From fecal impaction to colon perforation.
The authors present the case of an elderly, nonverbal nursing home resident with dementia who developed fecal impaction, despite interventions such as enema. Subsequent stercoral perforation of the sigmoid colon resulted in peritonitis, sepsis, and death. The authors discuss colon perforation as a result of fecal impaction, as well as the difficulties of pain assessment and communication in patients with dementia.


An embryonic inducing factor: isolation by high performance liquid chromatography and chemical properties.
A protein (vegetalizing factor) which induces amphibian gastrula ectoderm to tissues which in normal development are derived from endoderm and mesoderm has been isolated from chicken embryo trunks by a combination of size exclusion and reversed phase HPLC. An amount of 0.5 ng factor per gastrula evokes inductions in 80-100% of the cases. The protein (apparent Mr approximately 13 000) is split by NaBH4 to polypeptide chains of about half the size under conditions in which disulfide bridges are reduced. The biological activity is lost.


The effect of PCSK9 inhibitors on brain stroke prevention: A systematic review and meta-analysis.
Although proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to improve cardiovascular outcomes, their effects on brain stroke risk are unclear. The present meta-analysis aimed to evaluate the effects of PCSK9 inhibitors on brain stroke prevention. We searched PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov for research published until December 30, 2020, to find randomized controlled trials (RCTs) of PCSK9 inhibitors for brain stroke prevention. Relative risk (RR) and 95% confidence intervals (CIs) were used to represent the outcomes. Seven RCTs with 57,440 participants, including 29,850 patients treated with PCSK9 inhibitors and 27,590 control participants, were included. PCSK9 inhibitors were associated with significant reductions in total brain stroke risk (RR, 0.77; 95% CI, 0.67-0.88; P < 0.001) and ischemic brain stroke risk (RR, 0.76; 95% CI, 0.66, 0.89; P < 0.001) in comparison with the control group. There was no significant difference in cardiovascular mortality (RR, 0.95; 95% CI, 0.84-1.07; P = 0.382) and the risk of hemorrhagic brain stroke (RR, 1.00; 95% CI, 0.66-1.51; P = 0.999) between patients treated with PCSK9 inhibitors and controls. PCSK9 inhibitors did not significantly increase the incidence of neurocognitive adverse events (RR, 1.02; 95% CI, 0.81-1.29; P = 0.85). Moreover, subgroup analysis showed no difference in cognitive function disorder risks among different PCSK9 inhibitors and treatment times. PCSK9 inhibitors significantly reduced the risk of total brain stroke and ischemic brain stroke without increasing the risk of brain hemorrhage and neurocognitive impairment.


Subchondral bone microarchitecture and failure mechanism under compression: A finite element study.
Subchondral bone (SCB) microdamage is commonly observed in traumatic joint injuries and has been strongly associated with post-traumatic osteoarthritis (PTOA). Knowledge of the three-dimensional stress and strain distribution within the SCB tissue helps to understand the mechanism of SCB failure, and may lead to an improved understanding of mechanisms of PTOA initiation, prevention and treatment. In this study, we used high-resolution micro-computed tomography (µCT)-based finite element (FE) modelling of cartilage-bone to evaluate the failure mechanism and the locations of SCB tissue at high-risk of initial failure under compression. The µCT images of five cartilage-bone specimens with an average SCB thickness of 1.23±0.20mm were used to develop five µCT-based FE models. The FE models were analysed under axial compressions of approximately 30MPa applied to the cartilage surface while the bone edges were constrained. Strain and stress-based failure criteria were then applied to evaluate the failure mechanism of the SCB tissue under excessive compression through articular cartilage. µCT-based FE models predicted two locations in the SCB at high-risk of initial failure: (1) the interface of the calcified-uncalcified cartilage due to excessive tension, and (2) the trabecular bone beneath the subchondral plate due to excessive compression. µCT-based FE models of cartilage-bone enabled us to quantify the distribution of the applied compression which was transferred through the articular cartilage to its underlying SCB, and to investigate the mechanism and the mode of SCB tissue failure. Ultimately, the results will help to understand the mechanism of injury formation in relation to PTOA.


Efficacy of wIRA in the treatment of sacroiliitis in male patients with ankylosing spondylitis and its effect on serum VEGF levels.
This study aimed to assess the efficacy of water-filtered infrared A (wIRA) in sacroiliitis in male patients with ankylosing spondylitis (AS) and the effect of wIRA therapy on serum vascular endothelial growth factor (VEGF). One hundred twenty male AS patients with active sacroiliitis were randomly divided into wIRA group and control group. wIRA treatment was performed twice daily for 5 consecutive days with 24-h interval before switching the treatment (crossover design). Bath ankylosing spondylitis disease activity index (BASDAI) scores, pain visual analogue scale (VAS), and morning stiffness VAS were recorded prior to and after each treatment period. Additionally, C-reactive protein (CRP), serum VEGF, and resistance index (RI) of sacroiliac joints detected by ultrasonography were recorded at baseline and after the first and second treatment period, respectively. The efficacy was examined by using repeated measures analysis of variance (ANOVA). BASDAI, pain VAS, and morning stiffness VAS scores decreased significantly (P < 0.001) after wIRA treatment and no-wIRA treatment (control group), and the difference between the two groups was significant (P < 0.001). CRP declined and RI increased during the wIRA treatment as compared with the no-wIRA treatment (P < 0.001). The increase in RI was associated with improvement of pain VAS scores (P = 0.018), while serum VEGF was unaffected by the treatment. wIRA treatment achieved symptom and pain relief for AS patients with active sacroiliitis. wIRA treatment also improved RI revealed by ultrasonography, and this effect was associated with improved pain VAS scores.


Subretinal neovascularization in anterior ischemic optic neuropathy.
A 66-year-old man with typical anterior ischemic optic neuropathy in one eye suffered from edema of the optic disc without functional changes in the fellow eye. However, 7 months later, a reduction in visual acuity, a change in the visual field and a worsening of the contrast-sensitivity curve demonstrated the development of typical anterior ischemic optic neuropathy in this eye as well. After another 6-month period, in addition to these changes, an extensive subretinal neovascular membrane developed in the papillomacular area, which further reduced the patient's visual acuity and required treatment with laser photocoagulation. To our knowledge, this is the first case report of the occurrence of a subretinal neovascular membrane as a complication of anterior ischemic optic neuropathy.


Time-domain NMR analysis for the determination of water content in pharmaceutical ingredients and wet granules.
The application of time-domain NMR (TD-NMR) analysis to quantify water content in pharmaceutical ingredients is demonstrated. The initial phase of the study employed a range of disintegrants with defined amounts of added water (0-30% of the total weight) as samples; the disintegrants included croscarmellose sodium, corn starch, low-substituted hydroxypropyl cellulose, and crospovidone. After acquisition of the T2 relaxation curves of the samples by TD-NMR measurements, these curves were analyzed by partial least squares (PLS) regression. According to the analysis, accurate and reliable PLS models were created that enabled accurate assessment of water content in the samples. A powder blend consisting of acetaminophen (paracetamol) and tablet excipients was also examined. Both a physical mixture of the powder blend and a wet granule prepared with a high-speed granulator were tested as samples in this study. Precise determination of water content in the powder blend was achieved by using the TD-NMR method. The accuracy of water content determination was equivalent to or better than that of the conventional loss on drying method. TD-NMR analysis samples were measured nondestructively and rapidly with low cost; thus, it could be a powerful quantitative method for determining water content in pharmaceuticals.


The Rutter scale for completion by teachers: factor structure and relationships with cognitive abilities and family adversity for a sample of New Zealand children.
A large sample of 7-year-old children (n = 940) was rated by teachers using the Rutter Child Scale B, a 26-item questionnaire covering a variety of behavioural problems. A factor analysis of the data revealed three main factors of interest, identified as aggressiveness, hyperactivity and anxiety-fearfulness. Measures based upon these factors had a reasonably high level of reliability and were moderately stable over a 2-year interval. An analysis of the relationship between these three behavioural measures and some cognitive measures indicated that only hyperactivity was negatively associated with cognitive ability. However, both hyperactivity and aggressiveness were related to adversity in the child's family background. The findings suggest the usefulness of distinguishing between aggressive and hyperactive dimensions of behaviour.


Determinant factors of low birth weight in Indonesia: Findings from the 2017 Indonesian demographic and health survey.
Low birth weight (LBW) is still a significant problem in Indonesia because it affects the growth and development of infants. It is also one of the factors that increase the risk of developing chronic disease later in life. The study aimed to analyse the determinants of LBW in Indonesia. This cross-sectional analytic study used secondary data from the 2017 Indonesian Demographic and Health Survey (IDHS). Data on the maternal factors (maternal age, frequency of antenatal care (ANC) visits, education, and maternal smoking status), children's birth order, and socio-demographic factors of the 14,239 respondents were examined. The association between LBW and the independent variables was analysed using bivariate analysis with a chi-square test (X2), followed by multivariate analysis in the form of binary logistic regression. LBW was identified in 960 infants (6.74%). Fewer than four ANC visits [AOR = 1.86; 95% CI = 1.44-2.42], uneducated mothers [AOR = 2.09; 95% CI = 1.00-4.37], and mothers who finished only primary school [AOR = 1.45; 95% CI = 1.05-2.00] were significantly associated with the incidence of LBW. This study revealed that the frequency of ANC visits was a dominant factor in the incidence of LBW. To reduce LBW in Indonesia, the government must increase ANC visits through health promotion programmes and maintain ANC facilities and quality.


Mass spectrometry imaging of L-[ring-13C6]-labeled phenylalanine and tyrosine kinetics in non-small cell lung carcinoma.
Metabolic reprogramming is a common phenomenon in tumorigenesis and tumor progression. Amino acids are important mediators in cancer metabolism, and their kinetics in tumor tissue are far from being understood completely. Mass spectrometry imaging is capable to spatiotemporally trace important endogenous metabolites in biological tissue specimens. In this research, we studied L-[ring-13C6]-labeled phenylalanine and tyrosine kinetics in a human non-small cell lung carcinoma (NSCLC) xenografted mouse model using matrix-assisted laser desorption/ionization Fourier-transform ion cyclotron resonance mass spectrometry imaging (MALDI-FTICR-MSI). We investigated the L-[ring-13C6]-Phenylalanine (13C6-Phe) and L-[ring-13C6]-Tyrosine (13C6-Tyr) kinetics at 10 min (n = 4), 30 min (n = 3), and 60 min (n = 4) after tracer injection and sham-treated group (n = 3) at 10 min in mouse-xenograft lung tumor tissues by MALDI-FTICR-MSI. The dynamic changes in the spatial distributions of 19 out of 20 standard amino acids are observed in the tumor tissue. The highest abundance of 13C6-Phe was detected in tumor tissue at 10 min after tracer injection and decreased progressively over time. The overall enrichment of 13C6-Tyr showed a delayed temporal trend compared to 13C6-Phe in tumor caused by the Phe-to-Tyr conversion process. Specifically, 13C6-Phe and 13C6-Tyr showed higher abundances in viable tumor regions compared to non-viable regions. We demonstrated the spatiotemporal intra-tumoral distribution of the essential aromatic amino acid 13C6-Phe and its de-novo synthesized metabolite 13C6-Tyr by MALDI-FTICR-MSI. Our results explore for the first time local phenylalanine metabolism in the context of cancer tissue morphology. This opens a new way to understand amino acid metabolism within the tumor and its microenvironment.


iTRAQ-based quantitative proteomic analysis of low molybdenum inducing thymus atrophy and participating in immune deficiency-related diseases.
Molybdenum is a trace element with extremely uneven distribution in the environment. It constitutes the active sites of molybdenum enzymes that can catalyze redox reactions in almost all organisms. In this study, a mouse model with a low molybdenum diet was established to investigate the differential protein expressions in the thymus and the mechanism of molybdenum regulating thymocyte development. Results showed that the thymus evidently atrophied, and the weight and organ index of the thymus substantially decreased under the condition of low molybdenum (P < 0.01). A total of 274 differentially expressed proteins (DEPs) were screened through isobaric tag for relative and absolute quantification; amongst them, ribosomal proteins (38) were the most abundant. Bioinformatics analysis revealed that DEPs were mainly involved in protein metabolism (18%), nucleus (15%) and nucleic acid binding activity (17%), corresponding to biological process, cellular component and molecular function, respectively. Moreover, DEPs induced by low molybdenum were enriched in 94 pathways, of which typical maps including ribosome, oxidative phosphorylation and systemic lupus erythematosus. Flow cytometry analysis indicated the prominent imbalances of CD4+ and CD8+ cell ratios (P < 0.05, P < 0.01), suggesting the disordered development of T cell subsets. Overall, low molybdenum resulted in thymus atrophy by interfering with ribosomal protein expression and protein metabolism. This study provides a data platform for revealing the linkage between molybdenum and thymus-dependent immunity.


Value of middle ear inflation as a diagnostic indicator of eustachian tube patency.
The value of tubal inflation as a diagnostic procedure for Eustachian tube patency and function is controversial. In an attempt to assess the diagnostic value of air douche in atelectatic ears, 49 such ears of 40 patients were politzerized. The procedure was successful in 45 ears. However, of the four unsuccessful cases, two of the patients were able to autoinflate their ears. These results show that air douches pass regularly through the Eustachian tube into the tympanic cavity even in atelectatic ears, which by definition suffer from aeration deficiency, which is often considered to be secondary to 'Eustachian tube obstruction', or alternatively 'Eustachian tube dysfunction'. Thus, the ability to force air through the Eustachian tube by politzerization is of no diagnostic value as an indicator of normal or abnormal tubal patency or functioning in atelectatic ears and most probably in allied conditions.


Techniques to address fractured instruments in the middle or apical third of the root canal in human permanent teeth: a systematic review of the in vitro studies.
The objective of this study is to investigate techniques for approaching fractured instruments in the root canal and to present possible outcomes in relation to dentin thickness, fracture resistance, technique success, and clinical time. The bibliographic research was carried out in PubMed, Cochrane, Lilacs, Web of Science, Scopus, grey literature, and manual search. Following the inclusion and exclusion criteria, the titles and abstracts of 506 articles were read. Of these, 60 articles were selected and read in full. Fourteen articles were included in this systematic review. The most studied technique was the ultrasonic technique and obtained good general results. The more apically the instrument is located, the more difficult it is to remove, the more dentin is removed, and the lower the fracture resistance of the tooth. When removal is not possible, the bypass technique can be performed (bypassing), and on weakened teeth or with little dental remnants, the GentleWave System technique can be used. This systematic review shows the evidence from laboratory studies that the curvature and the root third in which the fracture of instruments occurred is relevant to fracture resistance and success. The ultrasonic technique got the best results. Well-conducted clinical studies should be performed for clinical practice. The approach of fractured instruments in the root canal is efficient with the use of ultrasound, bypass technique, and Gentle Wave System.


A "new" low incidence red cell antigen, NFLD.
A "new" low incidence red cell antigen, NFLD, is described. It was found in a Caucasian family and is inherited as an autosomal dominant. The antigen is not part of the AB0, MNSs, Duffy, Kidd, or Yt blood group systems and probably does not belong to the Rh or Kell blood group systems.


Optimal control at the quantum speed limit.
Optimal control theory is a promising candidate for a drastic improvement of the performance of quantum information tasks. We explore its ultimate limit in paradigmatic cases, and demonstrate that it coincides with the maximum speed limit allowed by quantum evolution.


Interferon-inducer antivirals: Potential candidates to combat COVID-19.
Coronavirus disease 2019 (COVID-19) is an infective disease generated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the pandemic urgency and lack of an effective cure for this disease, drug repurposing could open the way for finding a solution. Lots of investigations are ongoing to test the compounds already identified as antivirals. On the other hand, induction of type I interferons are found to play an important role in the generation of immune responses against SARS-CoV-2. Therefore, it was opined that the antivirals capable of triggering the interferons and their signaling pathway, could rationally be beneficial for treating COVID-19. On this basis, using a database of antivirals, called drugvirus, some antiviral agents were derived, followed by searches on their relevance to interferon induction. The examined list included drugs from different categories such as antibiotics, immunosuppressants, anti-cancers, non-steroidal anti-inflammatory drugs (NSAID), calcium channel blocker compounds, and some others. The results as briefed here, could help in finding potential drug candidates for COVID-19 treatment. However, their advantages and risks should be taken into account through precise studies, considering a systemic approach. Even though the adverse effects of some of these drugs may overweight their benefits, considering their mechanisms and structures may give a clue for designing novel drugs in the future. Furthermore, the antiviral effect and IFN-modifying mechanisms possessed by some of these drugs might lead to a synergistic effect against SARS-CoV-2, which deserve to be evaluated in further investigations.


Multibore sample cell increases EPR sensitivity for aqueous samples.
We have performed calculations, verified by experiment, to explain why the sensitivity of biological EPR can be dramatically increased by dividing the aqueous sample into separate compartments. In biological EPR, the major factor affecting sensitivity is the number of spins in the sample. For an aqueous sample at ambient temperature, this is limited by the requirement for a small volume, due to strong non-resonant absorption of microwaves by water. However, recent empirical studies have shown that this volume limitation can be greatly relieved by dividing the aqueous sample into separate volumes, which allows much more aqueous sample to be loaded into a resonant cavity without significant degradation of the cavity quality factor. Calculations, based on the Bruggeman mixing rule, show quantitatively that the composite aqueous sample has a permittivity much less than that of bulk water, depending on the aqueous volume fraction f. Analysis for X-band EPR spectroscopy shows that the optimal volume fraction of an aqueous composite sample, producing maximum sensitivity, is f=0.15, increasing the sensitivity by a factor of 8.7, compared with an aqueous sample in a single tube.


Frontal alpha asymmetry during prayerful and resting states: An EEG study in Catholic sisters.
Life expectancy in the US is 78.6 years, and although people are living longer, they are also living with chronic diseases. As women age, they are more susceptible to chronic disease including mental health conditions and Alzheimer's Disease (AD) dementia. Therefore, practical and cost effective ways to prevent the onset of cognitive, mental and physical ailments and increase the quality of life among aging populations is timely and warranted. The purpose of this study in aging adult women was to explore if prayer is associated with electrical brain activity patterns consistent with meditation and therefore a likely pro-health behavior. A sample of 33 healthy women (Mage = 80.1, SD = 8.3) were recruited from a Midwestern Catholic Sisters community. Participants completed 6 consecutive, counterbalanced electroencephalogram (EEG) sessions: three resting sessions and three praying sessions equating to 18 min of recorded EEG data for each participant. Differences in alpha power and frontal alpha asymmetry (FAA) between praying and resting conditions and the influence of age on the association between inter-individual differences in alpha power were explored. Results indicated significant higher alpha power detected in electrodes positioned in the occipital area for praying sessions compared to resting sessions. Additionally, we found significant positive correlations between FAA values and age of the participants for both conditions (rest: r = 0.436, p = 0.016; pray: r = 0.434, p = 0.017), indicating more approach-related brain activity in older participants. Taken collectively, our results suggest that prayerful meditation increased alpha power and that positive and approach-related (left frontal-central) brain activity increased as Sisters aged. Future studies should explore the mediating role of age as it relates to meditation and cognitive outcomes.


Aquaporin 1 and 3 as local vitality markers in mechanical and thermal skin injuries.
Assessment of the vitality of an injury is one of to the main tasks in daily forensic casework. Aquaporins belong to the family of water channels. They enable the transport of water and of small molecules like glycerol through biological channels. So far, 13 classes of aquaporins are identified in vertebrates. The classical aquaporin channels 1, 2 and 4 are only permeable for water. The aquaporin channels 3, 7, 9 and 10 are also called aquaglycerolporins since they can also transport glycerol. Aquaporin 3 is expressed in epidermal keratinocytes. In the present investigation, the aquaporin 1 and 3 expression in mechanically and thermally damaged skin is investigated by immunohistochemistry. The study collective comprises 30 cases (63.3% male and 36.7% female) with an age range between 19 and 95 years (mean value 54.6 years). The skin injury comprises different kinds of blunt force, sharp force, strangulation marks, thermal injury, gunshot wounds and frost erythema. In all kinds of mechanical and trauma injury, an increased expression of aquaporin 3 in the keratinocytes of the epidermis was found. There is no correlation of the aquaporin 3 expression with age, sex, body mass index, duration of agonal period and postmortem interval. Concerning aquaporin 1, there were no differences between injured and uninjured skin. Aquaporin 3 is independently from the kind of skin injury and appears to be a valuable immunohistochemical parameter of vitality.


Assessment of attribution algorithms for resolving CIN3-related HPV genotype prevalence in mixed-genotype biopsy specimens using laser capture microdissection as the reference standard.
To make accurate determinations regarding potential and actual impact of HPV vaccine programs, precise estimates of genotype-specific contributions to disease are required for pre- and post-vaccine populations. Definitive determination of lesion-specific genotypes, particularly where multiple genotypes are detected in a sample, can be technically demanding and resource intensive; therefore, most prevalence studies use mathematical algorithms to adjust for multiple genotype detections. There are currently several algorithms, which can produce genotype estimates within a wide range of variability. The use of these for cervical cytology samples has recently been assessed for accuracy against a definitive reference standard, but none have yet been assessed for multiple-genotype-containing whole biopsy specimens. Using laser capture microdissection (LCM) on biopsy samples, lesion-specific genotype prevalence data were generated for a cohort of 516 young Australian women (aged 18-32 years) with cervical intraepithelial neoplasia grade 3 or adenocarcinoma in situ. Using whole tissue section genotype data from the same cohort, including 71 (13.7%) with multiple genotypes, lesion-associated genotype prevalence was estimated using four different attribution algorithms. The proportion of lesions attributable to HPV16 and HPV18 by LCM were 58.4% and 5%, respectively; hierarchical, proportional, single type/minimum and any type/maximum attribution estimates were comparable across genotypes. For analyses utilising whole tissue biopsy cervical specimens, attribution estimates are appropriate for estimating the proportional contribution of individual genotypes to lesions in a population.


Statin-associated focal myositis.
Myositis is an infrequent side effect of statin therapy, usually presenting as diffuse myositis with muscle weakness and cramping involving multiple body parts. We report a case of focal myositis of a hip muscle diagnosed on magnetic resonance imaging, as the underlying pathology was suspected to be related to an orthopaedic disease due to isolated hip symptoms, and which was finally attributed to statin intake. Awareness to this rare cause of musculoskeletal symptoms is indicated in case a patient presents with probable orthopaedic disease and is on statin therapy.


Linoleic acid-grafted chitosan oligosaccharide micelles for intracellular drug delivery and reverse drug resistance of tumor cells.
Intracellular drug delivery is an important rout to reverse drug resistance of tumor cells. In this study, the linoleic acid (LA)-grafted chitosan oligosaccharide (CSO) was synthesized to construct a micellar delivery system for intracellular delivery. The synthesized linoleic acid-grafted chitosan oligosaccharide (CSO-LA) with 10.3% graft ratio of LA could form micelles in aqueous with 86.69 μg/ml critical micellar concentration (CMC). The CSO-LA micelle had 46.2±3.6 nm number average diameter and 36.0±3.3 mV zeta potential. Taking doxorubicin base (DOX) as a model drug, the drug-loaded CSO-LA micelles (CSO-LA/DOX) was then prepared. The drug encapsulation efficiencies of CSO-LA/DOX were as high as 80%, and the drug loading capacity could be improved by increasing the charged DOX. Using MCF-7, Doxorubicin·HCl resistant MCF-7 (MCF-7/ADR), K562 and Doxorubicin·HCl resistant K562 (K562/ADR) cells as model drug sensitive and drug resistant tumor cells, the experiments demonstrated the CSO-LA had excellent cellular uptake ability by either drug sensitive tumor cells or drug resistance tumor cells. The CSO-LA micelles could deliver DOX into tumor cells, and the DOX in cells was increased with incubation time. As a result, the cytotoxicities of DOX encapsulated in CSO-LA micelles against drug resistance tumor cells were improved significantly, comparing to that of Doxorubicin·HCl solution.


The cost of resistance to colistin in Acinetobacter baumannii: a proteomic perspective.
Colistin resistance in Acinetobacter baumannii, a pathogen of clinical concern, was induced in the susceptible strain ATCC 19606 by growth under increasing pressure of the antibiotic, the only drug universally active against multi-resistant clinical strains. In 2-D difference gel electrophoresis (DIGE) experiments, 35 proteins with differences in expression between both phenotypes were identified, most of them appearing as down regulated in the colistin-resistant strain. These include outer membrane (OM) proteins, chaperones, protein biosynthesis factors, and metabolic enzymes, all suggesting substantial loss of biological fitness in the resistant phenotype, as substantiated by complementary experiments in the absence of colistin. Results shed light on the scarcity of widespread clinical outbreaks for resistant phenotypes.


Regression analysis between heart rate variability and baroreflex-related vagus nerve activity in rats.
Many previous studies have suggested that the high-frequency (HF) power of the heart rate variability may represent cardiac vagal activity although direct evidence of a correlation between the HF and vagal neuronal activity is still lacking. In the present study, we performed a regression analysis of the HF and vagal neurograms. Experiments were carried out on adult male Sprague-Dawley rats anesthetized with a continuous infusion of pentobarbital sodium. The baroreflex-related vagus neuronal activities were obtained by nerve or single-fiber recordings. The transient baroreflex response was employed to alter vagus neuronal activities using a bolus injection of phenylephrine (PE). On-line power spectral analysis of the heart rate and a vagal neurogram was performed during the acute baroreflex response. During the test period, systemic arterial pressure immediately increased in response to the PE injection, after which the R-R interval (RR), HF (0.6-2.4 Hz), and vagus nerve and unit activities all dramatically increased. Both nerve and unit activities exhibited good correlations (r > or = 0.7 in all nerve recordings and r > or = 0.6 in 91% of single-fiber recordings) with the HF. There were insignificant differences between the right- and left-side baroreflex-related vagus nerve recordings. Our present study provides a direct linkage between the HF and vagus neuronal electrical activity in anesthetized rats.


Embedding LGBTQI+ competency into nursing education: Formative evaluation of an interdisciplinary project.
In order to avoid perpetuating inequities faced by lesbian, gay, bisexual, transgender, queer, intersex, and other minority (LGBTQI+) communities, future nurses need to recognize and resist discriminatory, oppressive, heteronormative and cisnormative health and social systems. To share the development, embedding, and formative evaluation of an interdisciplinary project to improve LGBTQI+ health content across an undergraduate nursing curriculum. This paper describes a collaborative interdisciplinary project to embed LGBTQI+ health content across a 3-year undergraduate nursing degree. An anonymous cross-sectional online survey was sent to 87 student nurses enrolled in the final semester of their undergraduate degree. The survey included six Likert scale-type questions and five open-ended questions. Qualitative data were analyzed by inductive, reflexive thematic analysis. Most students rated the topic relevant 'extremely' relevant (77 %) to nursing. Students' self-reported comfort discussing LGBTQI+ health in class varied from 'extremely' (42 %) through to 'not at all' (6 %). Thematic analysis of student responses to open-ended questions identified five themes: (1) Becoming aware of LGBTQI+ diversity; (2) Personal values and beliefs; (3) Learning in order to improve clinical encounters; (4) Inconsistency and a lack of incorporation across the curriculum; and (5) (Dis)comfort in the learning environment. Opportunities to better embed LGBTQI+ competency included clear acknowledgement of wider systems of power and oppression, integration and consistent modeling by nursing faculty, and linkage of content to other equity issues to address the intersectional nature of inequities.


Linking environmental effects to health impacts: a computer modelling approach for air pollution.
STUDY OBJECTIVE AND SETTING: To develop a computer model, using a geographical information system (GIS), to quantify potential health effects of air pollution from a new energy from waste facility on the surrounding urban population. Health impacts were included where evidence of causality is sufficiently convincing. The evidence for no threshold means that annual average increases in concentration can be used to model changes in outcome. The study combined the "contours" of additional pollutant concentrations for the new source generated by a dispersion model with a population database within a GIS, which is set up to calculate the product of the concentration increase with numbers of people exposed within each enumeration district exposure response coefficients, and the background rates of mortality and hospital admissions for several causes. The magnitude of health effects might result from the increased PM10 exposure is small-about 0.03 deaths each year in a population of 3 500 000, with 0.04 extra hospital admissions for respiratory disease. Long term exposure might bring forward 1.8-7.8 deaths in 30 years. This computer model is a feasible approach to estimating impacts on human health from environmental effects but sensitivity analyses are recommended. The availability of GIS and dispersion models on personal computers enables quantification of health effects resulting from the additional air pollution new industrial development might cause. This approach could also be used in environmental impact assessment. Care must be taken in presenting results to emphasise methodological limitations and uncertainties in the numbers.


Evaluation of volatile organic compounds coupled to seasonality effects in indoor air from a commercial office in Madrid (Spain) applying chemometric techniques.
Volatile organic compounds (VOCs) concentrations depend on several sources and factors, such as temperature, ventilation, and humidity. Sources can be external atmospheric pollution or indoor release from furniture, coatings or occupants. In this context, this study focused on quantification of VOCs present in a confined atmosphere in a commercial office in downtown Madrid, Spain. The influence of seasonal changes in VOCs concentrations was evaluated using chemometric approaches. Indoor air was systematically monitored for one year using stainless steel tubes filled with Tenax® TA. Sampling was conducted one week a month, for three days during that week (Monday, Wednesday and Friday) for 60 min, every 2 h, totaling 24 h, using an autosampler carousel. The analyses were performed using thermal desorption, and compounds were analyzed by a gas chromatograph coupled with a mass spectrometer. The correlation between these compounds and their concentrations, climatic variations, seasons, among others, were explained by multivariate statistics. Considering the current legislation in Spain, only benzene was present above the maximum permissible concentration (threshold value < 1 μg/m3) from all analyzed compounds. The results indicate that concentrations are related to significant environmental changes, such as ventilation, the number of occupants in the office and types of activity undertaken in the environment. The chemometric analyses allowed the identification of structure analyses correlations between multiple variables for the one-year study. These results underscore the importance of indoor atmosphere studies and chronic exposure to these contaminants.


Integrating total quality management and quality assurance at the University of Michigan Medical Center.
Staff members from the University of Michigan Medical Center (UMMC), 1990 winner of the Commitment to Quality Award, describe how they integrated its quality assurance (QA) program into its total quality management (TQM) strategy. The QA program has changed in recent years to establish quality as a central priority, to educate staff in the importance of quality, and to disseminate information more effectively. While these initiatives were underway, UMMC began to embrace TQM as an operating philosophy. Recognizing both the strengths and weaknesses of QA, staff members have worked to apply TQM principles (eg, focus on processes) to QA while using the ongoing monitoring of QA to identify opportunities for improvement within the organization's TQM management system.


Surveillance for colorectal cancer and chemoprevention in ulcerative and Crohn's colitis: The need for clinical strategies to increase effectiveness.
This review considers why current strategies for surveillance and the prevention of colorectal cancer as a long-term complication are ineffective. The role of endoscopists, pathologists, and patients are investigated. Colorectal cancer is linked to poor compliance with therapy, and attention may be better directed at improving adherence to treatment than strengthening current surveillance programs. Clearly, 5-ASA compounds, particularly mesalazine, are the most appropriate agents to choose, but there may also be a place for the daily intake of folic acid. Currently, the evidence in support of ursodeoxycholic acid is mixed, and it cannot be recommended, in general, to patients for the prophylaxis of colorectal cancer risk. An alternative approach through better concordance with medications is considered. The situation in Crohn's colitis is less clear. Although the risk of colorectal cancer mirrors that in ulcerative colitis, there are no published community-based studies that exclusively assess the effects of surveillance on the early detection of cancer, and the benefits of 5-ASA compounds in treatment seem less certain than in ulcerative colitis. In addition, there have been no assessments of the effects of any medications on cancer risk in Crohn's disease.


[Influence of the modification of Phe-tRNA synthetase from Escherichia coli by lysine- and arginine-specific reagent on the ionic interactions of the enzyme with tRNA Phe].
The influence of modification of Phe-RSase from E. coli MRE-600 by lysine- and arginine-specific reagent 2,4-pentandione on the Phe-RSase.tRNAPhe interactions was investigated. It was shown that modification of Phe-RSase with 2,4-pentandion leads to a decrease of the aminoacylation rate without any influence on the value of Km for tRNAPhe in this reaction and only a slight increase of the value of Kdiss for Phe-RSase.tRNAPhe complex. The log Km (Km-1)--ionic strength dependence for native enzyme and log Kdiss (K-1diss) for native enzyme and two forms modified on arginine and lysine residues were investigated. Results were interpreted quantitatively by Debye--Huckel approximation for two spherical macroions and by Daune approximation assuming that the region of tRNA implicated in ionic interactions is locally a cylindrical polyelectrolyte. It was shown that there are 2-4 electrostatic contacts in Phe-RSase.tRNAPhe interactions in limits of both approximations; modification of arginine residues in Phe-RSase doesn't change the number of electrostatic contacts, modification of lysine residues leads to an increase in the number of contacts. It was assumed that there are lysine residues in Phe-RSase essential for the tRNAPhe recognition. The possibility of participation of negative amino acid residues in electrostatic interactions with tRNAPhe is not excluded.


The adjuvant effect induced by di-(2-ethylhexyl) phthalate (DEHP) is mediated through oxidative stress in a mouse model of asthma.
Di-(2-ethylhexyl) phthalate, as the most commonly used plasticizer, is considered to be related to the asthma prevalence. There are studies affirming that the DEHP has an adjuvant effect in the pathogenesis of allergy asthma. Oxidative stress is one possible pathway for DEHP-adjuvant effect. Thus, this study explored whether DEHP could induce adjuvant effect in mouse asthma model via oxidative stress pathway. Male BALB/c mice were randomly divided into six groups: (1) saline group, (2) DEHP group, (3) ovalbumin (OVA) group, (4) DEHP+OVA group, (5) OVA+vitamin E (Vit E) group, (6) DEHP+OVA+Vit E group. The exposure dose of DEHP was 30 mg/kg body weight (bw)/day. After 18 days of the exposure protocol. Reactive oxygen species (ROS), glutathione (GSH) and malonaldehyde (MDA) levels and biomarkers related to asthma model were measured. Collectively, these data indicated higher ROS and MDA levels and lower GSH contents in DEHP+OVA group than that in OVA group, while Vit E, an antioxidant, could restore ROS, MDA and GSH levels to control levels and attenuate the DEHP and/or OVA effects. Our observations suggested that there was a relationship between oxidative stress and the adjuvant effect induced by DEHP in this mouse asthma model.


On neotypes and nomina nova: commentary on "Comparative analysis of Faecalibacterium prausnitzii genomes shows a high level of genome plasticity and warrants separation into new species-level taxa", by C.B. Fitzgerald et al. (BMC Genomics (2018) 19:931).
In their paper entitled "Comparative analysis of Faecalibacterium prausnitzii genomes shows a high level of genome plasticity and warrants separation into new species-level taxa" (BMC Genomics (2018) 19:931), Fitzgerald et al. proposed a neotype strain for F. prausnitzii (strain A2-165 = DSM 17677 = JCM 31915) and assigned strain ATCC 27768 = NCIMB 13872 to a newly established taxon, Faecalibacterium moorei nom. Nov. These proposals contravene the Rules of the International Code of Nomenclature of Prokaryotes (ICNP). Neotype strains can only be established following a formal proposal in the International Journal of Systematic and Evolutionary Microbiology in accordance with Rule 18c and Appendix 7 of the ICNP. A proposed neotype becomes an established neotype after 2 years, provided that no objections were submitted to the Judicial Commisson of the International Committee on Systematics of Prokaryotes within the first year following publication of the request. F. moorei as proposed by Fitzgerald et al. is a later homotypic synonym of F. prausnitzii. It cannot be a 'nom. nov.' (nomen novum): based on Rule 34a of the ICNP: this term is only used when an author transfers a species to another genus or a subspecies to another species as a new combination, but the original specific epithet cannot be used as 'comb. nov.' (combinatio nova) as a result of homonymy. Moreover, ATCC 27768 and NCIMB 13872 cannot be proposed as the type strain of F. moorei as these remain permanently associated with the type strain of F. prausnitzii unless the Judicial Commission of the ICSP will decide otherwise.


The incidence of Epstein-Barr virus in nasopharyngeal carcinoma of Jordanian patients.
Aim of this study was to investigate the incidence of Epstein-Barr virus (EBV) in patients diagnosed with undifferentiated nasopharyngeal carcinoma (UNPC) from the Northern Province of Jordan. All cases diagnosed with UNPC at King Abdullah University Hospital, Irbid, Jordan, between the years 1991 and 2009 inclusive were examined. Clinical data including age, gender, mode of presentation, site of biopsy were retrieved from pathology reports. In situ hybridization for (EBV)--EBERs was performed on cases with available paraffin blocks. Correlation between the different clinical variables and results of in situ hybridization was performed. There were 49 cases diagnosed with UNPC, only 39 specimens were available and studied. The median age of presentation was 41 years (range 9-70 years). Bimodal age distribution was noted, the first peak between 15 and 19 years of age and second between 60 and 64 years of age. Males were slightly more commonly affected than females. Cervical lymph node enlargement was the most common mode of presentation, followed by nasal obstruction. Biopsies were obtained primarily from the posterior nasal space, followed by cervical lymph node. Positive staining for EBERs by in situ hybridization was seen in 92.3% of the cases examined. There was no difference in detection rate between males and females or adults and pediatrics. All cases obtained from posterior nasal space were positive. The three negative cases were from biopsies obtained from cervical lymph nodes, which was statistically significant (P value <0.05). Nasopharyngeal carcinoma in Jordan is seen in both children and adults. It is associated with EBV infection in most, but not all cases. Posterior nasal space shows a more consistent staining for EBERs than cervical lymph nodes. The presence of other association with UNPC including cigarette smoking could possibly explain the cases with negative association.


A Randomized, Double-Blind, Crossover Study to Determine the Available Energy from Soluble Fiber.
Determining the available energy (caloric value) of dietary non-digestible fibers that are fermented to varying degrees by intestinal microbes and metabolized to short chain fatty acids is important for provision of accurate information to food and beverage manufacturers for reformulation and labeling purposes. The objective of this human study was to determine the available energy of soluble fiber products by measuring post consumption breath hydrogen, with inulin as a control. PROMITOR® Soluble Corn Fiber 70 (SCF70) and PROMITOR® Soluble Corn Fiber 85B (SCF85B) are Tate & Lyle dietary fiber products with 70% and 85% fiber, respectively. The fiber portion of these products is structurally representative of the fiber portion of all PROMITOR® SCF products. The study conducted was a randomized, double-blind, crossover design. Breath hydrogen was quantified following consumption of beverages consisting of 8 oz. of water and: inulin (control), SCF70, or SCF85B at 5, 10, or 15 g (total ingredient weight, "as is"). Subjects were generally healthy men and women (N = 19), age 18 to 34 years, with body mass index (BMI) 19.3 to 24.8 kg/m2. The primary outcome was incremental area under the curve over 10 h (iAUC0-10 h) for inulin, SCF70, and SCF85B at each dose. The available energy (kcal/g ingredient and kcal/g fiber) from SCF70 and SCF85B at each dose was then calculated using inulin as the reference. Results demonstrated that breath hydrogen production was significantly lower following consumption of SCF70 and SCF85B compared to inulin at all consumption amounts. There were no significant differences in breath hydrogen production following consumption of SCF70 compared to SCF85B. The available energy per gram of fiber was not significantly different between the SCF70 and SCF85B PROMITOR® products. The available energy of the fiber portion of PROMITOR® SCF products was determined to be 0.2 kcal/gram.


Psychotic symptoms in narcolepsy: phenomenology and a comparison with schizophrenia.
Patients with narcolepsy often experience pervasive hypnagogic hallucinations, sometimes even leading to confusion with schizophrenia. We aimed to provide a detailed qualitative description of hypnagogic hallucinations and other "psychotic" symptoms in patients with narcolepsy and contrast these with schizophrenia patients and healthy controls. We also compared the prevalence of formal psychotic disorders between narcolepsy patients and controls. We used SCAN 2.1 interviews to compare psychotic symptoms between 60 patients with narcolepsy, 102 with schizophrenia and 120 matched population controls. In addition, qualitative data was collected to enable a detailed description of hypnagogic hallucinations in narcolepsy. There were clear differences in the pattern of hallucinatory experiences in narcolepsy vs. schizophrenia patients. Narcoleptics reported multisensory "holistic" hallucinations rather than the predominantly verbal-auditory sensory mode of schizophrenia patients. Psychotic symptoms such as delusions were not more frequent in narcolepsy compared to population controls. In addition, the prevalence of formal psychotic disorders was not increased in patients with narcolepsy. Almost half of narcoleptics reported moderate interference with functioning due to hypnagogic hallucinations, mostly due to related anxiety. Hypnagogic hallucinations in narcolepsy can be differentiated on a phenomenological basis from hallucinations in schizophrenia which is useful in differential diagnostic dilemmas.


Evaluation of Sickle Cell Module for Quality of Life in Egyptian Children and Adolescents Patients: Impact of Psychiatric and Disease Specific Variables.
Sickle cell disease (SCD) impacts the physical, emotional, and psychological aspects of life. We aimed to study the quality of life (QoL) in Egyptian children and adolescents with SCD using the sickle cell module in relations to social, psychological and disease variables. A cross sectional study included 40 patients with SCD between 5 and 18 years. Details of diagnosis, SCD related complications, socioeconomic status were revised. Psychological assessment was done using children depression inventory, revised Children's Manifest anxiety scale and Health related QoL for both patients and parents using a validated Arabic age specific version of sickle cell module. Significant better scores for communication problems in mothers with college degree was found compared with other academic levels with no significant difference in QoL in relation to father education and significant higher communication problems with high rate of hospitalization (P = .021). Pain score was higher in 8-13 years compared with 13-18 years age groups. Significant worse scores for worrying was found in females, P = 0.033; Depression was found in 90% of studied patients. The main determinants of QoL in patients with SCD were maternal education and frequency of hospitalization. Depression is of alarming frequency for intervention.


Essential thrombocythaemia presenting with subclavian artery thrombosis and multiple embolic events.
The present report describes a case of in situ thrombosis of the left subclavian artery complicated by posterior circulation stroke, left arm ischaemia and possibly ischaemic pancreatitis. Essential thrombocythaemia was found to be the underlying cause.


A carbohydrate-degrading enzyme from Candida albicans: correlation between alpha-glucosidase activity and fungal growth.
Attempts to detect inducible carbohydrate-degrading enzymes from C. albicans were performed using carbohydrate-restricted media. Although alpha-amylase (polysaccharide hydrolase) was not induced from media containing starch or dextrin, alpha-glucosidase (disaccharide hydrolase) was induced from maltose-containing medium. alpha-Glucosidase activity was detected from the intact cells in suspension and from the supernatant of both spheroplasted and mechanically broken cells, but not from the media. Enzyme activity in intact cells was pH independent and increased during logarithmic growth phase and in media containing lower concentrations of maltose. The addition of 5 mM 1-deoxynojirimycin, a competitive inhibitor of alpha-glucosidase, suppressed fungal growth by more than 50%. These results suggest that alpha-glucosidase activity is crucial for fungal growth in medium containing maltose as a sole carbon source.


Single-Cell Sorting of HBsAg-Binding Memory B Cells from Human Peripheral Blood Mononuclear Cells and Antibody Cloning.
The isolation of human antibodies with naturally paired heavy and light chains is crucial for understanding the human antibody immune response. Here, we present a protocol for antibody cloning from the sorted single human memory B cells recognizing hepatitis B virus (HBV) S antigen (HBsAg). A two-fluorescent-dye labeling strategy against HBsAg allows for an improved sorting specificity, while non-relevant protein staining allows for the exclusion of non-specific B cells. This protocol could also be widely adapted for other antigens. For complete details on the use and execution of this protocol, please refer to Wang et al. (2020).


Ecological processes differ in community assembly of Archaea, Bacteria and Eukaryotes in a biogeographical survey of groundwater habitats in the Quebec region (Canada).
Aquifers are inhabited by microorganisms from the three major domains of life: Archaea, Eukaryotes and Bacteria. Although interest in the processes that govern the assembly of these microbial communities is growing, their study is almost systematically limited to one of the three domains of life. Archaea, Bacteria and Eukaryotes are however interconnected and essential to understand the functioning of their living ecosystems. We, therefore, conducted a spatial study of the distribution of microorganisms by sampling 35 wells spread over an area of 10,000 km2 in the Quebec region (Canada). The obtained data allowed us to define the impact of geographic distance and geochemical water composition on the microbial communities. A null model approach was used to infer the relative influence of stochastic and determinist ecological processes on the assembly of the microbial community from all three domains. We found that the organisms from these three groups are mainly governed by stochastic mechanisms. However, this apparent similarity does not reflect the differences in the processes that govern the phyla assembly. The results obtained highlight the importance of considering all the microorganisms without neglecting their individual specificities.


Impairment and Longitudinal Recovery of Older Adults Treated with Radical Cystectomy for Muscle Invasive Bladder Cancer.
Treatment for muscle invasive bladder cancer includes radical cystectomy, a major surgery that can be associated with significant toxicity. Limited data exist related to changes in patient global health status and recovery following radical cystectomy. We used geriatric assessment to longitudinally compare health related impairments in older and younger patients with muscle invasive bladder cancer who undergo radical cystectomy. Older and younger patients (70 or older and younger than 70 years) with muscle invasive bladder cancer undergoing radical cystectomy at an academic institution were enrolled between 2012 and 2019. Patients completed the geriatric assessment before radical cystectomy, and 1, 3 and 12 months after radical cystectomy. For each geriatric assessment measure the Wilcoxon rank sum test was used to compare score distribution between age groups at each time point. The Wilcoxon signed rank test was used to compare distributions between time points within each age group. A total of 80 patients (42 younger and 38 older) were enrolled. Before radical cystectomy 78% of patients were impaired on at least 1 geriatric assessment measure. Both age groups had worsening physical function and nutrition at 1 month after radical cystectomy, with older patients having a greater decline in function than younger patients. Both groups recovered to baseline at 3 months after radical cystectomy and maintained this status at 1 year. High rates of impairments were found across age groups in the short term after radical cystectomy, followed by recovery to baseline.


Comparative evaluation of rapidity of action of benzydamine hydrochloride 0.3% oromucosal spray and benzydamine hydrochloride 3 mg lozenges in patients with acute sore throat: A phase IV randomized trial.
Acute sore throat (ST) can occur as part of a common cold of viral origin or caused by pharyngeal bacterial pathogens. The majority of patients with acute ST complain of pain on swallowing and dry scratchiness which can have a negative impact on the quality of life (QoL). This study aimed to evaluate the time to pain relief in patients with acute ST, following a single administration of benzydamine hydrochloride (HCl) 0.3% oromucosal spray or benzydamine HCl 3 mg lozenges. This multicenter, randomized, active-controlled, open label, parallel-group, international phase IV study was conducted at 12 investigational centers in Poland, Hungary, and Russian Federation. The study population consisted of 363 adult patients with recent onset (≤3 days) of ST and a diagnosis of tonsillopharyngitis. The primary endpoint was to assess the efficacy of benzydamine HCl in ST pain relief at 2 minutes after a single-dose administration. Secondary endpoints included, among others, the assessment of a first perceived ST relief at 1 minute after a single-dose administration of benzydamine HCl spray or lozenge. Both the spray and lozenges are effective in providing a ST relief starting already at 2 minutes after a single administration, with an effect lasting up to up to 4 hours. Clinical efficacy after 7 days of treatment and a good safety profile were also demonstrated. Anesthetic and analgesic properties of benzydamine spray and lozenges effectively addressed the patient priority of a rapid relief of symptoms of upper respiratory tract infections (URTI).


Inhibition of breast tumor growth by N(G)-nitro-l-arginine methyl ester (l-NAME) is accompanied by activation of fibroblasts.
Nitric Oxide (NO) is involved in many physiological and pathological processes. It is generated by a family of NO synthases (NOS), being the inducible isoform, iNOS, responsible for higher amounts of NO. Here, we report that pharmacological inhibition of NO production by l-NAME reduces both viability and MAPK activated signalling pathways in iNOS positive human and murine cancer cell lines. In vivo, using syngeneic models, in parallel with tumor reduction induced by l-NAME, collagen deposition and α-SMA positive stromal cells are observed. This observation takes place only when tumor cells express iNOS. In vitro, l-NAME induces viability and differentiation on fibroblast. Our results reveal that NO inhibition contributes to stimulate proliferation and activation of fibroblasts in parallel with tumor reduction of iNOS positive breast cancer.


Acute and chronic effects of carrier solvents in aquatic organisms: a critical review.
Recognising the scientific and regulatory need for testing relatively hydrophobic or 'difficult substances', the OECD currently recommends that selected organic solvents may be used in aquatic toxicity testing in order to help achieve more effective dispersion of the toxicant. The OECD recommends a maximum solvent concentration of 100 microl l(-1) (with specific gravity equivalents to 100 microl l(-1) in parentheses) for acetone (79 mg l(-1)), dimethylformamide (95 mg l(-1)), dimethylsulfoxide (1.10 mg l(-1)), ethanol (78.9 mg l(-1)), methanol (79.2 mg l(-1)) and triethylene glycol (1.12 mg l(-1)). While this recommendation is supported by historical data, we have recently observed evidence that some solvents may affect the reproduction of certain fish species, and also impact biomarkers of endocrine disruption. This review presents available data on the effects of solvents in aquatic organisms, supplemented by relevant information from mammalian studies (e.g. effects on liver enzyme induction potentially altering the metabolism of sex hormones). In conclusion, it is recommended that maximum effort should be given to avoiding the use of carrier solvents wherever possible, for example through the use of saturation columns or other physical methods (e.g. stirring or ultrasonification). Where solvent use is necessary, however, it is recommended that in reproduction studies with aquatic organisms, the maximum solvent concentration should not exceed 20 microl l(-1) of dilution water.


Involvement of the peroxisome proliferator-activated receptor alpha in the immunomodulation caused by peroxisome proliferators in mice.
Peroxisome proliferators (PPs) are a large class of structurally diverse chemicals, which includes drugs designed to improve the metabolic abnormalities linking hypertriglyceridemia to diabetes, hyperglycemia, insulin-resistance and atherosclerosis. We have recently demonstrated that exposure of rodents to potent PPs indirectly causes a number of immunomodulating effects, resulting in severe adaptive immunosuppression. Since the peroxisome proliferator-activated receptor alpha (PPARalpha) plays a central role in mediating the pleiotropic responses exerted by PPs, we have compared here the immunomodulating effects of the PPs perfluorooctanoic acid (PFOA) and Wy-14,643 in wild-type and PPARalpha-null mice. The reductions in spleen weight and in the number of splenocytes caused by PP treatment in wild-type mice was not observed in PPARalpha-null mice. Furthermore, the reductions in thymus weight and in the number of thymocytes were potently attenuated in the latter animals. Similarly, the dramatic decreases in the size of the CD4(+)CD8(+) population of cells in the thymus and in the number of thymocytes in the S and G2/M phases of the cell cycle observed in wild-type mice administered PPs were much less extensive in PPARalpha-null mice. Finally, in contrast to the case of wild-type animals, the response of splenocytes isolated from the spleen of PP-treated PPARalpha-null mice to appropriate T- or B-cell activators in vitro was not reduced. Altogether, these data indicate that PPARalpha plays a major role in the immunomodulation caused by PPs. The possible relevance of these changes to the alterations in plasma lipids also caused by PPs is discussed.


The impact of pancreas transplantation on kidney allograft survival.
Whether pancreas after kidney transplantation (PAK) compromises kidney allograft survival, and what pre-PAK glomerular filtration rate (GFR) should be used to select patients for PAK is unclear. We analyzed all (n = 2776) PAK recipients in the United States between 1989 and 2007 and compared their risk of kidney failure to a comparator group of n = 13 635 young adult diabetic kidney only transplant recipients during the same time after accounting for selection bias by the use of a propensity score for PAK in a multivariate time to event analysis. In a secondary analysis, we determined the association of pre-PAK GFR with subsequent kidney allograft survival. Despite an increased risk of death early after pancreas transplantation, PAK recipients had a decreased long-term risk of kidney allograft failure compared to diabetic kidney only transplant recipients HR = 0.89; 95% CI: [0.78-1.00]; p = 0.05. An association of pre-PAK GFR with kidney survival was not evident until 3 years after pancreas transplantation, and patients with a pre-PAK GFR of 30-39 mL/min still attained 10-year post-PAK kidney survival of 69%. We conclude that PAK is associated with improved kidney allograft survival, and pre-PAK GFR 30-39 mL/min should not preclude PAK. Expanded use of PAK is warranted.


Aldosterone synthase (CYP11B2) -344 C/T polymorphism is related to antihypertensive response: result from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial.
Our aim was to determine whether the aldosterone synthase (CYP11B2) -344 C/T polymorphism was associated with the blood pressure (BP)-lowering response to antihypertensive treatment. Patients with mild-to-moderate primary hypertension and left ventricular hypertrophy were randomized in a double-blind study to receive treatment with either the angiotensin II type 1 (AT1) receptor antagonist irbesartan (n = 43), or the beta1-adrenergic receptor blocker atenolol (n = 43). The aldosterone synthase (CYP11B2) -344 C/T polymorphism was analyzed using solid-phase minisequencing and related to BP reduction after 3 months treatment. Serum aldosterone levels were measured. After 3 months treatment the mean reductions in BP were similar for both treatment groups. When assessing the systolic BP reduction in the irbesartan group, patients with the TT variant had a more pronounced reduction (-21 +/- 19 SD mm Hg, n = 17) than both the TC (-14 +/- 18 mm Hg, n= 18) and CC (0 +/- 17 mm Hg, n = 8) genotypes (P = .04). There was no association between this polymorphism and the diastolic BP response. The -344 C/T polymorphism was not associated with the BP response to atenolol. Nor was it related to the baseline serum aldosterone level. The aldosterone synthase -344 C/T polymorphism was related to the BP-lowering response in hypertensive patients treated with the AT1-receptor antagonist irbesartan.


The effect of limbal autograft location at primary pterygium excision on anterior and posterior corneal astigmatism: a comparative prospective study.
The aim of the study is to evaluate the effect of limbal autograft location on corneal astigmatism in inferior and superior conjunctival autografted pterygium surgery. Patients were divided into 2 groups as diagnosed with primary pterygium and planned to receive surgical treatment. Pterygium surgery was performed on 25 patients with superior and 25 patients with inferior limbal autograft who have similar epidemiologic features. Cornea anterior and posterior surface keratometry (K) 1, K2, Kmax, peripheric radius (Rper) (the mean radius of curvature of the 7.0-9.0 mm ring area), refractive astigmatism and axis values, were examined. Corneal irregularity indices were the index of surface variance (ISV), index of vertical asymmetry (IVA, mm), index of height asymmetry (IHA, μm), index of height decentration (IHD, μm). The data were compared pre- and postoperative and the effect of graft location on results was evaluated. K1 which is from the values of the cornea front face has risen after surgery both of superior and inferior groups (p = 0.011). However, no postoperative significant difference was detected in terms of the change. Otherwise, both groups have changed regarding astigmatism and Rper (p < 0.001), but no postoperative significant difference was found in terms of the change. There were not any differences between groups regarding the changes of postoperative back face values. Although there were significant decreases in ISV, IVA, and IHD values in both groups in terms of all corneal surface indices, there was no significant difference between the lower and upper groups in terms of postoperative results (p > 0.05). The effects of pterygium surgery with limbal autograft provide significant improvement on corneal astigmatism. However, we think that the location of the conjunctiva has no effect, but in cases where the bulbar conjunctiva needs to be preserved or cannot be used, the choice of the lower bulbar conjunctiva can achieve successful results.


Mitochondrial dysfunction in cardiac ischemia-reperfusion injury: ROS from complex I, without inhibition.
A key pathologic event in cardiac ischemia reperfusion (I-R) injury is mitochondrial energetic dysfunction, and several studies have attributed this to complex I (CxI) inhibition. In isolated perfused rat hearts, following I-R, we found that CxI-linked respiration was inhibited, but isolated CxI enzymatic activity was not. Using the mitochondrial thiol probe iodobutyl-triphenylphosphonium in conjunction with proteomic tools, thiol modifications were identified in several subunits of the matrix-facing 1alpha sub-complex of CxI. These thiol modifications were accompanied by enhanced ROS generation from CxI, but not complex III. Implications for the pathology of cardiac I-R injury are discussed.


Estimating disease survey intensity and wildlife population size from the density of survey devices: Leg-hold traps and the brushtail possum.
Wildlife disease surveillance requires accurate information on the proportion of managed populations sampled or their population density, parameters that are typically expensive to measure. However, these parameters can be estimated using spatially explicit modelling of capture probabilities, based on the distribution and deployment times of capture devices, given accurate information on the relationships between these variables. This approach is used in New Zealand's surveillance programme aimed at confirming areas free of bovine tuberculosis (bTB1) in brushtail possums (Trichosurus vulpecula). However, there is uncertainty about the accuracy of the underpinning parameters characterizing possum trappability (g), given the distance between where a trap is placed and the possum home range centre. Sampling intensity (SI: the percentage of the population sampled during a population survey) and sigma (σ; 95% home range radius/2.45) were measured, using leg-hold traps deployed under a set protocol to standardize survey effort, at four sites containing previously radio- and GPS-collared individuals. Those data were used to derive an estimate of the nightly probability of capture of possums in a trap set at their home range centre (g0). Those estimates were compared to the standard assumptions currently used as defaults in the day-to-day approach used by bTB managers. Home-range size (and therefore σ) varied widely between sites (range 3.6-49.4 ha), probably largely in response to differences in possum density. Field measured SI also varied widely between sites, and was closely positively correlated with home range size (R2 = 0.967; P = 0.017); wide-ranging possums were more trappable than sedentary ones. We found that g0 was inversely related to σ, but the magnitude of increases in g0 with declining σ appeared to be insufficient to compensate for the fewer places at which each possum could be trapped when those home ranges were small. SI was, therefore, not constant across sites where a standard survey effort was applied. The assumed relationship between g0 and σ in the current spatial model may, therefore, need reassessment. The management implication of these result is that the sampling effort required to attain a target sampling intensity is dependant on the target animal density, and for bTB management of possums in New Zealand, is under-estimated by the current default parameters in a model of freedom-from-disease for higher density possum populations.


Structure-based discovery of SIAIS001 as an oral bioavailability ALK degrader constructed from Alectinib.
Fusion proteins of the anaplastic lymphoma kinase (ALK) are promising therapeutic targets for cancer and other human diseases, especially for non-small cell lung cancer (NSCLC) and anaplastic large-cell lymphomas (ALCLs). We described herein a structure-based design, synthesis, and evaluation of ALK PROTACs (proteolysis-targeting chimeras) based on Alectinib as the warhead. We firstly screened CRBN ligands as the E3 ligase moiety, then obtained a series of potent ALK degraders based on different CRBN ligands, exemplified by SIAIS091 and SIAIS001 with lenalidomide/thalidomide-based linkers. Both of them induced effective ALK degradation at low nanomolar concentrations in cells, and showed much better growth inhibition effects than Alectinib. SIAIS091 or SIAIS001 also promoted cell cycle arrest in G1/S phase. Finally, SIAIS001 exhibited good oral bioavailability in Pharmacokinetics study.


Longitudinal patient-reported outcomes in patients receiving chimeric antigen receptor T-cell therapy.
Chimeric antigen receptor T-cell therapy (CAR-T) has transformed the treatment for relapsed/refractory hematologic malignancies; however, data on patient-reported outcomes in CAR-T are limited. We conducted a longitudinal study of adults with hematologic malignancies receiving CAR-T. We assessed quality of life (QOL; functional assessment of cancer therapy-general), psychological distress (hospital anxiety and depression scale, patient health questionnaire-9, posttraumatic stress disorder [PTSD] checklist), and physical symptoms (Edmonton symptom assessment scale-revised) at baseline, 1 week, 1, 3, and 6 months after CAR-T. We used linear mixed models to identify factors associated with QOL trajectory. We enrolled 103 of 142 eligible patients (3 did not receive CAR-T). QOL (B = 1.96; P < .001) and depression (B = -0.32; P = .001) worsened by 1 week and improved by 6 months after CAR-T. At 6 months, 18%, 22%, and 22% reported clinically significant depression, anxiety, and PTSD symptoms, respectively. At 1 week, 52% reported severe physical symptoms, declining to 28% at 6 months after CAR-T. In unadjusted linear mixed models, worse Eastern Cooperative Oncology Group performance status (B = 1.24; P = .042), receipt of tocilizumab (B = 1.54; P = .042), and receipt of corticosteroids for cytokine release syndrome and/or neurotoxicity (B = 2.05; P = .006) were associated with higher QOL trajectory. After CAR-T, QOL declined, and depression increased early, followed by improvements in QOL, psychological distress, and physical symptoms by 6 months after infusion. A significant minority of patients reported substantial psychological distress and physical symptoms longitudinally.


POEMS syndrome: cryoglobulinemia an unusual association.
Associations between plasma cell dyscrasia and peripheral neuropathy were well recognized as early as the 1950s. In 1980, Bardwick coined the acronym POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes). We report a 56-year-old woman who presented with excessive sweating, lethargy, intermittent clawing of fingers and painful limb spasms for 2 years. Clinical examination showed hyperpigmented skin lesions, bilateral pleural effusions and organomegaly. Relevant investigations revealed the presence of sensorimotor polyneuropathy, raised cerebrospinal fluid protein, IgM monoclonal band on serum protein electrophoresis, and reactive bone marrow. The patient was treated with combination therapy which included cyclophosphamide, dexamethasone, and intravenous immunoglobulin with moderate response. Presence of cryoglobulinemia in this case has not been described in the literature.


Subjective reactions to major connector designs for removable partial dentures.
Simlated partial denture frameworks were fabricated for 12 dentists (subjects) who had intact dentitions and who had intact dentitions and who had had no previous experience in wearing partial dentures. The outline of the major connectors was modified during a 1 week interval. The data obtained from questionnaires brought about the following conclusions: 1. Preferences in maxillary major connector design were as follows: (1) broad posterior strap, (2) anteroposterior bar, (3) ring-type design, and (4) full palatal coverage. 2. The mandibular lingual bar was chosen over the lingual plate by a 3:1 ratio. 3. The natural palatal metal finish was perferred to the highly polished finish. 4. Metal borders parallel to tongue movement were better tolerated than those lying transverse. 5. Thickening of the posterior strap to permit its narrowing was not clinically feasible. 6. In general, patients adapted best to major connectors that covered the least amount of soft tissues.


Effects of exogenous noise in a silent neuron model: firing induction and em signal detection.
Neuronal intrinsic noise has already shown to play a constructive role in stimuli detection. Here, an exogenous noise, applied to the neuron model as a random membrane voltage perturbation, has been considered. Properly choosing its frequency band, such a noise is able to induce firing activity in a silent neuron and to enhance the detectability of an exogenous signal, representative of an electromagnetic stimulation, through the phenomenon known as stochastic resonance.


Synaptotagmin 1 and SNAREs form a complex that is structurally heterogeneous.
Synaptotagmin 1 (syt1) functions as a Ca(2+)-sensor for neuronal exocytosis. Here, site-directed spin labeling was used to examine the complex formed between a soluble fragment of syt1, which contains its two C2 domains, and the neuronal core soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. Changes in electron paramagnetic resonance lineshape and accessibility for spin-labeled syt1 mutants indicate that in solution, the assembled core SNARE complex contacts syt1 in several regions. For the C2B domain, contact occurs in the polybasic face and sites opposite the Ca(2+)-binding loops. For the C2A domain, contact is seen with the SNARE complex in a region near loop 2. Double electron-electron resonance was used to estimate distances between the two C2 domains of syt1. These distances have broad distributions in solution, which do not significantly change when syt1 is fully associated with the core SNARE complex. The broad distance distributions indicate that syt1 is structurally heterogeneous when bound to the SNAREs and does not assume a well-defined structure. Simulated annealing using electron paramagnetic resonance-derived distance restraints produces a family of syt1 structures where the Ca(2+)-binding regions of each domain face in roughly opposite directions. The results suggest that when associated with the SNAREs, syt1 is configured to bind opposing bilayers, but that the syt1/SNARE complex samples multiple conformational states.


Variations of the hypoxic fraction in the SCC VII tumors after single dose and during fractionated radiation therapy: assessment without anesthesia or physical restraint of mice.
Variations of the hypoxic fraction (HF) after single dose (13 Gy or 4 Gy) and during fractionated (5 fractions of 4 Gy, 1 or 2 fractions per day) radiation therapy were studied in SCC VII tumors implanted subcutaneously in the hind legs of C3H/He/Jms mice using the paired survival curve method. Whole-body irradiation was delivered to tumor-bearing mice without anesthesia or physical restraint, because both are known to increase the HF artificially. The HF decreased after a single 13 Gy dose in a biphasic fashion: extremely rapidly within 1 hr and comparatively slowly during the following 12-72 hr. On the other hand, nearly no fall of HF was observed in 24 hr following a single 4 Gy dose. Also, reoxygenation was found to occur more rapidly in the interfraction period as the number of fractions of 4 Gy increased irrespective of differences of interfraction time. However, the HF just before each radiation fraction was significantly higher than the pretreatment level for both fractionated regimens. Thus, the reoxygenation patterns observed after single low and high doses of irradiation were different from each other, and reoxygenation in each interfraction period did not always proceed in a similar manner to that after single low dose irradiation. Reoxygenation was facilitated as fractionated radiation therapy proceeded, but it was not sufficient for the HF to remain at a level comparable to that before irradiation.


Dextromethorphan-induced delirium and possible methadone interaction.
Dextromethorphan is a commonly used antitussive agent that can be purchased over the counter. It is metabolized primarily by the cytochrome P450 (CYP) 2D6 isozyme. Methadone has been found to inhibit CYP2D6, indicating a potential for interaction with dextromethorphan. An 83-year-old woman was evaluated for delirium, hypersomnia, confusion, lethargy, impaired concentration, and poor food intake. Symptoms resolved soon after discontinuing dextromethorphan. Vulnerability to delirium was potentially caused by coadministration of methadone, which can inhibit the CYP2D6 isozyme. Evaluation of delirium should include close investigation of the patient's medications for potential interactions with dextromethorphan.


Metabolic reprogramming of terminally exhausted CD8+ T cells by IL-10 enhances anti-tumor immunity.
T cell exhaustion presents one of the major hurdles to cancer immunotherapy. Among exhausted CD8+ tumor-infiltrating lymphocytes, the terminally exhausted subset contributes directly to tumor cell killing owing to its cytotoxic effector function. However, this subset does not respond to immune checkpoint blockades and is difficult to be reinvigorated with restored proliferative capacity. Here, we show that a half-life-extended interleukin-10-Fc fusion protein directly and potently enhanced expansion and effector function of terminally exhausted CD8+ tumor-infiltrating lymphocytes by promoting oxidative phosphorylation, a process that was independent of the progenitor exhausted T cells. Interleukin-10-Fc was a safe and highly efficient metabolic intervention that synergized with adoptive T cell transfer immunotherapy, leading to eradication of established solid tumors and durable cures in the majority of treated mice. These findings show that metabolic reprogramming by upregulating mitochondrial pyruvate carrier-dependent oxidative phosphorylation can revitalize terminally exhausted T cells and enhance the response to cancer immunotherapy.


Two waves of platelet secretion induced by thromboxane A2 receptor and a critical role for phosphoinositide 3-kinases.
Thromboxane A2 (TXA2)-mediated platelet secretion and aggregation are important in thrombosis. Here, we present a novel finding that the stable TXA2 analogue, U46619, induces two waves of platelet secretion, each of which precedes a distinct wave of platelet aggregation. ADP released from platelets during the first wave of secretion played a major role in augmenting the first wave of platelet aggregation. The second wave of platelet secretion and aggregation required the first wave of both ADP secretion and aggregation and were blocked by either the integrin inhibitor RGDS or a P2Y12 receptor antagonist, indicating a requirement for both the integrin outside-in signal and ADP-activated Gi pathway. U46619 stimulated phosphoinositide 3-kinase (PI3K)-dependent phosphorylation of Akt, which was augmented by ADP but did not require integrin outside-in signaling. Platelets from PI3Kgamma knock-out mice or PI3K inhibitor-treated platelets showed an impaired second wave of platelet secretion and aggregation. However, the second wave of platelet aggregation was restored by addition of exogenous ADP to PI3Kgamma deficient or PI3K inhibitor-treated platelets. Thus, our data indicate that PI3K, together with the integrin outside-in signaling, play a central role in inducing the second wave of platelet secretion, which leads to the second wave of irreversible platelet aggregation.


Social connection and gene regulation during the COVID-19 pandemic: Divergent patterns for online and in-person interaction.
Social connection has been linked to reduced disease risk and enhanced antiviral immunity, but it is unclear whether online social connections have similar effects to those previously documented for in-person/offline social relationships, or whether online connections can substitute for in-person social relations when the latter are restricted. We examined this question in the context of the COVID-19 pandemic, focusing specifically on an immune system gene regulation profile known as the conserved transcriptional response to adversity (CTRA), which is characterized by up-regulation of proinflammatory genes and down-regulation of genes linked to innate antiviral responses and antibody production. We analyzed CTRA RNA profiles in blood samples from 142 healthy young adults (69% female, 87% white) during the "social distancing" period of the COVID-19 pandemic. Mixed effect linear models quantified the relation of CTRA gene expression to measures of in-person social connection (number of friends, social eudaimonia, loneliness) and online psychosocial connection (online loneliness, perceived social value in online leisure and educational contexts, and internet use) while controlling for demographic and health factors. Multiple indicators of in-person and generalized social connection were associated with lower CTRA gene expression, whereas no measure of online social connection showed any significant association with CTRA gene expression. Experiences of in-person social connection are associated with reduced CTRA gene expression during a period of restricted social interaction. In contrast, online social relationships show no such association. Digitally mediated social relations do not appear to substantially offset the absence of in-person/offline social connection in the context of immune cell gene regulation.


Euthanasia and Assisted Suicide: Realization or Abandonment of Self-determination?
There are undoubtedly sick people who suffer terribly, and of course this should not be. No patient with incurable cancer is to be so tortured for months or years that they want only to die and lack the means to do so. Being unable to die can be worse than death, one might say or think. But until we ourselves have crossed that frontier, we do not know this for certain. To die could be worse than not being able to die. One case is difficult to distinguish from the other. But we pretend we can distinguish them if we praise assisted suicide and euthanasia as solutions to a problem that we not only do not solve, but make worse. Do we need assisted suicide in the face of non-dying skills? The author's answer is no: we do not need euthanasia, neither in that nor in any other case. The logic of euthanasia itself decrees that it cannot be restricted to exceptional cases, based as it is on the idea that the patient's autonomy is to be valued more highly than their actual illness. But if autonomy were of absolute value, it could not be limited to cases of severe disease. The reasons which supporters of euthanasia cite for limiting assisted suicide to the most serious cases of illness, therefore, speak against euthanasia in general. Once the first step has been taken, the application can no longer be limited if, on the one hand, the 'autonomous' desire for death is superior to any counter-argument, and on the other hand, no state of illness is conceivable that could call into question the alleged autonomy.


MDR1 haplotypes conferring an increased expression of intestinal CYP3A4 rather than MDR1 in female living-donor liver transplant patients.
This study investigated whether haplotypes in the multidrug resistance 1 (MDR1) gene had effects on mRNA expression levels of MDR1 and cytochrome P450 (CYP) 3A4, and on the pharmacokinetics of tacrolimus in living-donor liver transplant (LDLT) patients, considering the gender difference. Haplotype analysis of MDR1 with G2677T/A and C3435T was performed in 63 de novo Japanese LDLT patients (17 to 55 years; 44.4% women). The expression levels of MDR1 and CYP3A4 mRNAs in jejunal biopsy specimens were quantified by real-time PCR. Intestinal CYP3A4 mRNA expression levels (amol/microg total RNA) showed significantly higher values in women carrying the 2677TT-3435TT haplotype (median, 10.7; range, 5.92-15.2) than those with 2677GG-3435CC (3.03; range 1.38-4.68) and 2677GT-3435CT (median, 4.31; range, 0.07-9.42) (P = 0.022), but not in men (P = 0.81). However, MDR1 haplotype did not influence mRNA expression levels of MDR1 nor the concentration/dose ratio [(ng/mL)/(mg/day)] of oral tacrolimus for the postoperative 7 days, irrespective of gender. MDR1 haplotype may have a minor association with the tacrolimus pharmacokinetics after LDLT, but could be a good predictor of the inter-individual variation of intestinal expression of CYP3A4 in women.


Telomere length assessments of muscle stem cells in rodent and human skeletal muscle sections.
Measurements of telomere length in skeletal muscle stem cells (MuSCs), a rare cell population within muscles, provide insights into cellular dysfunction in diseased conditions. Here, we describe a protocol (cryosection muscle quantitative fluorescent in situhybridization) using skeletal muscle cryosections for assessments of telomere length in MuSCs, in their native environment. Using a free software, telomere length measurements are assessed on a single-cell level. We also provide methodology to perform data analyses in several ways. For complete details on the use and execution of this protocol, please refer to Tichy et al. (2021).


Key cellular components and interactive histocompatibility molecules regulating tolerance to the fetal allograft.
Implantation is a major landmark in life. It involves the correct apposition of the embryo in the maternal endometrium. The cellular environment influences placenta development, and direct contact of the fetus with maternal tissues is achieved through decidual cells. At the decidua, and at systemic level, the correct balance of cells potentially acting as antigen-presenting cells and histocompatibility products play a pivotal role in achieving feto-maternal tolerance. Here, we review some of the current issues associated with the interplay between cells and molecules needed for pregnancy development.


Measuring the Head Circumference on MRI in Children: an Interrater Study.
The head circumference is typically used as a surrogate parameter for the development of the central nervous system and intracranial structures and is an important clinical parameter in neuropediatrics. As magnetic resonance images (MRI) can be freely zoomed, visual analysis of the head size often relies on impressions, such as the craniofacial ratio or a simplified gyral pattern. Aim of this study was to validate an MRI-based method to measure the head circumference. Head circumferences of 85 children (41 microcephalies, 22 macrocephalies and 22 normal controls; 47 male, mean age 3.22 ± 2.45 years, range 0.19-10.42 years) were retrospectively measured using sagittal 3D-T1w (MPRAGE) data sets. Three readers independently placed an ovoid region of interest in an axial plane starting from the supraorbital bulge and covering the largest supra-auricular head circumference. Clinical measurements of the head circumference taken within an acceptable period served for comparative purposes. Reliability was assessed by calculating the total error of measurement (TEM) and the intraclass correlation coefficient (ICC). A close correlation was found between MRI-based and clinical measurements. The interrater reliability was excellent (ICC 0.985, 95% confidence interval 0.952-0.993). Absolute TEM ranged from 0.47-0.75, resulting in relative TEM ranging from 1.0-1.6%. Thus, TEMs were classified as acceptable. The mean accuracy of MRI-based measurements was high at 0.94. The head circumference can be reliably determined with a simple measurement on 3D sequences using multiplanar reformations. This approach may help to diagnose microcephaly and macrocephaly, especially when the head circumference is not reported by the referring physician.


Management of Intracerebral Hemorrhage: Update and Future Therapies.
Intracerebral hemorrhage (ICH) represents about 15% of all strokes in the USA, but almost 50% of fatal strokes. There are many causes of ICH, but the most common are hypertension and cerebral amyloid angiopathy. This review will discuss new advances in the treatment of intracerebral hemorrhage. The treatment of ICH focuses on management of edema, aggressive blood pressure reduction, and correction of coagulopathy. Early initiation of supportive medical therapies, including blood pressure management, in a neurological intensive care unit reduces mortality, but at present there is no definitive, curative therapy analogous to mechanical thrombectomy for ischemic stroke. Nonetheless, new medical and surgical approaches promise more successful management of ICH patients, especially new approaches to surgical management. In this review, we focus on the current standard of care of acute ICH and discuss emerging therapies that may alter the landscape of this devastating disease.


Taste-masked formulation of sodium phenylbutyrate (ACER-001) for the treatment of urea cycle disorders.
Urea cycle disorders (UCDs) are a group of rare inherited metabolic diseases caused by a deficiency of one of the enzymes or transporters that constitute the urea cycle. Defects in these enzymes lead to acute accumulation (hyperammonemic crises, HAC) or chronically elevated levels (hyperammonemia) of ammonia in the blood and/or various tissues including the brain, which can cause persistent neurological deficits, irreversible brain damage, coma, and death. Ongoing treatment of UCDs include the use of nitrogen-scavenging agents, such as sodium phenylbutyrate (salt of 4-phenylbutyric acid; NaPBA) or glycerol phenylbutyrate (GPB). These treatments provide an alternative pathway for nitrogen disposal through the urinary excretion of phenylacetylglutamine. ACER-001 is a novel formulation of NaPBA with polymer coated pellets in suspension, which is designed to briefly mask the unpleasant bitter taste of NaPBA and is being developed as a treatment option for patients with UCDs. Four Phase 1 studies were conducted to characterize the bioavailability (BA) and/or bioequivalence (BE) of ACER-001 (in healthy volunteers) and taste assessment relative to NaPBA powder (in taste panelists). ACER-001 was shown to be bioequivalent to NaPBA powder under both fed and fasting conditions. Lower systemic exposure of phenylacetate (PAA) and phenylbutyrate (PBA) was observed when ACER-001 was administered with a high-fat meal relative to a fasting state suggesting that the lower doses of PBA administered under fasting conditions may yield similar efficacy with potentially fewer dose dependent adverse effects relative to higher doses with a meal. ACER-001 appeared to be adequately taste-masked, staying below the aversive taste threshold for the first 3 min after the formulation was prepared and remaining palatable when taken within 5 min.


Metastases of unknown primary site.
Despite the fact that effective therapy does not currently exist for the majority of patients presenting with metastases of unknown primary site, the last decade has witnessed significant advances in the approach to this heterogeneous disease. The use of modern pathologic techniques that frequently provide better diagnostic precision and the recognition of specific subgroups with a favorable prognosis and responsiveness to treatment has improved the outcome for some patients. Currently the diagnostic strategy should emphasize the rapid identification of patients likely to benefit from available therapy, whereas clinical research should focus on the development of more effective treatments for those patients with unresponsive tumors. In the future, continued improvements in the molecular characterization of these tumors will likely enhance understanding of the metastatic process, allow for more specific definitions of cell lineage, and provide insights for better therapy.


Integration of epigenetic and genetic profiles identifies multiple sclerosis disease-critical cell types and genes.
Genome-wide association studies (GWAS) successfully identified multiple sclerosis (MS) susceptibility variants. Despite this notable progress, understanding the biological context of these associations remains challenging, due in part to the complexity of linking GWAS results to causative genes and cell types. Here, we aimed to address this gap by integrating GWAS data with single-cell and bulk chromatin accessibility data and histone modification profiles from immune and nervous systems. MS-GWAS associations are significantly enriched in regulatory regions of microglia and peripheral immune cell subtypes, especially B cells and monocytes. Cell-specific polygenic risk scores were developed to examine the cumulative impact of the susceptibility genes on MS risk and clinical phenotypes, showing significant associations with risk and brain white matter volume. The findings reveal enrichment of GWAS signals in B cell and monocyte/microglial cell-types, consistent with the known pathology and presumed targets of effective MS therapeutics.


Adsorption of glycine at the anatase TiO2/water interface: Effects of Ca2+ ions.
Adsorption reactions of amino acids (AAs) on TiO2 nanoparticles (NPs) play an important role in the available nutrients in soils and sediments. The pH effects on glycine adsorption have been studied, but little is known about its coadsorption with Ca2+ at the molecular level. Combined attenuated total reflectance Fourier transform infrared (ATR-FTIR) flow-cell measurements and density functional theory (DFT) calculations were used to determine the surface complex and corresponding dynamic adsorption/desorption processes. The structures of glycine adsorbed onto TiO2 were closely associated with its dissolved species in the solution phase. The presence of Ca2+ exerted different influences on glycine adsorption within pH 4-11, thus affecting its migration rate in soils and sediments. The mononuclear bidentate complex at pH 4-7, involving the COO- moiety of zwitterionic glycine, remained unchanged in the absence and presence of Ca2+. At pH 11, the mononuclear bidentate complex with deprotonated NH2 can be removed from the TiO2 surface upon coadsorption with Ca2+. The bonding strength of glycine on TiO2 was much weaker than that of the Ca-bridged ternary surface complexation. Glycine adsorption was inhibited at pH 4 but was enhanced at pH 7 and 11.


GPlates dataset for the tectonic reconstruction of the Northern Andes-Caribbean Margin.
This contribution contains a GPlates digital reconstruction of the northern Andes and southern Caribbean margin for the last 90 Ma. It is built using different strain datasets fully described in "Continental Margin Response to Multiple Arc-Continent Collisions: the Northern Andes-Caribbean Margin" [1]. Two digital reconstructions are included here: one is a rigid block reconstruction, and the other is a continuously closing polygon reconstruction digitized every one -million years. We placed the South and North American plates at the root of the reconstruction tree, so that the Andean blocks move with respect to the former, and the Caribbean Plate, and related intra-oceanic arcs with respect to the latter. These reconstructions can be used as templates to place in palinspastic space any dataset that can be represented by lines or points.


Lung Adenocarcinoma with Metachronous Ovarian Metastasis: a long survival case report.
Lung adenocarcinoma which invades ovaries is very rare. However, with the increase of long-survival female lung cancer, more patients will suffer ovarian metastasis. On grounds of the paucity of reported cases, the clinicopathological features and treatment strategies remain unknown. This patient was stage IV lung adenocarcinoma at first diagnosis. Following multiple-line systemic treatments, she experienced extensive pelvic metastasis. After debulking surgery and reevaluation about the drive genes, she was administered by targeted therapy. Up to now, the patient has shown no evidence of progression for 8 years after the initial diagnosis of primary lung cancer and 46 months after her ovarian metastasis. The comprehensive treatment modality for the bilateral ovarian metastasis is effective in clinical course.