graph-theoretic network measures. From regional brain perfusion measured by 99mTc-hexamethyl-propylene-aminoxime (HMPAO)-SPECT in 46 regions, we calculated relative cerebral perfusion in these patients. Patient groups were classified pairwise with a linear support vector machine. Classification was conducted separately for each biomarker, and then again for each EEG- biomarker combined with SPECT. Combination of SPECT with EEG-biomarkers outperformed single use of SPECT or EEG when classifying aSCC vs. AD (90%), aMCI vs. AD (70%), and AD vs. DCI (100%), while a selection of EEG measures performed best when classifying aSCC vs. aMCI (82%) and aMCI vs. DCI (90%). Only the contrast between aSCC and DCI did not result in above-chance classification accuracy (60%). In general, accuracies were higher when measures of interaction (i.e., connectivity measures) were applied directly than when graph-theoretical measures were derived. We suggest that quantitative analysis of EEG and machine-learning techniques can support differentiating AD, aMCI, aSCC, and DCC, especially when being combined with imaging methods such as SPECT. Quantitative analysis of EEG connectivity could become an integral part for early differential diagnosis of cognitive impairment.


Modulation of progesterone receptor binding to progesterone response elements by positioned nucleosomes.
In cells, steroid hormone receptors interact with target enhancer elements on nucleosomes to regulate transcription of genes. To elucidate how nucleosomes can potentially regulate the interactions of steroid receptors with steroid response elements, we have examined the effects of nucleosome positioning and histone source on the binding of the progesterone receptor to DNA elements on nucleosomes reconstituted in vitro. We find that the affinity of the receptor for its response element is dependent on the position of the element within the nucleosome, but not on the histone source, active or inactive chromatin. Our results suggest that the strength of DNA-histone interactions within the nucleosome modulates the binding of progesterone receptor to response elements. Thus, nucleosome positioning is likely to influence the function of steroid receptors in vivo.


[Morphologic features of the gastric mucosa in systemic lupus erythematosus and antiphospholipid syndrome].
Morphology of gastric mucosa is characterized in the presence of Helicobacter pylori (HP) and Herpes viruses (HSV-1 and CMV). A total of 85 patients were examined (20 patients with primary APS and 65 with SLE). Chronic active gastritis was revealed in 85% patients with APS and 96% with SLE. 60% patients with APS and 45% with SLE had mucosal erosions. HP was detected in 70-87% of cases. Mixed infection of the gastric mucosa was observed in all the groups which was significantly associated with increased fibroblast and plasma cell number in the tunica propria. Tissue eosinophilia of the antral part of the stomach was observed in 39% of SLE patients. Glucocorticoid therapy was not associated with erosions and was combined with vascular thrombosis of gastric mucosa.


Classification of THz pulse signals using two-dimensional cross-correlation feature extraction and non-linear classifiers.
This work provides a performance comparison of four different machine learning classifiers: multinomial logistic regression with ridge estimators (MLR) classifier, k-nearest neighbours (KNN), support vector machine (SVM) and naïve Bayes (NB) as applied to terahertz (THz) transient time domain sequences associated with pixelated images of different powder samples. The six substances considered, although have similar optical properties, their complex insertion loss at the THz part of the spectrum is significantly different because of differences in both their frequency dependent THz extinction coefficient as well as differences in their refractive index and scattering properties. As scattering can be unquantifiable in many spectroscopic experiments, classification solely on differences in complex insertion loss can be inconclusive. The problem is addressed using two-dimensional (2-D) cross-correlations between background and sample interferograms, these ensure good noise suppression of the datasets and provide a range of statistical features that are subsequently used as inputs to the above classifiers. A cross-validation procedure is adopted to assess the performance of the classifiers. Firstly the measurements related to samples that had thicknesses of 2mm were classified, then samples at thicknesses of 4mm, and after that 3mm were classified and the success rate and consistency of each classifier was recorded. In addition, mixtures having thicknesses of 2 and 4mm as well as mixtures of 2, 3 and 4mm were presented simultaneously to all classifiers. This approach provided further cross-validation of the classification consistency of each algorithm. The results confirm the superiority in classification accuracy and robustness of the MLR (least accuracy 88.24%) and KNN (least accuracy 90.19%) algorithms which consistently outperformed the SVM (least accuracy 74.51%) and NB (least accuracy 56.86%) classifiers for the same number of feature vectors across all studies. The work establishes a general methodology for assessing the performance of other hyperspectral dataset classifiers on the basis of 2-D cross-correlations in far-infrared spectroscopy or other parts of the electromagnetic spectrum. It also advances the wider proliferation of automated THz imaging systems across new application areas e.g., biomedical imaging, industrial processing and quality control where interpretation of hyperspectral images is still under development.


Assessment of weight loss, food intake, fat metabolism, malabsorption, and treatment of pancreatic insufficiency in pancreatic cancer.
In 12 patients with biopsy-proven pancreatic ductal adenocarcinoma, the following were determined: (1) whether decreased food intake, malabsorption, or altered fat metabolism were associated with weight loss; (2) the effect of pancreatic extract as treatment for malabsorption; and (3) the accuracy of the triolein breath test for detection of steatorrhea. Weight loss occurred in 11 patients and only in patients who had either malabsorption (n = 5), low coefficients of caloric consumption (n = 2), or both (n = 4). Nine patients had fat malabsorption, six had protein malabsorption, and caloric consumption was decreased in seven patients. Metabolism of oleic acid was significantly decreased (P less than 0.01) compared to normal subjects and correlated with basal metabolic rates (r = 0.6; P less than 0.05) which were within the range of normal values for age and sex. Body weight loss correlated only with coefficients of fat and protein absorption (r = 0.59; P less than 0.05). Treatment of patients with pancreatic extract resulted in significant improvement in absorption in those with moderate to severe fat or protein malabsorption (coefficient of absorption less than 80%) but no significant improvement occurred in patients with mild fat or protein malabsorption. The triolein breath test was abnormal in all patients with fat malabsorption and predicted improvement of fat absorption in five of six patients with steatorrhea who were treated with pancreatic extract. Thus, in pancreatic cancer, weight loss is associated with malabsorption; exogenous pancreatic extract significantly improves moderate to severe fat or protein malabsorption, and the triolein breath test detects fat malabsorption and predicts the treatment response to pancreatic extract.


Angiotensin-converting enzyme in skeletal muscle: sentinel of blood pressure control and glucose homeostasis.
Recent evidence suggests a coordinated regulation by the local renin-angiotensin system (RAS) and tissue kallikrein-kinin system (TKKS) of blood flow and substrate supply in oxidative red myofibres of skeletal muscle tissue during endurance exercise. The performance of these myofibres is dependent on the increased oxidation of substrates facilitated by augmenting nutritive blood flow and glucose uptake. Humoral factors released by the contracting fibres, such as adenosine and kinins, are suggested to be responsible for this metabolic adjustment. The considerable drain of blood volume and the enormous consumption of glucose during endurance exercise require a control mechanism for the maintenance of blood pressure (BP) and glucose homeostasis. This is achieved by the sympathetic nervous system and its subordinate RAS, which is located in the nutritive vessels and parenchyma of the red myofibres. The angiotensin-converting enzyme (ACE) is the primary enzyme responsible for kinin degradation during exercise, underscoring the important interrelationship between the RAS and the TKKS in the critical role of kinins in the multifactorial regulation of muscle bioenergetics and glucose and BP homeostasis. Importantly, overactivity of the ACE, as occurs in individuals displaying risk factors such as overweight, causes exaggerated BP response and reduced glucose disposal. If they persist over years, compensatory responses to this ACE overactivity, such as hypersecretion of insulin and compliance of the vessel walls, will inevitably be exhausted, leading ultimately to the manifestation of type 2 diabetes and hypertension. This concept also provides a unifying explanation for the beneficial effects of ACE-inhibitors and Angiotensin II receptor antagonists in the treatment of hypertension and insulin resistance.


Study of key RNA metabolism proteins in Enterococcus faecalis.
The control of mRNA turnover is essential in bacteria to allow rapid adaptation, especially in opportunistic pathogen like Enterococcus faecalis. This mechanism involves RNase and DEAD-box helicases that are key elements in RNA processing and their associations form the degradosome with accessory proteins. In this study, we investigated the function of four RNases (J1, J2, Y and III) and three DEAD-box helicases (CshA, CshB, CshC) present in most Enterococci. The interactions of all these RNA metabolism actors were investigated in vitro, and the results are in accordance with a degradosome structure close to the one of Bacillus subtilis. At the physiological level, we showed that RNase J1 is essential, whereas RNases J2 and III have a role in cold, oxidative and bile salts stress response, and RNase Y in general fitness. Furthermore, RNases J2, Y and III mutants are affected in virulence in the Galleria mellonella infection model. Concerning DEAD-box helicases, all of them are involved in cold shock response. Since the ΔcshA mutant was the most stress impacted strain, we studied this DEAD-box helicase CshA in more detail. This showed that CshA autoregulates its own expression by binding to its mRNA 5'Unstranslated Region. Interestingly, CshC is also involved in the expression control of CshA by a hitherto unprecedented mechanism.


Alcohol and pregnenolone interaction on cerebral arteries through targeting of vascular smooth muscle Ca2+- and voltage-gated K+ channels of big conductance.
Despite the significant number of people who may be taking pregnenolone supplements while drinking alcohol (ethanol), the widely documented cerebrovascular actions of pregnenolone and ethanol, and the critical dependence of cerebrovascular function on cerebral artery diameter, there are no studies addressing the effect of pregnenolone + ethanol in combination on cerebral artery diameter. We investigated this by evaluating the effect of this combination on middle cerebral artery diameter in male and female C57BL/6J mice, both in vivo and in vitro. The use of de-endothelialized, in vitro pressurized middle cerebral artery segments allowed us to conduct a concentration-response study of constriction induced by pregnenolone ± ethanol, in which drug action could be evaluated independently of circulating and endothelial factors. In both male and female animals, pregnenolone at lower concentrations (≤1 μM) was found to synergize with 50 mM ethanol to cause vasoconstriction. In both sexes, this synergism was lost as one or both vasoconstrictors approached their maximally effective concentrations (75 mM and 10 μM for ethanol and pregnenolone, respectively), whether this was evaluated in vitro or in vivo using a cranial window. Vasoconstriction by pregnenolone + ethanol was abolished by 1 μM paxilline, indicating BK channel involvement. Moreover, cell-free recordings of BK channel activity in cerebral artery myocyte membranes showed that 10 μM pregnenolone and pregnenolone +50 mM ethanol reduced channel activity to an identical extent, suggesting that these drugs inhibit cerebrovascular BK channels via a common mechanism or mechanisms. Indeed, pregnenolone was found to disrupt allosteric coupling to Ca2+-driven gating, as previously reported for ethanol.


A Biochemical and Pharmacological Characterization of Phospholipase A2 and Metalloproteinase Fractions from Eastern Russell's Viper (Daboia siamensis) Venom: Two Major Components Associated with Acute Kidney Injury.
Acute kidney injury (AKI) following Eastern Russell's viper (Daboia siamensis) envenoming is a significant symptom in systemically envenomed victims. A number of venom components have been identified as causing the nephrotoxicity which leads to AKI. However, the precise mechanism of nephrotoxicity caused by these toxins is still unclear. In the present study, we purified two proteins from D. siamensis venom, namely RvPLA2 and RvMP. Protein identification using LCMS/MS confirmed the identity of RvPLA2 to be snake venom phospholipase A2 (SVPLA2) from Thai D. siamensis venom, whereas RvMP exhibited the presence of a factor X activator with two subunits. In vitro and in vivo pharmacological studies demonstrated myotoxicity and histopathological changes of kidney, heart, and spleen. RvPLA2 (3-10 µg/mL) caused inhibition of direct twitches of the chick biventer cervicis muscle preparation. After administration of RvPLA2 or RvMP (300 µg/kg, i.p.) for 24 h, diffuse glomerular congestion and tubular injury with minor loss of brush border were detected in envenomed mice. RvPLA2 and RvMP (300 µg/kg; i.p.) also induced congestion and tissue inflammation of heart muscle as well as diffuse congestion of mouse spleen. This study showed the significant roles of PLA2 and SVMP in snake bite envenoming caused by Thai D. siamensis and their similarities with observed clinical manifestations in envenomed victims. This study also indicated that there is a need to reevaluate the current treatment strategies for Thai D. siamensis envenoming, given the potential for irreversible nephrotoxicity.


Clustering of colorectal neoplasia: characteristics of coexisting adenomas in patients with severely dysplastic polyps or invasive (malignant) polyps as compared to patients with benign adenomas or carcinomas.
This study compared the size, histology and morphology of coexisting neoplastic polyps found in colonoscopy, and evaluated the clustering of these polyps in patients with either colorectal carcinoma, cancerous polyps or benign adenomas. Patients were divided by their most malignant form of neoplasia: Group A included 58 patients with early invasive cancerous polyps, and Group B included 73 patients with in situ carcinoma within an adenoma. Group C consisted of 335 patients with benign adenomas, and Group D had 289 patients with colorectal carcinoma. There were no significant differences between the four groups regarding sex, age and ethnicity. The cancerous polyps were significantly larger than the benign polyps. There were significantly (P less than 0.01) more patients with multiple (greater than or equal to 5) colonic lesions in Groups A or B than in Groups C or D. Coexisting polyps were much closer to the index growth, and demonstrated more severe dysplastic changes in the case of cancerous polyps than those associated with benign polyps or cancer. Based on our data we speculate that cancerous polyps are not merely a middle link in adenoma-carcinoma sequence, but rather mark a subset of patients who are especially prone to develop neoplastic changes in their colonic mucosa. These patients should be included in a more strict colonoscopic surveillance programme.


Molecular Composition of Anthropogenic Oxygenated Organic Molecules and Their Contribution to Organic Aerosol in a Coastal City.
Organic aerosols (OA) have gained attention as a substantial component of atmospheric aerosols owing to their impact on atmospheric visibility, climate, and human health. Although oxygenated organic molecules (OOMs) are essential contributors to OA formation, the sources, transformations, and fates of the OOMs are not fully understood. Herein, anthropogenic OOMs (AOOMs), anthropogenic volatile organic compounds (AVOCs), and OA were concurrently measured in Xiamen, a coastal city in southeastern China. Our results show that the AOOMs exhibited a high nitrogen content (76%) and a low oxidation degree. Strong photochemical processes of aromatic VOCs were the predominant sources of AOOMs. Also, NOx concentrations and the occurrence of multigeneration OH radical oxidations were the critical factors that might influence the formation of AOOMs. Finally, the newly developed aerosol dynamic model's results show that more than 35% of the OA mass growth rate is attributed to the gas-particle partitioning of AOOMs. Further sensitivity testing demonstrates that the contribution of AOOMs to OA growth is significantly enhanced during high-particulate-concentration periods, especially under low-temperature conditions. This study emphasizes the vital role of photochemically produced AOOMs derived from AVOCs in OA growth in a coastal urban atmosphere.


Laparoscopic and hand-assisted distal pancreatectomy.
With the increased use of CT, discovering incidental pancreatic lesions has become commonplace. Lesions in the distal pancreas lend themselves well to laparoscopic resection. We reviewed our experience with laparoscopic distal pancreatectomy. During the study period, 32 distal pancreatectomies were performed. There were 20 females. Mean patient age was 58.0 years (range, 23-83 years) and mean body mass index was 29.9 Kg/m2 (range, 19.9-44.7 Kg/m2). Technique was laparoscopic (25) or hand-assisted (seven) with one conversion in each group. The spleen was preserved in six patients (18.8%). Mean operative time overall was 238 minutes (range, 140-515 minutes); hand-assisted was 222 minutes and laparoscopic was 254 minutes. Estimated blood loss averaged 221 mL (range, 50-1800 mL). Mean tumor size was 2.7 cm (range, 0.6-7 cm). Tumor pathology was serous cystadenoma (10), neuroendocrine tumor (six), mucinous cystic neoplasm (four), intrapapillary mucinous neoplasm (four), adenocarcinoma (three), other (four), and solid pseudopapillary neoplasm (one). Mean length of stay was 5 days (range, 3-11 days). Complications were pancreatic fistula (six), wound infection (two), pulmonary embolism (one), pancreatitis (one), myocardial infarction (one), postoperative bleed from combined laparoscopic bilateral oophorectomy (one), and pancreatic stump staple line bleed requiring reoperation (one). There were no perioperative deaths. All pancreatic fistulas resolved with conservative management.


The socioeconomic impact of hearing loss in U.S. adults.
To evaluate the associations between hearing loss and educational attainment, income, and unemployment/underemployment in U.S. adults. National cross-sectional survey. Ambulatory examination centers. Adults aged 20 to 69 years who participated in the 1999 to 2002 cycles of the NHANES (National Health and Nutrition Examination Survey) audiometric evaluation and income questionnaire (N = 3,379). Pure-tone audiometry, with hearing loss defined by World Health Organization criteria of bilateral pure-tone average of more than 25 dB (0.5, 1, 2, 4 kHz). Low educational attainment, defined as not completing high school; low income, defined as family income less than $20,000 per year; and unemployment or underemployment, defined as not having a job or working less than 35 hours per week. Individuals with hearing loss had 3.21 times higher odds of low educational attainment (95% confidence interval [95% CI], 2.20-4.68) compared with normal-hearing individuals. Controlling for education, age, sex, and race, individuals with hearing loss had 1.58 times higher odds of low income (95% CI, 1.16-2.15) and 1.98 times higher odds of being unemployed or underemployed (95% CI, 1.38-2.85) compared with normal-hearing individuals. Hearing loss is associated with low educational attainment in U.S. adults. Even after controlling for education and important demographic factors, hearing loss is independently associated with economic hardship, including both low income and unemployment/underemployment. The societal impact of hearing loss is profound in this nationally representative study and should be further evaluated with longitudinal cohorts. Received institutional review board approval (National Center for Health Statistics Institutional Review Board Protocol no. 98-12).


[Hospital admission of nursing home patients considered but not carried out: role of the nursing home physician and the involved parties and various differences with realized hospital admissions].
The objective of the study was to establish in which way nursing home patients, for whom is refrained from hospitalization, differ from hospitalized nursing home patients. The question was also raised of how the decision to refrain from hospitalization is taken: which point of view and method the nursing home physician has, on which arguments decisions are based and which parties are involved and in which way. The design of the study was retrospective and descriptive. Data obtained from semi-structured interviews held in 1987 with 24 nursing home physicians on 45 situations were compared with registration data on 387 hospitalizations of patients from 30 nursing homes. In the non-hospitalized patients malignancies were relatively more frequent than in the hospitalized patients (29% versus 7%). The mean age of hospitalized patients was 78 and of non-hospitalized patients 80 years. The physical condition of non-hospitalized patients was more frequently judged as poor and the life expectancy as more limited. Already at an early stage nursing home physicians appeared to have a point of view, with which they determined the decision making procedure: in favour of (40%), opposing (35%) and in doubt of hospitalization (25%). In 'non-hospitalizations' there was much more involvement in decision making of family members and nurses, and less involvement of patients and medical specialists than in decisions to hospitalization. Non-medical arguments opposing hospitalization had slightly the upper hand above medical arguments. The decisive arguments opposing hospitalization were in the case of psychogeriatric patients more often of medical origin than in the case of somatic patients. The 'quality of live' mentioned arguments were of limited importance. The nursing home physician needs good communicative qualities in such decision making processes. He has to be skilled to judge competency of patients and, if needed, to balance in the right way the information of relatives, nurses, colleagues and specialists.


Pleural recurrence after transthoracic needle lung biopsy in stage I lung cancer: a systematic review and individual patient-level meta-analysis.
Conflicting results exist regarding whether preoperative transthoracic biopsy increases the risk of pleural recurrence in early lung cancer. We conducted a systematic, patient-level meta-analysis to evaluate the risk of pleural recurrence in stage I lung cancer after percutaneous transthoracic lung biopsy. A systematic search of OVID-MEDLINE, Embase and the Cochrane Database of Systematic Reviews was performed through October 2018. Eligible studies were original articles on the risk of pleural recurrence in stage I lung cancer after transthoracic biopsy. We contacted the corresponding authors of eligible studies to obtain individual patient-level data. We used the Fine-Gray model for time to recurrence and lung cancer-specific survival and a Cox proportional hazards model for overall survival. We analysed 2394 individual patient data from 6 out of 10 eligible studies. Compared with other diagnostic procedures, transthoracic biopsy was associated with a higher risk for ipsilateral pleural recurrence, which manifested solely (subdistribution HR (sHR), 2.58; 95% CI 1.15 to 5.78) and concomitantly with other metastases (sHR 1.99; 95% CI 1.14 to 3.48). In the analysis of secondary outcomes considering a significant interaction between diagnostic procedures and age groups, reductions of time to recurrence (sHR, 2.01; 95% CI 1.11 to 3.64), lung cancer-specific survival (sHR 2.53; 95% CI 1.06 to 6.05) and overall survival (HR 2.08; 95% CI 1.12 to 3.87) were observed in patients younger than 55 years, whereas such associations were not observed in other age groups. Preoperative transthoracic lung biopsy was associated with increased pleural recurrence in stage I lung cancer and reduced survival in patients younger than 55 years.


Descemet membrane endothelial keratoplasty (DMEK): intraoperative and postoperative complications and clinical results.
To evaluate the complications and clinical results of Descemet membrane endothelial keratoplasty (DMEK) in patients with endothelial failure that occurred during the learning curve of a surgeon. Fifty eyes of 50 patients with DMEK and ≥6 months of follow-up were included. The patients were divided into the first 25 (group 1) and the second 25 (group 2) procedures performed by the surgeon. Best corrected visual acuity (BCVA), central corneal thickness (CCT), unfolding time of the Descemet membrane (DM) graft, and intraoperative and postoperative complications were compared between groups. The differences in postoperative increase of BCVA (p=0.595) and decrease of CCT (p=0.725) in the two groups were not significant. The unfolding time of the DM was longer in group 1 than in group 2 (p=0.001). Primary graft failure occurred in three patients in group 1 and none in group 2. At the last visit, 42 (85.7%) of patients' corneas were clear, with significant difference between groups (p=0.584). A patient in group 1 with a history of pars plana vitrectomy, inferior iridectomy, and fluid as a tamponade experienced drop of the DM graft into the iridectomy space. All other intraoperative complications occurred in group 1. Occurrence of intraoperative and postoperative complications was increased in patients with coexisting ocular pathology or complicated endothelial dysfunction and during the surgeon's learning curve of DM endothelial keratoplasty procedures.


Polymyositis--a further investigation.
In essence, this paper describes the model-based interpretation of measurements in order to gain insight into physiological processes. The paper extends the mathematical model developed previously to control and monitor a polymyositis patient. The extension considers two further yet different types of muscle attack. The model is applied to simulate, first, the total serum creatine kinase levels, which then are matched to the observed values. The outcomes of this approach yield considerable information about the reactions taking place including various concentration levels over time such as prednisolone. The changes in the muscle attack are estimated. Examples illustrate how the model may be used to assess, for a single patient, the maximum reduction of the muscle attack whilst keeping the prednisolone concentration as low as possible. The model has been successfully used to interpret variations in daily heart rate measurements of a polymyositis patient. Consequently, it is shown how daily heart rate measurements may now be used to complement the control and monitoring of the polymyositis patient. The model is used to explore multi-patient statistics. It shows the dangers of using such an approach. The model illustrates the need for longitudinal studies.


Occupational exposure to cosmetic talc and mesothelioma in barbers, hairdressers, and cosmetologists: A systematic review of the epidemiology.
Inhalation exposure to cosmetic talc has generated much scientific debate regarding its potential as a risk factor for mesothelioma, a rare, but fatal cancer. Barbers, hairdressers, and cosmetologists have regularly used cosmetic talc-containing products, but the collective epidemiological evidence for mesothelioma in these occupations has yet to be described. As such, we conducted a systematic review of PubMed and the National Institute for Occupational Safety and Health's (NIOSH) Numbered Publications list to identify original epidemiological literature reporting measures of association between these occupations and incidence of or death from mesothelioma. Literature screening was performed independently twice, the results of which were summarized and tabulated and underwent a review for their accuracy. A total of 12 studies met our inclusion criteria, including three cohort, six case-control, and three proportionate mortality/registration studies. The data from these studies were collected in 13 European and North American countries, spanning more than 50 years. We supplemented this review with queries of occupational mortality databases that are managed by the Washington State Department of Health and NIOSH for 26 U.S. states. Most findings were null and if statistically significant, nearly all showed an inverse relationship, indicative of a protective effect of these occupations on mesothelioma risk. Overall, the epidemiological evidence does not support an increased risk of mesothelioma for these occupations. This research fills an important data gap on the etiology of mesothelioma in barbers, hairdressers, and cosmetologists, and provides a benchmark for those with comparatively less exposure, such as non-occupational users of similar cosmetic talc-containing products.


Bernauer's bands.
Ferdinand Bernauer proposed in his monograph, "Gedrillte" Kristalle (1929), that a great number of simple, crystalline substances grow from solution or from the melt as polycrystalline spherulites with helically twisting radii that give rise to distinct bull's-eye patterns of concentric optical bands between crossed polarizers. The idea that many common molecular crystals can be induced to grow as mesoscale helices is a remarkable proposition poorly grounded in theories of polycrystalline pattern formation. Recent reinvestigation of one of the systems Bernauer described revealed that rhythmic precipitation in the absence of helical twisting accounted for modulated optical properties [Gunn, E. et al. J. Am. Chem. Soc. 2006, 128, 14234-14235]. Herein, the Bernauer hypothesis is re-examined in detail for three substances described in "Gedrillte" Kristalle, potassium dichromate, hippuric acid, and tetraphenyl lead, using contemporary methods of analysis not available to Bernauer, including micro-focus X-ray diffraction, electron microscopy, and Mueller matrix imaging polarimetry. Potassium dichromate is shown to fall in the class of rhythmic precipitates of undistorted crystallites, while hippuric acid spherulites are well described as helical fibrils. Tetraphenyl lead spherulites grow by twisting and rhythmic precipitation. The behavior of tetraphenyl lead is likely typical of many substances in "Gedrillte" Kristalle. Rhythmic precipitation and helical twisting often coexist, complicating optical analyses and presenting Bernauer with difficulties in the characterization and classification of the objects of his interest.


Growth Differentiation Factor 15 Maturation Requires Proteolytic Cleavage by PCSK3, -5, and -6.
Growth differentiation factor 15 (GDF15) is a secreted protein with pleotropic functions from the transforming growth factor β (TGF-β) family. GDF15 is synthesized as a precursor and undergoes proteolytic cleavage to generate mature GDF15. The strong appetite-suppressing effect of mature GDF15 makes it an attractive therapeutic agent/target for diseases such as obesity and cachexia. In addition, clinical studies indicate that circulating, mature GDF15 is an independent biomarker for heart failure. We recently found that GDF15 functions as a heart-derived hormone that inhibits liver growth hormone signaling and postnatal body growth in the pediatric period. However, little is known about the mechanism of GDF15 maturation, in particular the enzymes that mediate GDF15 precursor cleavage. We investigated which candidate proteases can cleave GDF15 precursor and generate mature GDF15 in cardiomyocytes in vitro and mouse hearts in vivo We discovered that three members of the proprotein convertase, subtilisin/kexin-type (PCSK) family, namely, PCSK3, PCSK5, and PCSK6, can efficiently cleave GDF15 precursor, therefore licensing its maturation both in vitro and in vivo Our studies suggest that PCSK3, -5, and -6 mediate a crucial step of GDF15 maturation through proteolytic cleavage of the precursor. These results also reveal new targets for therapeutic application of GDF15 in treating obesity and cachexia.


Biophysical studies of lipopeptide-membrane interactions.
There are a number of naturally occurring motifs for lipidation of peptides and proteins. In cases in which this involves adding a single hydrocarbon chain to the peptide, it is either a fatty acid or an isoprenyl group. Lipopeptides will partition between membrane and aqueous phases. When only one hydrocarbon chain is attached to the peptide, the affinity of the lipopeptide for the membrane is only marginally increased over that of the free peptide. The resulting partitioning is largely determined by the extent of the interaction of the peptide moiety with the membrane. In contrast, lipidation involving two hydrocarbon chains, either as two single chains attached at distinct locations of the peptide or a double-chain lipid anchor, firmly attaches the lipopeptide to the membrane. This can allow the placement of specific binding sites on a membrane surface. Such a strategy can be used, for example, to place specific antibodies on the surface of drug-carrying liposomes for the purpose of targeting drug delivery. In addition, lipopeptides will alter the physical properties of membranes. One of these effects is to increase the bilayer to hexagonal phase transition temperature. Substances having this property may also alter functional properties of membranes. While it is unlikely that these changes in the biophysical properties of the membranes. While it is unlikely that these changes in the biophysical properties of the membrane are responsible for specific functions of lipopeptides, such changes may be used to modulate certain properties of a membrane, such as the rate of viral fusion.


Odf2-deficient mother centrioles lack distal/subdistal appendages and the ability to generate primary cilia.
Outer dense fibre 2 (Odf2; also known as cenexin) was initially identified as a main component of the sperm tail cytoskeleton, but was later shown to be a general scaffold protein that is specifically localized at the distal/subdistal appendages of mother centrioles. Here we show that Odf2 expression is suppressed in mouse F9 cells when both alleles of Odf2 genes are deleted. Unexpectedly, the cell cycle of Odf2(-/-) cells does not seem to be affected. Immunofluorescence and ultrathin-section electron microscopy reveals that in Odf2(-/-) cells, distal/subdistal appendages disappear from mother centrioles, making it difficult to distinguish mother from daughter centrioles. In Odf2(-/-) cells, however, the formation of primary cilia is completely suppressed, although approximately 25% of wild-type F9 cells are ciliated under the steady-state cell cycle. The loss of primary cilia in Odf2(-/-) F9 cells can be rescued by exogenous Odf2 expression. These findings indicate that Odf2 is indispensable for the formation of distal/subdistal appendages and the generation of primary cilia, but not for other cell-cycle-related centriolar functions.


[The influence of biliary diversion on canine gastric acid secretion and gut hormones].
The effect of biliary reconstruction on gastric acid secretion and gut hormones was studied. Canine models undergoing either surgical biliary diversion or jejunal exclusion were compared and the following results were obtained. The acid output from Heidenhain pouch after test meal loading remained in the same levels in the cholecystoduodenostomy (CD) group, the Thiry-Vella's fistula (TVF) group and the cholecystojejunostomy (CJ) group compared to the control group, while it decreased in the cholecystoileostomy group. The integrated gastrin response after test meal loading decreased in the CI group. The integrated total GLI response remained unchanged in the CD group and CJ group, but markedly elevated in the TVF group and CI group. The integrated GIP response decreased in the TVF group and no response was obtained in the CI group. The integrated GI response was almost the same in all groups. In conclusion, gut hormone secretion was found to be affected by jejunal exclusion and most strongly influenced by biliary diversion into the ileum. The present study also suggested that enteroglucagon had enterogastrone effect and that compensating mechanism existed among various gut hormones.


Effects of superparasitism on immature and adult stages of Diachasmimorpha longicaudata Ashmead (Hymenoptera: Braconidae) reared on Ceratitis capitata Wiedemann (Diptera: Tephritidae).
The optimal use of available host by parasitoid insects should be favoured by natural selection. For solitary parasitoids, superparasitism (i.e. the egg-laying of several eggs/host) may represent a detrimental phenomenon both in a biological and an applied sense, but under certain circumstances it may be adaptive. Here, we studied the effects of increasing levels of superparasitism (LSPs, number of parasitoid larvae/host) on fitness-related parameters of the immature and adult stages of Diachasmimorpha longicaudata, a solitary endoparasitoid parasitizing Ceratitis capitata. We investigated the moment when supernumerary parasitoid larvae are eliminated and the effects produced by this process, together with its repercussion on female fecundity, parasitism rate, sex ratio, adult survival, flight ability and body size. Complete elimination of competitors occurred soon after larval hatching, before reaching the second larval stage. Elimination process took longer at higher LSPs, although a normal developmental (egg-adult) time was achieved. For LSPs 1, 2, 3 and 5 the effects on parasitoid emergence were mild, but LSP 10 led to the death of all developing parasitoids. Aside from this, to develop in superparasitized hosts did not significantly affect any of the evaluated parameters, and only a female-biased sex ratio was observed at higher LSPs. However, the effects of superparasitism on the adults may have a different outcome under more variable conditions in the field, once they are released for biological control purposes.


[Benign or malignant thrombosis of the jugular vein? - Differentiation with colour-Doppler sonography].
Thrombosis can lead to physical impairment and cost-intensive investigations. In some cases, a thrombosis is caused by infiltration of an adjacent tumour. It is therefore important to differentiate between a benign or malignant thrombosis. We report the case of a woman with a malignant thrombosis of the jugular vein. She was hospitalised for suspected malignant disease of unknown origin. Her family doctor had made the diagnosis of a "partially organised thrombosis". At sonography, vessels with an arterial blood flow were detected in the thrombus. A carcinoma of the thyroid gland was therefore suspected and confirmed by histology. This case report demonstrates that the differentiation between a benign and malignant thrombosis is possible with colour-Doppler sonography.


Collagen COL22A1 maintains vascular stability and mutations in COL22A1 are potentially associated with intracranial aneurysms.
Collagen XXII (COL22A1) is a quantitatively minor collagen, which belongs to the family of fibril-associated collagens with interrupted triple helices. Its biological function has been poorly understood. Here, we used a genome-editing approach to generate a loss-of-function mutant in zebrafish col22a1 Homozygous mutant adults exhibit increased incidence of intracranial hemorrhages, which become more prominent with age and after cardiovascular stress. Homozygous col22a1 mutant embryos show higher sensitivity to cardiovascular stress and increased vascular permeability, resulting in a greater percentage of embryos with intracranial hemorrhages. Mutant embryos also exhibit dilations and irregular structure of cranial vessels. To test whether COL22A1 is associated with vascular disease in humans, we analyzed data from a previous study that performed whole-exome sequencing of 45 individuals from seven families with intracranial aneurysms. The rs142175725 single-nucleotide polymorphism was identified, which segregated with the phenotype in all four affected individuals in one of the families, and affects a highly conserved E736 residue in COL22A1 protein, resulting in E736D substitution. Overexpression of human wild-type COL22A1, but not the E736D variant, partially rescued the col22a1 loss-of-function mutant phenotype in zebrafish embryos. Our data further suggest that the E736D mutation interferes with COL22A1 protein secretion, potentially leading to endoplasmic reticulum stress. Altogether, these results argue that COL22A1 is required to maintain vascular integrity. These data further suggest that mutations in COL22A1 could be one of the risk factors for intracranial aneurysms in humans.


Membrane permeability to the molecular and ionic forms of DMO in barnacle muscle.
The time course of the intracellular pH (pHi) of barnacle muscle fibers was followed using microelectrodes while the fibers were exposed to 15 mM of the weak acid 5,5-dimethyloxazolidine-2,4-dione (DMO) at pH 6.5. The rapid initial fall in pHi was used to determine the membrane permeability to the DMO molecule, while the much slower fall during the subsequent plateau phase yielded the permeability to the DMO ion. This experimental approach and the mathematical treatment of the data can be used to obtain the membrane permeabilities to other weak acids or bases. We found values of 1.9 X 10(-4) cm/s for the permeability to the DMO molecule and 1.5 X 10(-7) cm/s for the permeability to the ion, assuming the fiber to be a cylinder. Thus the permeability of the neutral form is about 10(3) times that of the ionized form. At commonly encountered conditions of pHi = 7.3, outside pH = 7.5, and membrane potential = -52 mV, this permeability ratio introduces an error of only -0.01 to -0.02 into the determination of pHi based on the distribution of DMO.


Clinical implications of pneumococcal serotypes: invasive disease potential, clinical presentations, and antibiotic resistance.
Streptococcus pneumoniae can asymptomatically colonize the nasopharynx and cause a diverse range of illnesses. This clinical spectrum from colonization to invasive pneumococcal disease (IPD) appears to depend on the pneumococcal capsular serotype rather than the genetic background. According to a literature review, serotypes 1, 4, 5, 7F, 8, 12F, 14, 18C, and 19A are more likely to cause IPD. Although serotypes 1 and 19A are the predominant causes of invasive pneumococcal pneumonia, serotype 14 remains one of the most common etiologic agents of non-bacteremic pneumonia in adults, even after 7-valent pneumococcal conjugate vaccine (PCV7) introduction. Serotypes 1, 3, and 19A pneumococci are likely to cause empyema and hemolytic uremic syndrome. Serotype 1 pneumococcal meningitis is prevalent in the African meningitis belt, with a high fatality rate. In contrast to the capsule type, genotype is more closely associated with antibiotic resistance. CC320/271 strains expressing serotype 19A are multidrug-resistant (MDR) and prevalent worldwide in the era of PCV7. Several clones of MDR serotype 6C pneumococci emerged, and a MDR 6D clone (ST282) has been identified in Korea. Since the pneumococcal epidemiology of capsule types varies geographically and temporally, a nationwide serosurveillance system is vital to establishing appropriate vaccination strategies for each country.


Physician Attitudes Toward Homosexuality and HIV: The PATHH-III Survey.
The aims of this study were (1) to evaluate current physician attitudes toward homosexuality and homosexual, transgender, and HIV-positive individuals and (2) to compare current attitudes of those from prior surveys of the same population, the San Diego County medical community. An online survey was conducted during November-December 2017 to assess general attitudes toward homosexuality and medically focused items that addressed homosexual orientation, transgender identity, and HIV. Responses were weighted for nonresponse. Predictors of stigma were assessed using generalized linear models. Trends across three surveys of the same population in 1982, 1999, and 2017 using common items were assessed using unweighted responses. Of 4418 eligible physicians, 491 (11.1%) responded (median age 55 years, 38% female and 8.7% gay or bisexual). Regarding admission to medical school, 1% opposed admitting a homosexual applicant, 2% a transgender applicant, and 5% an HIV-positive applicant. Regarding consultative referral to a pediatrician, 3% would discontinue referral to a homosexual pediatrician, 5% to a transgender pediatrician, and 10% to an HIV-positive pediatrician. Regarding discomfort treating patients, 7% reported discomfort treating homosexual patients, 22% transgender patients, and 13% HIV-positive patients. Earlier year of graduation from medical school, male gender, and heterosexual orientation were significant predictors of stigma-associated responses. Compared with the results from surveys in 1982 and 1999, the current results suggest substantively less stigma associated with homosexuality and HIV. There have been substantive declines over a 35-year period in the prevalence of stigmatizing attitudes toward sexual minorities and HIV-positive people among physician respondents in three survey waves of the San Diego County medical community.


Agonist-induced phosphorylation of the serotonin 5-HT2C receptor regulates its interaction with multiple PDZ protein 1.
Multiple PDZ domain protein 1 (MUPP1), a putative scaffolding protein containing 13 PSD-95, Dlg, ZO-1 (PDZ) domains, was identified by a yeast two-hybrid screen as a serotonin2C receptor (5-HT2C R)-interacting protein (Ullmer, C., Schmuck, K., Figge, A., and Lubbert, H. (1998) FEBS Lett. 424, 63-68). MUPP1 PDZ domain 10 (PDZ 10) associates with Ser458-Ser-Val at the carboxyl-terminal tail of the 5-HT2C R. Both Ser458 and Ser459 are phosphorylated upon serotonin stimulation of the receptor (Backstrom, J. R., Price, R. D., Reasoner, D. T., and Sanders-Bush, E. (2000) J. Biol. Chem. 275, 23620-23626). To investigate whether phosphorylation of these serines in the receptor regulates MUPP1 interaction, we used several approaches. First, we substituted the serines in the receptor carboxyl tail with aspartates to mimic phosphorylation (S458D, S459D, or S458D/S459D). Pull-down assays demonstrated that Asp mutations at Ser458 significantly decreased receptor tail interaction with PDZ 10. Next, serotonin treatment of 5-HT2C R/3T3 cells resulted in a dose-dependent reduction of receptor interaction with PDZ 10. Effects of serotonin on receptor-PDZ 10 binding could be blocked by pretreatment with a receptor antagonist. Alkaline phosphatase treatment reverses the effect of serotonin, indicating that agonist-induced phosphorylation at Ser458 resulted in a loss of MUPP1 association and also revealed a significant amount of basal phosphorylation of the receptor. We conclude that 5-HT2C R interaction with MUPP1 is dynamically regulated by phosphorylation at Ser458.


Cognitive-behavioral stress management reduces distress and 24-hour urinary free cortisol output among symptomatic HIV-infected gay men.
Stress management interventions can reduce symptoms of distress as well as modulate certain immune system components in persons infected with human immunodeficiency virus (HIV). These effects may occur in parallel with reductions in hypothalamic-pituitary-adrenal (HPA) axis hormones such as cortisol, which has been related in other work to a down-regulation of immune system components relevant to HIV infection. The present study tested the effects of a multimodal cognitive-behavioral stress management (CBSM) intervention on 24-hour urinary free cortisol levels and distressed mood in symptomatic HIV+ gay men. Symptomatic HIV-infected gay men who were randomized to either a 10-week group-based CBSM intervention or a 10-week wait-list period provided psychological responses and urine samples pre-post intervention. Of the 59 participants providing matched questionnaire data, men assigned to CBSM (n = 40) showed significantly lower posttreatment levels of self-reported depressed affect, anxiety, anger, and confusion than those in the wait-list control group (n = 19). Among the 47 men providing urine samples (34 CBSM, 13 controls), those assigned to CBSM revealed significantly less cortisol output as compared to controls. At the individual level, depressed mood decreases paralleled cortisol reductions over this period across the entire sample. A time-limited CBSM intervention reduced distress symptoms and urinary free cortisol output in symptomatic HIV+ gay men and greater reductions in some aspects of distress, especially depressed mood, paralleled greater decreases in cortisol over the intervention period. If persisting stressors and depressed mood contribute to chronic HPA axis activation in HIV-infected persons, then interventions such as CBSM, which teaches them to relax, alter cognitive appraisals, use new coping strategies, and access social support resources, may decrease distress and depressed mood and normalize HPA axis functioning.


Long-term survival of a HCC-patient with severe liver dysfunction treated with sorafenib.
Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver. Prognosis and treatment options are stage dependent. In general, prognosis of patients with unresectable HCC is poor, especially for those patients with impaired liver function. Whereas treatment with the novel molecular tyrosine kinase inhibitor sorafenib (Nexavar) was shown to result in prolonged survival in patients with preserved liver function, its' possible application in HCC-patients with strongly impaired liver function has not been clearly assessed. Here, we report on a 47-year-old male patient who presented with Child-Pugh class C liver cirrhosis and multifocal, non-resectable HCC. The patient was treated for 27 mo with Sorafenib, which was not associated with major drug-related side effects. During treatment, a reduction in tumour size of 24% was achieved, as assessed by regular CT scan. Moreover, within the 27 mo interval of stable tumour disease, liver function improved from Child-Pugh class C to class A.


Benign synovial disorders.
Collectively, benign synovial disorders are not uncommon, and they may be seen in general orthopaedic practices. Symptoms are nonspecific, often delaying diagnosis. In fact, synovial chondromatosis, pigmented villonodular synovitis, synovial hemangioma, and lipoma arborescens often mimic each other as well as other, more common joint disorders in presentation, making diagnosis extremely difficult. It is important to diagnose these disorders correctly in order to provide appropriate treatment and avoid secondary sequelae, such as bone erosion and cartilage degeneration.


Sulfated polysaccharides promote the assembly of amyloid beta(1-42) peptide into stable fibrils of reduced cytotoxicity.
The histopathological hallmarks of Alzheimer disease are the self-aggregation of the amyloid beta peptide (Abeta) in extracellular amyloid fibrils and the formation of intraneuronal Tau filaments, but a convincing mechanism connecting both processes has yet to be provided. Here we show that the endogenous polysaccharide chondroitin sulfate B (CSB) promotes the formation of fibrillar structures of the 42-residue fragment, Abeta(1-42). Atomic force microscopy visualization, thioflavin T fluorescence, CD measurements, and cell viability assays indicate that CSB-induced fibrils are highly stable entities with abundant beta-sheet structure that have little toxicity for neuroblastoma cells. We propose a wedged cylinder model for Abeta(1-42) fibrils that is consistent with the majority of available data, it is an energetically favorable assembly that minimizes the exposure of hydrophobic areas, and it explains why fibrils do not grow in thickness. Fluorescence measurements of the effect of different Abeta(1-42) species on Ca(2+) homeostasis show that weakly structured nodular fibrils, but not CSB-induced smooth fibrils, trigger a rise in cytosolic Ca(2+) that depends on the presence of both extracellular and intracellular stocks. In vitro assays indicate that such transient, local Ca(2+) increases can have a direct effect in promoting the formation of Tau filaments similar to those isolated from Alzheimer disease brains.


Mitotic Index Thresholds Do Not Predict Clinical Outcome for IDH-Mutant Astrocytoma.
Current histological grading recommendations for isocitrate dehydrogenase (IDH)-mutant astrocytoma are imprecise and not reliably predictive of patient outcome, while somatic copy number alterations are emerging as important prognostic biomarkers. One explanation for this relative underperformance of histological grading is that current criteria to distinguish World Health Organization (WHO) grade III anaplastic astrocytomas from lower-grade diffuse astrocytomas (WHO grade II) are vague ("increased mitotic activity"). This qualitative approach ensures diagnostic uncertainty and a broad "gray zone" where both diffuse and anaplastic designations can reasonably be assigned. Thus, we hypothesized that interobserver variability and lack of defined mitotic thresholds for IDH-mutant astrocytomas underlies poor predictive accuracy of current histologic grading approaches. To test this hypothesis, we quantified total mitotic figures and maximum mitotic activity per 10 high-powered fields in an institutional cohort of IDH-mutant astrocytomas. In our cohort, there was no mitotic activity threshold that was reflective of progression-free or overall survival (OS). Furthermore, in a multivariate Cox regression model consisting of mitotic activity, molecular markers, and clinical characteristics, only CDKN2A homozygous deletion was identified as a relevant variant for poor OS. We conclude that lack of defined mitotic figure thresholds may not contribute to underperformance of histological grading for IDH-mutant astrocytomas.


Operational experiences with the carbon adsorption plant at Church Wilne.
The Church Wilne Works now has a carbon treatment facility that allows water from a problematic source to be supplied to part of the City of Nottingham. The difficulties with odour from warm water have been overcome and the originally unsuspected problem of trace organic contamination has been satisfactorily resolved. The Works has its own self-contained carbon regeneration facility, which is covered in a separate paper at this conference.


Interleukin-6 expression in inflamed and non-inflamed temporal arteries from patients with giant cell arteritis.
To evaluate whether interleukin-6 expression in the temporal arteries could be a more sensitive marker of active inflammation compared to the presence of an inflammatory infiltrate. Sixty-three formalin-fixed, paraffin-embedded temporal artery biopsies performed between 2009 and 2012 from 32 patients with biopsy-proven giant cell arteritis, 8 patients with a negative biopsy but with a final diagnosis of giant cell arteritis, and 23 controls (patients with an initial clinical suspicion of giant cell arteritis in whom an alternative diagnosis subsequently was made) were examined. Biopsy specimens showing a transmural inflammatory infiltrate were considered positive for giant cell arteritis. Immunochemistry was performed to detect interleukin-6 in the temporal artery specimens. Slides of temporal artery biopsies were independently assessed by five readers. Interleukin-6 expression was graded as 0 (absent), 1 (mild), 2 (moderate) and 3 (marked). We considered anti-IL-6 staining positive if staining was of grade 2 or 3. Temporal artery biopsies specimens from patients with biopsy-proven giant cell arteritis, biopsy-negative giant cell arteritis and controls were positive for anti-interleukin-6 staining in 59%, 13% and 48% of cases, respectively. Interleukin-6 expression does not increase the sensitivity of temporal artery biopsy in patients with giant cell arteritis who have morphologically uninflamed arteries.


Lung cancer risk and residence in the neighborhood of a sewage plant in Italy. A case-control study.
Environmental pollution originating in sewage and industrial plants can be associated with lung cancer risk, as ecological and case-control studies have indicated. In the present study, the association between lung cancer occurrence and residence near a sewage plant in Prato (Italy) was investigated. A previous geographic study in the same area had shown an increasing trend of lung cancer mortality and incidence with propinquity to the plant. A case-control study was carried out in the male population of Prato. Incident cases in the period 1987-1997 were identified from the Tuscan Cancer Registry (no. 918). Controls were randomly extracted from the Registry Office of the Municipality of Prato (no. 1852). For all subjects, the residential history was reconstructed. A weighted average distance from the plant was computed and used as a proxy variable of exposure. Two analyses were performed: on the whole data set and on a subset of subjects for whom information on tobacco exposure and education was obtained through a postal questionnaire (response rate, 41.1%). Logistic regression models were applied to estimate odds ratios and 95% CI. Both analyses showed a significantly elevated lung cancer risk for subjects living within 1.5 km (ORwhole= 1.56, 1.06-2.28; ORsubset= 2.28, 1.06-4.86) and suggested a risk increase with a decrease of weighted average distance from the plant. The findings highlight a possible role, in lung cancer occurrence, for environmental pollution spread from the plant. Due to drawbacks of the study, further analyses are needed to evidence a noncontroversial etiological conclusion. When environmental data are not available, results of epidemiological studies using residential histories may be useful in preventive policies regarding point source emissions.


Deep brain optical measurements of cell type-specific neural activity in behaving mice.
Recent advances in genetically encoded fluorescent sensors enable the monitoring of cellular events from genetically defined groups of neurons in vivo. In this protocol, we describe how to use a time-correlated single-photon counting (TCSPC)-based fiber optics system to measure the intensity, emission spectra and lifetime of fluorescent biosensors expressed in deep brain structures in freely moving mice. When combined with Cre-dependent selective expression of genetically encoded Ca(2+) indicators (GECIs), this system can be used to measure the average neural activity from a specific population of cells in mice performing complex behavioral tasks. As an example, we used viral expression of GCaMPs in striatal projection neurons (SPNs) and recorded the fluorescence changes associated with calcium spikes from mice performing a lever-pressing operant task. The whole procedure, consisting of virus injection, behavior training and optical recording, takes 3-4 weeks to complete. With minor adaptations, this protocol can also be applied to recording cellular events from other cell types in deep brain regions, such as dopaminergic neurons in the ventral tegmental area. The simultaneously recorded fluorescence signals and behavior events can be used to explore the relationship between the neural activity of specific brain circuits and behavior.


Oral renin inhibitors in clinical practice: a perspective review.
Hypertension is an important risk factor for cardiovascular morbidity and mortality. The importance of the renin-angiotensin-aldosterone system (RAAS) in cardiovascular and renal diseases has long been recognized: for this reason the conventional therapies, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), β-blockers, and aldosterone antagonists represent the backbone of current antihypertensive therapy. Aliskiren is the first direct renin inhibitor (DRI) suitable for oral administration. By achieving more complete renin-angiotensin system inhibition, direct renin inhibitors may afford greater protection from hypertensive complications. Present evidence indicates that aliskiren reduces baseline systolic and diastolic blood pressure greater than placebo and that it is as effective as other first-line antihypertensive agents. Extra advantages can be reached when it is used in combination therapy. Clinical trials and in vitro studies also suggest that aliskiren has several cardioprotective and renoprotective effects. Therapy with aliskiren is well tolerated, but recently some concerns have arisen because of the early termination of the ALTITUDE study due to an increased incidence of adverse effects.


Resection of the piriform cortex for temporal lobe epilepsy: a Novel approach on imaging segmentation and surgical application.
The piriform cortex (PC) occupies both banks of the endorhinal sulcus and has an important role in the pathophysiology of temporal lobe epilepsy (TLE). A recent study showed that resection of more than 50% of PC increased the odds of becoming seizure free by a factor of 16. We report the feasibility of manual segmentation of PC and application of the Geodesic Information Flows (GIF) algorithm to automated segmentation, to guide resection. Manual segmentation of PC was performed by two blinded independent examiners in 60 patients with TLE (55% Left TLE, 52% female) with a median age of 35 years (IQR, 29-47 years) and 20 controls (60% Women) with a median age of 39.5 years (IQR, 31-49). The GIF algorithm was used to create an automated pipeline for parcellating PC which was used to guide excision as part of temporal lobe resection for TLE. Right PC was larger in patients and controls. Parcellation of PC was used to guide anterior temporal lobe resection, with subsequent seizure freedom and no visual field or language deficit. Reliable segmentation of PC is feasible and can be applied prospectively to guide neurosurgical resection that increases the chances of a good outcome from temporal lobe resection for TLE.


Discriminative validity of the lower and upper quarter Y balance test performance: a comparison between healthy trained and untrained youth.
The Lower (YBT-LQ) and Upper (YBT-UQ) Quarter Y Balance Test have been widely used for the assessment of dynamic balance and shoulder mobility/stability, respectively. However, investigations on the validity of the two tests in youth are lacking. Therefore, we performed two studies to determine discriminative validity of the YBT-LQ (study 1) and the YBT-UQ (study 2) in healthy youth. Sixty-nine male soccer players (age: 14.4 ± 1.9 yrs) and 69 age-matched untrained male subjects (14.3 ± 1.6 yrs) participated in study 1 and 37 young swimmers (age: 12.3 ± 2.1 yrs) as well as 37 age-/sex-matched individuals (age: 12.5 ± 2.0 yrs) took part in study 2. Absolute (cm) and relative (% leg/arm length) maximal reach distances per reach direction and the composite score of the YBT-LQ/UQ were used as outcome measures. One-way analysis of variance and the receiver operator characteristic curve analysis (i.e., calculating the area under the curve [AUC]) were conducted to assess discriminative validity. Concerning the relative values, youth athletes showed significantly better YBT-LQ (study 1: p < 0.001, d = 0.86-1.21) and YBT-UQ (study 2: p < 0.001, d = 0.88-1.48) test performances compared to age- and sex-matched untrained subjects. Further, AUC-values indicated a chance of ≥74% (YBT-LQ) and ≥ 71% (YBT-UQ) to discriminate between youth athletes and controls. These findings were confirmed when using the absolute data for analysis. According to our results, the YBT-LQ and the YBT-UQ seem to be useful test instruments to discriminate trained and untrained healthy youth performance for dynamic balance and shoulder mobility/stability, respectively.


Allergic Contact Dermatitis From Methylisothiazolinone in Residential Wall Paint.
A 33-year-old woman presented to our clinic for suspected photoallergic contact dermatitis with a recent episode of severe, vesicular dermatitis involving exposed skin and correlating with relocation to a new home. Biopsy results showed spongiotic and lichenoid dermatitis with eosinophils. Patch test results showed a very strong (+++) reaction to methylisothiazolinone (MI), mild (+) reaction to MI/methylchloroisothiazolinone, and no reaction to benzisothiazolinone. These allergens were found in several personal products. However, the patient was suspicious of 4 wall paints recently used in her home. Semiopen patch tests to 3 Behr interior paints showed positive results. Nine controls showed negative results. High-performance liquid chromatography demonstrated MI and benzisothiazolinone in all 4 paints at concentrations ranging from 50 to 100 ppm and 290 to 340 ppm, respectively. Although MI has been reported to cause occupational airborne contact dermatitis in European household painters, to our knowledge, this is the first documented case of paint-related MI allergy in the United States.


Associations between alcohol use disorder polygenic score and remission in participants from high-risk families and the Indiana Biobank.
In the United States, ~50% of individuals who meet criteria for alcohol use disorder (AUD) during their lifetimes do not remit. We previously reported that a polygenic score for AUD (PGSAUD ) was positively associated with AUD severity as measured by DSM-5 lifetime criterion count, and AUD severity was negatively associated with remission. Thus, we hypothesized that PGSAUD would be negatively associated with remission. Individuals of European (EA) and African ancestry (AA) from the Collaborative Study on the Genetics of Alcoholism (COGA) who met lifetime criteria for AUD, and two EA cohorts ascertained for studies of liver diseases and substance use disorders from the Indiana Biobank were included. In COGA, 12-month remission was defined as any period of ≥12 consecutive months without meeting AUD criteria except craving and was further categorized as abstinent and non-abstinent. In the Indiana Biobank, remission was defined based on ICD codes and could not be further distinguished as abstinent or non-abstinent. Sex and age were included as covariates. COGA analyses included additional adjustment for AUD severity, family history of remission, and AUD treatment history. In COGA EA, PGSAUD was negatively associated with 12-month and non-abstinent remission (p ≤ 0.013, βs between -0.15 and -0.10) after adjusting for all covariates. In contrast to the COGA findings, PGSAUD was positively associated with remission (p = 0.004, β = 0.28) in the Indiana Biobank liver diseases cohort but not in the Indiana Biobank substance use disorder cohort (p = 0.17, β = 0.15). PGSAUD was negatively associated with 12-month and non-abstinent remission in COGA EA, independent of behavioral measures of AUD severity and family history of remission. The discrepant results in COGA and the Indiana Biobank could reflect different ascertainment strategies: the Indiana Biobank participants were older and had higher rates of liver disease, suggesting that these individuals remitted due to alcohol-related health conditions that manifested in later life.


Assessment of the Halogen Content of Brazilian Inhalable Particulate Matter (PM10) Using High Resolution Molecular Absorption Spectrometry and Electrothermal Vaporization Inductively Coupled Plasma Mass Spectrometry, with Direct Solid Sample Analysis.
Halogens in the atmosphere play an important role in climate change and also represent a potential health hazard. However, quantification of halogens is not a trivial task, and methods that require minimum sample preparation are interesting alternatives. Hence, the aim of this work was to evaluate the feasibility of direct solid sample analysis using high-resolution continuum source molecular absorption spectrometry (HR-CS MAS) for F determination and electrothermal vaporization-inductively coupled plasma mass spectrometry (ETV-ICP-MS) for simultaneous Cl, Br, and I determination in airborne inhalable particulate matter (PM10) collected in the metropolitan area of Aracaju, Sergipe, Brazil. Analysis using HR-CS MAS was accomplished by monitoring the CaF molecule, which was generated at high temperatures in the graphite furnace after the addition of Ca. Analysis using ETV-ICP-MS was carried out using Ca as chemical modifier/aerosol carrier in order to avoid losses of Cl, Br, and I during the pyrolysis step, with concomitant use of Pd as a permanent modifier. The direct analysis approach resulted in LODs that were proven adequate for halogen determination in PM10, using either standard addition calibration or calibration against a certified reference material. The method allowed the quantification of the halogens in 14 PM10 samples collected in a northeastern coastal city in Brazil. The results demonstrated variations of halogen content according to meteorological conditions, particularly related to rainfall, humidity, and sunlight irradiation.


Less germs, less mucus, less snot: teachers' and health workers' perceptions of the benefits and barriers of ear health programs in lower primary school classes.
This study explored health and education professionals' perceptions of the health benefits and barriers of different ear health programs used in lower primary school classes in two district education areas in the Goldfields South East Health Region, Western Australia. Health and education staff providing services to children in kindergarten to year three primary school classes were sent a questionnaire about ear health programs provided in their school. Sixty-one questionnaires were returned from 43 teachers, 14 community health nurses, three Aboriginal health workers and one teacher's assistant. Some schools implemented all the ear health programs examined at all year levels while others implemented only one of the programs. Teachers, community health nurses and Aboriginal health workers identified that all ear health programs were beneficial to students. Reported physical health benefits included reduced ear infections, early detection of ear infections and improved hearing. Behavioural benefits included improved concentration, alertness and attention in the classroom. Barriers to implementing the programs were obtaining consent from parents/carers, student transience and attendance, time to implement and conduct the programs and human and physical resources. Evaluation methods used varied from no evaluation for the Breathe Blow Cough and tissue spearing programs to limited data collection for audiometry, otoscopy and ear toilet programs. Respondents perceived that ear health programs were effective in improving health and behavioural outcomes for children. A formal pre-post evaluation to provide objective data to confirm this is needed to inform policy around this important health issue.