Multisensory Processes: A Balancing Act across the Lifespan.
Multisensory processes are fundamental in scaffolding perception, cognition, learning, and behavior. How and when stimuli from different sensory modalities are integrated rather than treated as separate entities is poorly understood. We review how the relative reliance on stimulus characteristics versus learned associations dynamically shapes multisensory processes. We illustrate the dynamism in multisensory function across two timescales: one long term that operates across the lifespan and one short term that operates during the learning of new multisensory relations. In addition, we highlight the importance of task contingencies. We conclude that these highly dynamic multisensory processes, based on the relative weighting of stimulus characteristics and learned associations, provide both stability and flexibility to brain functions over a wide range of temporal scales.


Association of cimetidine and bone-marrow suppression in man.
A 29-year old woman who was on steroids for Behcet's disease received intravenous cimetidine for severe gastrointestinal bleeding. A bone-marrow examination performed a few days prior to cimetidine treatment showed a normally active marrow. On the fifth day of cimetidine therapy, agranulocytosis (800/ml) and a very low platelet count (40,000/ml) were observed; bone-marrow failure was documented both by biopsy and aspiration. No other drug known to be myelotoxic was given. This severe hematologic side effect of cimetidine resolved within 10 days after discontinuation of the drug.


Research publication by pharmacist authors in major medical journals: changes over a 10-year interval.
To determine the degree to which pharmacists were involved in major clinical research publications in 1993 and 2003, and to compare the difference in publication rates by pharmacists between these 2 years. Retrospective analysis. Thirty-seven medical journals that had high readership, had a focus on original research, were clinically oriented, and were highly regarded by the research community. Selection of the medical journals was first determined by those having the highest impact factors. Then journals with regular publication of original clinical research and listings of authors' degrees or licensure were included. All original research articles in these journals were reviewed for both 1993 and 2003. The primary outcome was the presence of a pharmacist as an author of one of their research articles in each of those 2 years. For those articles, the following data were collected: study subjects, study design, authors' affiliations, source of research funding, and position of author (first and/or corresponding). The primary outcome was analyzed by using multivariate logistic regression analysis. Other outcomes were compared between 1993 and 2003 by using a chi(2) test. The number of clinical research articles identified was 8127 in 1993 and 8793 in 2003. The median (mean, interquartile range) number of authors/article increased from 5 (5.3, 3-7) in 1993 to 6 (6.6, 4-8) in 2003 (p<0.01). There were 191 pharmacist-authored papers (2.4%) in 1993, compared with 271 (3.1%) in 2003, for a relative increase of 29.2%. Adjusting for the increase seen in the number of authors during that period, the odds ratio that a pharmacist was an author in 2003 compared with 1993 was 1.26 (95% confidence interval 1.04-1.53). Most (94.2%) pharmacist-authored papers described studies involving human subjects. The proportion of clinical pharmacists (but not the number) serving as the primary author declined over time, from 36.6% (70/191) in 1993 to 27.3% (74/271) in 2003 (p=0.041). The most frequent funding sources were industry (from 38.2% in 1993 to 39.5% in 2003) and federal (from 25.1% in 1993 to 31.4% in 2003); however, the differences were not statistically significant. An increase was noted in the proportion of publications involving pharmacists as an author in major medical journals in 2003 compared with 1993. Pharmacists must continue to be active in clinical research, with adequate training and funding remaining significant obstacles.


Parent-Child Automaticity: Links to Child Coping and Behavior and Engagement in Parent Training.
This research investigated parent-child automaticity (i.e., automatic ways of thinking, feeling, and interacting) as it relates to child coping and behavior and caregiver engagement in a preventive parenting program, as well as program-related changes in automaticity. 610 caregivers (93% mothers) of children ages 3-6 years (52% boys; 49% African American) enrolled in the Parenting our Children to Excellence (PACE) program, and completed pre- and post- intervention assessments (N = 544 at post-intervention). Daycare providers also provided reports of school coping and behavior. Parent-child automaticity predicted parent and teacher- reported child social coping and aggressive behavior. Contrary to hypotheses, parents reporting elevated parent-child automaticity attended significantly more PACE sessions. A significant time x attendance interaction indicated decreased automaticity following the PACE program. Parent-child automaticity during the preschool years is an important correlate of child behavior and coping, and may be a motivating factor for parents to attend parent training programs.


Model-guided design of ligand-regulated RNAi for programmable control of gene expression.
Progress in constructing biological networks will rely on the development of more advanced components that can be predictably modified to yield optimal system performance. We have engineered an RNA-based platform, which we call an shRNA switch, that provides for integrated ligand control of RNA interference (RNAi) by modular coupling of an aptamer, competing strand, and small hairpin (sh)RNA stem into a single component that links ligand concentration and target gene expression levels. A combined experimental and mathematical modelling approach identified multiple tuning strategies and moves towards a predictable framework for the forward design of shRNA switches. The utility of our platform is highlighted by the demonstration of fine-tuning, multi-input control, and model-guided design of shRNA switches with an optimized dynamic range. Thus, shRNA switches can serve as an advanced component for the construction of complex biological systems and offer a controlled means of activating RNAi in disease therapeutics.


Mechanistic exploration on neurodevelopmental toxicity induced by upregulation of alkbh5 targeted by triclosan exposure to larval zebrafish.
Because triclosan (TCS) has been confirmed to cause severe neurotoxicity, it is urgent to disclose the underlying toxicity mechanisms at varying levels. TCS exposure resulted in a series of malformations in larval zebrafish, including reduced neurons, blood-vessel ablation and abnormal neurobehavior. Apoptosis staining and the upregulated expression of proapoptotic genes demonstrated that TCS induced neuronal apoptosis and neurotransmitter disorders. By integrating RT-qPCR analysis with the effects of pathway inhibitors and agonists, we found that TCS triggered abnormal regulation of neuron development-related functional genes, and suppressed the BDNF/TrkB signaling pathway. TCS inhibited total m6A-RNA modification level by activating the demethylase ALKBH5, and induced neurodevelopmental toxicity based on the knockdown experiments of alkbh5 and molecular docking. The main novelties of this study lies in: (1) based on specific staining and transgenic lines, the differential neurotoxicity effects of TCS were unravelled at individual, physiological, biochemical and molecular levels in vivo; (2) from a epigenetics viewpoint, the decreasing m6A methylation level was confirmed to be mediated by alkbh5 upregulation; and (3) both homology modeling and molecular docking evidenced the targeting action of TCS on ALKBH5 enzyme. These findings open a novel avene for TCS's risk assessment and early intervention of the contaminant-sourcing diseases.


Epinephrine reversed high-concentration bupivacaine-induced inhibition of calcium channels and transient outward potassium current channels, but not on sodium channel in ventricular myocytes of rats.
Epinephrine is a first-line drug for cardiopulmonary resuscitation, but its efficacy in the treatment of bupivacaine-induced cardiac toxicity is still in question. We hypothesized that epinephrine can reverse cardiac inhibition of bupivacaine by modulating ion flows through the ventricular myocyte membrane channels of rats. The aim of this study was to observe and report the effects of epinephrine on high-concentration bupivacaine-induced inhibition of sodium (INa), L-type calcium (ICa-L), and transient outward potassium (Ito) currents in the ventricular myocytes of rats. The ventricular myocytes were isolated from Sprague-Dawley rats (250-300 g) by acute enzymatic dissociation. The whole-cell patch clamp technique was used to record the ion channel currents in single ventricular myocytes both before and after administration of medications. Administration of bupivacaine 100 μmol/L significantly reduced INa, (P < 0.05). However, administration of bupivacaine 100 μmol/L in conjunction with epinephrine 0.15 μg/ml had no effect in restoring INa to its previous state. Similarly, a sharp decline of ICa-L and Ito was observed after administration of bupivacaine 100 μmol/L (P < 0.05). In contrast to INa, ICa-L and Ito were significantly improved after the administration of the aforementioned combination of bupivacaine and epinephrine (P < 0.05). Epinephrine can reverse high-concentration bupivacaine induced inhibition of ICa-L and Ito, but not INa. Thus, epinephrine's effectiveness in reversal of bupivacaine-induced cardiac toxicity secondary to sodium channel inhibition may be limited.


CRISPR-assisted transposition: TnsC finds (and threads) the needle in the haystack.
Hoffmann et al. (2022) demonstrate that RNA-guided transposons are remarkably sequence specific due to the action of a AAA+ ATPase, TnsC, that recruits the transposase to the correct target site.


Determination of hydrogen concentration in solids by transmission ERDA under nuclear-elastically enhanced recoiling of H by 8 and 9 MeV He.
Hydrogen concentrations in thin self-supporting samples of polyphenylene sulfide (PPS) and muscovite have been determined by nuclear-elastic recoil detection analysis (ERDA) of transmission layout. The analysis procedure is based only on the database of stopping power and recoil cross section for material analysis, without using any reference sample of known H content. For the PPS sample, the determined value of(2.87±0.26)×1022H cm-3is in good agreement with the calculated value of3.01×1022H cm-3. For the muscovite sample, the H concentration originating each from bound water and absorbed water is uniform over the entire thickness of the sample. The determined concentration(9.43±0.75)×1021H cm-3of the muscovite agrees excellently with the value of9.36×1021H cm-3obtained from other quantitative analyses typically applied for minerals. The present results demonstrate the capability of accurate determination of H contents in materials and minerals by transmission ERDA.


Mixed hemimicelles solid-phase extraction of chlorophenols in environmental water samples with 1-hexadecyl-3-methylimidazolium bromide-coated Fe3O4 magnetic nanoparticles with high-performance liquid chromatographic analysis.
In this paper, 1-hexadecyl-3-methylimidazolium bromide (C(16)mimBr)-coated Fe(3)O(4) magnetic nanoparticles (NPs) as an adsorbent of mixed hemimicelles solid-phase extraction was investigated for the preconcentration of two chlorophenols (CPs) in environmental water samples prior to HPLC with UV detection at 285 nm. The high surface area and excellent adsorption capacity of the Fe(3)O(4) NPs after modification with C(16)mimBr were utilized adequately in the SPE process. By the rapid isolation of Fe(3)O(4) NPs through placing a strong magnet on the bottom of beaker, the time-consuming preconcentration process of loading large volume sample in conventional SPE method with a column can be avoided. A comprehensive study of the adsorption conditions such as the zeta-potential of Fe(3)O(4) NPs, added amounts of C(16)mimBr, pH value, standing time and maximal extraction volume were also presented. Under optimized conditions, two analytes of 2,4-dichlorophenol (2,4-DCP) and 2,4,6-trichlorophenol (2,4,6-TCP) were quantitatively determined. The method was then used to determine the two CPs in real environmental water samples. The accuracy of method was evaluated by recovery measurements on spiked samples. Good recovery results (74-90%) were achieved. It is important to note that satisfactory preconcentration factors and extraction recoveries for the two CPs were obtained with only a small amount of Fe(3)O(4) NPs (40 mg) and C(16)mimBr (24 mg).


Endobronchial hydatid cyst causing variable intrathoracic airflow limitation selectively during expiration acting as a ball valve.
Lung hydatid cyst is a frequently encountered site of echinococcus infection after the liver. Rupture of endobronchial hydatid cyst may lead to hydatemesis or may spread to the normal lung or can cause anaphylactic reactions. Performing bronchoscopy in cases with bronchial hydatid is controversial. The thoracic hydatid cyst may destroy the native lung parenchyma or may cause mass effect on the surrounding structures. Ball valve obstruction of the bronchial hydatid cyst is not documented in the literature and here the authors present such a case as the recognition of the ball valve mechanism is important as it may cause tension pneumothorax. The online version contains supplementary material available at 10.1007/s12055-023-01541-4.


Homes of choice: towards more effective linkages between housing and services.
Housing--especially when viewed in combination with the availability of long-term care services--is an important issue for older adults. This policy brief summarizes recent research on the potential of service-enriched housing, as well as the barriers that impede its development. Strategies to expand and improve service-enriched housing are analyzed along with the barriers and trade-offs that states may face.


Traumatic laceration of pericallosal artery resulting in interhemispheric subdural hematoma: a case report.
Interhemispheric subdural hematoma (IHSDH) usually manifests itself in a delayed fashion after trauma as a slow neurological deterioration with signs of the falx syndrome (paresis or seizures of the lower extremity contralateral to the hematoma). Several etiologies of IHSDH have been described, with tearing of bridging veins being especially associated with trauma. We present the second reported case of IHSDH due to traumatic arterial laceration. This lesion demonstrates a benign and delayed initial presentation. Conservative observation has been employed in the past with mixed results. Patients receiving early definitive surgical treatment have a lower mortality rate then those treated similarly having convexity SDHs. This review of 31 cases discusses the salient aspects of this clinical entity, emphasizing the need for prompt diagnosis and treatment, despite the patient's seemingly stable neurological status.


Olivomycin induces tumor cell apoptosis and suppresses p53-induced transcription.
Olivomycin (DNA-binding antibiotic) in nanomolar concentrations induces apoptosis of human tumor cells and inhibits p53-dependent transcription of the reporter gene (basal and induced by antitumor drugs). Olivomycin aglycon induces no cytotoxicity and does not block transcription.


Are fear memories made and maintained by the same NMDA receptor-dependent mechanisms?
A recent finding indicates that inducible knockout of the NR1 NMDA receptor subunit promotes the loss of fear memories formed months earlier. One view is that posttraining NMDA receptor activation protects modified synapses from "synaptic drift." An alternative view is that NMDA receptors help maintain appropriate connectivity in memory-encoding networks.


A survey of the difficulties encountered during routine hygiene and health care by persons with special needs.
This study aims to evaluate the difficulty experienced during routine hygiene and healthcare in various domains by persons with special needs attending a dental clinic compared to controls. Data were gathered from 98 patients (mean age 18 SD +/- 10.9 years) and 27 control subjects (mean age 17.3 SD +/- 10.6 years) using a 19-item questionnaire of difficulty. Seven acts showed greater difficulty in the study group: cleaning teeth (OR = 15.34; 95% CI: 3.46-70.10), washing ears (OR = 7.58; 95% CI: 1.70-33.94), dental treatment (OR = 5.54; 95% CI: 2.23-13.80), ear examination (OR = 3.80; 95% CI: 1.22- 11.86), dental examination (OR = 3.06; 95% CI: 1.27-7.42), blood tests (OR = 2.58; 95% CI: 1.08-6.16) and swallowing a tablet (OR = 2.06; 95% CI: 0.01-0.46). Patients treated under sedation expressed significantly greater difficulty without sedation for dental examination (OR = 3.04; 95% CI: 1.21-7.65) and dental treatment (OR= 3.87; 95% CI: 1.54-9.73). Difficulty encountered in the acceptance of routine hygiene and healthcare could be used as an indicator for the need for Special Care facilities for outpatient treatment. Educational, behavioural and pharmacological procedures that can improve these situations are discussed.


Reference of Temperature and Time during tempering process for non-stoichiometric FTO films.
In order to enhance the mechanical strength of Low-E glass, Fluorine-doped tin oxide (FTO) films have to be tempered at high temperatures together with glass substrates. The effects of tempering temperature (600 °C ~ 720 °C) and time (150 s ~ 300 s) on the structural and electrical properties of FTO films were investigated. The results show all the films consist of non-stoichiometric, polycrystalline SnO2 without detectable amounts of fluoride. 700 °C and 260 s may be the critical tempering temperature and time, respectively. FTO films tempered at 700 °C for 260 s possesses the resistivity of 7.54 × 10(-4) Ω • cm, the average transmittance in 400 ~ 800 nm of ~80%, and the calculated emissivity of 0.38. Hall mobility of FTO films tempered in this proper condition is mainly limited by the ionized impurity scattering. The value of [O]/[Sn] at the film surface is much higher than the stoichiometric value of 2.0 of pure crystalline SnO2.


Peptide barcoding for one-pot evaluation of sequence-function relationships of nanobodies.
Optimisation of protein binders relies on laborious screening processes. Investigation of sequence-function relationships of protein binders is particularly slow, since mutants are purified and evaluated individually. Here we developed peptide barcoding, a high-throughput approach for accurate investigation of sequence-function relationships of hundreds of protein binders at once. Our approach is based on combining the generation of a mutagenised nanobody library fused with unique peptide barcodes, the formation of nanobody-antigen complexes at different ratios, their fine fractionation by size-exclusion chromatography and quantification of peptide barcodes by targeted proteomics. Applying peptide barcoding to an anti-GFP nanobody as a model, we successfully identified residues important for the binding affinity of anti-GFP nanobody at once. Peptide barcoding discriminated subtle changes in KD at the order of nM to sub-nM. Therefore, peptide barcoding is a powerful tool for engineering protein binders, enabling reliable one-pot evaluation of sequence-function relationships.


Identification of various urinary metabolites of fluorene using derivatization solid-phase microextraction.
A method for the qualitative analysis of various metabolites of fluorene is presented. The method uses solid-phase microextraction with an 85 microm polyacrylate fiber for extraction, headspace silylation with BSTFA and MTBSTFA without any catalyst for on-fiber derivatization and GC-MS in the selected ion monitoring mode for separation and detection. The suitability of the method for profile analysis of polycyclic aromatic hydrocarbon metabolites is shown by analyzing an urine of an occupationally exposed person after enzymatic cleavage of the excreted conjugates. Satisfactory separation of all investigated metabolites was achieved without interferences due to matrix peaks.


Long-term Incidence of Hematuria, Urethral Stricture and Bladder Cancer after Radiation Therapy for Prostate Cancer.
Approximately 25% of patients diagnosed with prostate cancer choose radiation therapy as the primary treatment for this malignancy. Urinary tract toxicity after radiation therapy impacts patients years after treatment of the malignancy. We describe the incidence of hematuria, urethral stricture and bladder cancer after radiation therapy, and measure the effect of the radiation therapy modality in patients with prostate cancer. We performed a retrospective review of 886 consecutive patients who received radiation therapy for prostate cancer between 1992 and 2013. Prostate cancer clinical characteristics, radiation therapy treatment modality and events of interest (hematuria, urethral stricture disease and bladder cancer) were recorded. The Kaplan-Meier method was used to estimate the incidence of events of interest and multivariate stepwise Cox regression was performed to analyze associations. Radiation therapy modalities included external beam radiation therapy (379), brachytherapy (225), combination therapy (35) or post-prostatectomy radiation therapy (adjuvant 47 or salvage 201). Overall the 5 and 10-year risk (95% CI) of hematuria was 23% (19-27) and 42% (36-48), urethral stricture 7% (5-9) and 12% (8-16), and bladder cancer 2% (1-3) and 5% (3-7), respectively. On multivariate regression smoking was associated with hematuria (HR 2.5, p <0.001). Obesity (HR 2.5, p=0.005), combination therapy (HR 3.8, p=0.006) and adjuvant radiation therapy (HR 3.1, p=0.015) were associated with urethral stricture. Hematuria, urethral stricture and bladder cancer continue to develop several years after radiation therapy for prostate cancer, thereby warranting continued, long-term followup for these conditions.


[Investigation of the effect of Na-butyrate on TNBS induced rat colitis].
To observe the effect of Na-butyrate on trinitrobenzene sulfonic acid (TNBS) induced rat colitis and discuss its mechanism. 0.85 ml of 50% ethanol enema containing 30 mg TNBS was instillated into rat colon to produce distal colitis. On the 5th day after TNBS enema, the rats were divided into 3 groups and were given respectively 100 mmol/L Na-butyrate, 100 mg/kg SASP or 0.9% saline enema daily. On the 19th day, macroscopical, histological injury scores of colonic mucosa and tissue myeloperoxidase (MPO) activity were evaluated, and the mitotic index in Na-butyrate group was compared with that in SASP group. Diarrhea was apparently improved, weight gain was not apparently different, the scores of macroscopical and histological injury and MPO activity decreased in the SASP group and the Na-butyrate group, compared with the control (P < 0.05). However, there was not obvious difference between the Na-butyrate group and SASP group (P > 0.05). Mitotic index in Na-butyrate group was higher than that in SASP group (P < 0.05). Na-butyrate enema can expedite the restoration of the experimental colitis, and its therapeutic effect is as good as that of SASP.


Reproductive toxicity of 2-methoxyethanol applied dermally to occluded and nonoccluded sites in male rats.
12-Methoxyethanol (2-ME), also known as Methyl Cellosolve, was applied on the backs of Sprague-Dawley male rats at dose levels of 0, 625, 1250, or 2500 mg/kg/day on occluded (covered) sites, and 0, 1250, 2500, or 5000 mg/kg/day on nonoccluded (uncovered) sites for 7 consecutive days. Because deaths occurred at a dose level of 2500 mg/kg/day among rats with occluded test sites, dosing of this group was discontinued after 5 days. The number and morphology of caudal epididymal sperm, number of testicular spermatids, and weights of reproductive organs were determined on Weeks 4, 7, 10, and 15; fertility was assessed on Weeks--1, 4, 7, 10, and 14. The effects of treatment were dose-related and included a decline in epididymal sperm count and testicular spermatid count, a reduction in weights of testes and epididymides, an increase in the number of sperm with abnormal morphology, and a reduction in fertility in rats exposed to 2-ME. The above effects were seen with or without occlusion, but they were more severe and recovery proceeded at a slower rate when the skin sites were covered.


The use of composting for the treatment of animal by-products: Experiments at lab scale.
Animal by-products (ABP), containing mainly rabbit and chicken carcasses were composted at laboratory scale. Results indicate that if proper conditions are used, wastes can be successfully composted and stabilised meeting current European hygienisation standards regarding the disposal of this type of wastes. During the process, temperatures above 60 degrees C were easily reached and maintained for 2 days at least, due to the high energy potential of these materials. However, care must be taken to ensure that these temperatures are reached in the entire reactor to guarantee proper hygienisation of the material. These high temperatures may bring about operational problems such as moisture losses due to very high airflows required for their control. Biological activity indices, such as respiration index (RI) and oxygen uptake rate (OUR) used for the monitoring of the process, were able to indicate potential and actual conditions within the composting reactor, respectively.


Physical properties of resistance vessel wall in peripheral blood flow regulation--I. Mathematical model.
A mathematical model is introduced to investigate the influence of the physical properties of the resistance vessel wall on the metabolic and myogenic mechanisms. The resistance vessel wall is assumed to have an elastic property and the elastic modulus to be a function of pressure (myogenic) and flow (metabolic). Blood is Poiseuille's flow. The resulting mathematical equations for pressure-flow, pressure-diameter, pressure-wall tension and pressure-wall elastic modulus relationships introduced obey Laplace's law. Poiseuille's law and Hooke's law. In comparison with the experimental data (pressure diameter), the mathematical model is confirmed to explain well the dynamic behavior of the resistance vessel wall in vivo.


Effects of growth hormone on lipid metabolism in humans.
The most immediate effect of growth hormone (GH) administration in humans is a significant increase in free fatty acids after 1-2 h, reflecting stimulation of lipolysis and ketogenesis. This stimulation represents an important physiological adaptation to stress and fasting. When the capacity of GH to increase lipolysis is blocked, the protein-retaining and insulin-antagonistic effects of GH on glucose metabolism are either abolished or weakened dramatically, compatible with a key role for lipolysis in orchestrating the metabolic actions of GH.


Risk of liver toxicity with the angiogenesis inhibitor pazopanib in cancer patients.
The angiogenesis inhibitor pazopanib has been approved for the treatment of advanced renal cell cancer (RCC) and soft tissue sarcoma. Severe and fatal hepatotoxicity has been observed in its clinical studies. This analysis was conducted to determine the risk of liver toxicity by a systematic review and meta-analysis of clinical trials. Databases from PubMed, Web of Science and abstracts presented at ASCO meetings up to January, 2012 were searched to identify relevant studies. Eligible studies included prospective trials of cancer patients treated with pazopanib starting at 800 mg daily. Summary incidence rates, relative risks, and 95% confidence intervals (CIs) were calculated using a fixed- or random-effects model. A total of 1478 patients from 10 clinical trials were included. The incidences of all-grade aspartate aminotransferase (AST), alanine transaminase (ALT), and bilirubin elevation were 39.6% (95% CI 31.2-48.6%), 41.4% (95% CI 34.1-49.0%), and 24.8% (95% CI 16.3-35.3%), respectively. The incidences of high-grade (Grade 3 and 4) AST, ALT and bilirubin elevation were 6.9% (95% CI 5.5-8.6%), 9.4% (95% CI 7.8-11.4%), and 3.4% (2.4-5.0%), respectively. In comparison with placebo, pazopanib significantly increased the risk of high-grade AST elevation (RR 6.56, 95% CI 2.04-21.07, p = 0.002) and ALT elevation (RR 4.33, 95% CI 1.88-10.0, p = 0.001). However, the risks of high-grade bilirubin elevation (RR 1.31, 95% CI 0.47-3.64) and fatal hepatotoxicity (RR 2.51, 95% CI 0.12-51.91, p = 0.55) were not significantly elevated. The use of pazopanib was associated with a significantly increased risk of severe non-fatal hepatotoxicity in cancer patients.


Role of IL-1β, IL-6, IL-8 and IFN-γ in pathogenesis of central nervous system neuropsychiatric systemic lupus erythematous.
We discussed the role of IL-1β, IL-6, IL-8 and IFN-γ in the pathogenesis of central nervous system neuropsychiatric systemic lupus erythematous (CNS-NPSLE). Serum and cerebrospinal fluid samples were collected from CNS-NPSLE patients, non-CNS SLE patients, patients with intracranial infection and normal subjects. Levels of IL-1β, IL-6, IL-8 and IFN-γ in serum and cerebrospinal fluid were detected by ELISA, and the results were compared across the groups. All subjects received cerebral MRI. The risk threshold for each cytokine in CNS-NPSLE group was set as 2.5%. The positive rates of cytokines for different lesions in cerebral MRI findings in CNS-NPSLE group were compared. The correlations between cytokine levels and cerebral MRI findings were analyzed. All groups did not show significant differences in age and gender (F=1.34, P>0.05; x (2)=2.05, P>0.05); The IL-1β, IL-6, IL-8 and IFN-γ levels of serum and cerebrospinal fluid in CNS-NPSLE group were obviously higher than those of the normal control (serum Z14 =6.22, 6.04, 6.22, 5.70; cerebrospinal fluid Z14 =6.38, 7.10, 6.97, 6.34, P<0.0083); IL-1β, IL-6 and IL-8 levels of cerebrospinal fluid of CNS-NPSLE group were higher than those of the non-CNS SLE group (Z12 =2.73, Z12 =3.18, Z12 =3.86; P<0.0083); IL-1β, IL-6, IL-8 and IFN-γ levels of cerebrospinal fluid of CNS-NPSLE group were higher than those of the serum (Z=3.19, 6.30, 5.44, 3.19, P<0.05); IL-6>20.0679 pg/ml and IL-8>87.1811 pg/ml in the cerebrospinal fluid predicted a higher risk of CNS-NPSLE (x (2)=11.98, P<0.05; x (2)=4.65, P<0.05); The positive rates of IL-1β and IL-6 in the cerebrospinal fluid of CNS-NPSLE patients with demyelinating diseases were considerably higher than those of CNS-NPSLE patients with normal MRI findings (x (2)=10.89, P<0.005; x (2)=18.47, P<0.005). The positive rates of IL-6 and IFN-γ in the cerebrospinal fluid of CNS-NPSLE patients presenting with multiple ischemic foci were significantly higher than those with normal MRI findings (x (2)=5.56, P<0.005; x (2)=14.59, P<0.005). Some cytokines are involved in the pathogenesis of CNS-NPSLE and correlated with cerebral MRI findings in CNS-NPSLE.


Transradial interventions with the GuideLiner catheter: role of proximal vessel angulation.
Transradial coronary intervention (TRI) is increasingly common, but anatomic variations and lack of guide catheter support may increase the complexity of TRI. The GuideLiner catheter (Vascular Solutions, Minneapolis,MN) is a guide catheter extension developed to provide increased guide catheter support. We hypothesized that TRI cases requiring GuideLiner support would have a greater proximal vessel angle and increased lesion angle tortuosity. This was a retrospective study reviewing 146 TRI cases performed at a single institution between August 2010 and June 2012. 22 cases (15%) required use of the GuideLiner support catheter. Procedural and angiographic characteristics of all cases were analyzed. Multivariable analysis and receiver operator curves (ROC) were used to analyze predictors of GuideLiner use. The indications for TRI were similar between both groups. Subjects who required use of the GuideLiner support catheter at the time of TRI were significantly older (69±12years vs. 62±13years, p=0.03). The proximal vessel angle was significantly greater in the cases requiring GuideLiner support (74°±35° vs. 37°±23°, p<0.001). Lesion angle in the Guideliner group was also significantly greater (48°±32° vs. 28°±25°, p<0.001). On multivariable analysis, proximal vessel angle independently predicted the need for GuideLiner support (AOR 1.4 per 10°, p<0.001). A 45° proximal vessel angle predicted the need for GuideLiner use with a sensitivity of 73% and specificity of 74% (c-statistic 0.79). None of the Guideliner TRI cases required conversion to femoral access. TRIs requiring GuideLiner catheter support had significantly increased lesion complexity and vessel tortuosity. Proximal vessel angulation is significantly associated with the need for GuideLiner use during transradial intervention. Use of the Guideliner facilitated successful completion of PCI despite the use of a wide variety of guiding catheters in this series.


Photoredox Reaction of 2-Mercaptothiazolinium Salts with Silyl Enol Ethers.
A method for the generation of free radicals from thiazolinium salts upon photocatalytic reduction is described. The thiazolinium salts are generated by treatment with methyl triflate of 2-mercaptothiazolines, which can be readily obtained from alkyl bromides and tosylates via a nucleophilic substitution reaction or by hydrothiolation of alkenes. Silyl enol ethers were used to trap the radicals, furnishing ketones after successive single-electron oxidation and elimination of the silyl cation.


Frameshift and nonsense mutations in a human genomic sequence homologous to a murine UDP-Gal:beta-D-Gal(1,4)-D-GlcNAc alpha(1,3)-galactosyltransferase cDNA.
We have previously isolated a murine UDP-Gal:beta-D-Gal(1,4)-D-GlcNAc alpha(1,3)-galactosyltransferase (alpha(1,3)-GT) cDNA (Larsen, R. D., Rajan, V. P., Ruff, M. M., Kukowska-Latallo, J., Cummings, R. D., and Lowe, J. B. (1989) Proc. Natl. Acad. Sci. U. S. A. 86, 8227-8231). This enzyme constructs the terminal alpha(1,3)-galactosyl linkage within the epitope Gal alpha 1----3Gal. This epitope is expressed by New World monkeys and many nonprimate mammals but generally not by Old World primates, anthropoid apes, or man. To investigate the molecular basis for the apparent species-specific absence of this enzyme and its oligosaccharide product, we have sequenced a human genomic DNA fragment homologous to the murine alpha(1,3)-GT cDNA. This fragment contains a 703-nucleotide region that shares 82% identity with a region of the murine cDNA encoding part of the enzyme's catalytic domain. The human sequence, however, has suffered deletion of single nucleotides at two separate positions, relative to the murine sequence. These frameshift mutations disrupt the translational reading frame that would otherwise maintain a 76% amino acid sequence identity between the human sequence and the murine alpha(1,3)-GT. Moreover, nonsense mutations exist within this disrupted reading frame that would truncate the human polypeptide, relative to the murine enzyme. We therefore propose that this human sequence represents a pseudogene and cannot determine expression of Gal alpha 1----3Gal epitopes on human cells.


Alzheimer-related altered white matter microstructural integrity in Down syndrome: A model for sporadic AD?
Virtually all adults with Down syndrome (DS) develop Alzheimer's disease (AD)-associated neuropathology by the age of 40, with risk for dementia increasing from the early 50s. White matter (WM) pathology has been reported in sporadic AD, including early demyelination, microglial activation, loss of oligodendrocytes and reactive astrocytes but has not been extensively studied in the at-risk DS population. Fifty-six adults with DS (35 cognitively stable adults, 11 with mild cognitive impairment, 10 with dementia) underwent diffusion-weighted magnetic resonance imaging (MRI), amyloid imaging, and had assessments of cognition and functional abilities using tasks appropriate for persons with intellectual disability. Early changes in late-myelinating and relative sparing of early-myelinating pathways, consistent with the retrogenesis model proposed for sporadic AD, were associated with AD-related cognitive deficits and with regional amyloid deposition. Our findings suggest that quantification of WM changes in DS could provide a promising and clinically relevant biomarker for AD clinical onset and progression.


Anti-inflammatory and antinociceptive activities of Croton urucurana Baillon bark.
Croton urucurana (Euphorbiaceae) is popularly used in Brazil to treat inflammatory processes, pain, and gastric ulcers. To evaluate the anti-inflammatory and antinociceptive properties of the methanol extract from the bark of C. urucurana (MECu) in mice and identify its chemical constituents. The extract was characterized by UHPLC-DAD-ESI-Q-TOF-MS/MS. Extract doses of 25, 100, and 400mg/kg were employed in the biological assays. Evaluation of anti-inflammatory activity was based on paw edema and leukocyte recruitment into the peritoneal cavity of mice, both induced by carrageenan. Abdominal writhing caused by acetic acid and duration of formalin-induced paw-licking were the models employed to evaluate antinociceptive activity. Ten compounds were identified in the extract: (+)-gallocatechin (1), procyanidin B3 (2), (+)-catechin (3), (-)-epicatechin (4), tembetarine (5), magnoflorine (6), taspine (7), methyl-3-oxo-12-epi-barbascoate (8), methyl-12-epi-barbascoate (9), and hardwickiic acid (10). This is the first report of compounds 2, 4, 6, 7, and 10 in C. urucurana and compound 5 in the genus Croton. In addition to inhibiting paw edema and leukocyte recruitment (particularly of polymorphonuclear cells) into the peritoneal cavity of mice, MECu reduced the number of abdominal writhings induced by acetic acid and the duration of formalin-induced paw licking. The methanol extract of C. urucurana bark exhibited anti-inflammatory and antinociceptive properties, corroborating its use in folk medicine. These effects may be related to the presence of diterpenes, alkaloids, and flavonoids.


The urban contrast: A nationwide assessment of avian diversity in Mexican cities.
In this study we focused on urban bird diversity across Mexico, a megadiverse country, with a special focus on the relative role of urban greenspaces and heavily-built sites. We considered a country-wide approach, including 24 different sized Mexican cities. Our aims were to describe the urban bird diversity in focal cities and further assess the relationships between it and the biogeographic region where cities are located, their size, elevation, and annual rainfall. Additionally, we evaluated differences in the functional composition of bird communities in both studied urban scenarios (i.e., urban greenspaces, heavily-built sites). Our results confirm that urban greenspaces are home to a large proportion of species when contrasted with heavily-built sites. While total species richness and species richness of greenspaces were related with the cities' biogeographic region -with higher species richness in the Neotropical region and Transition Zone-, the relationship did not hold true in heavily-built sites. We found that annual rainfall was negatively related to bird richness in heavily-built sites, suggesting that species from arid systems can be more tolerant to urbanization. Regarding the bird functional group assessment, results show a clear differentiation between the functional groups of greenspaces and those of heavily-built sites, with granivores and omnivores associated with the latter and a highly diverse array of functional groups associated with urban greenspaces.


Where Does EEG Come From and What Does It Mean?
Electroencephalography (EEG) has been instrumental in making discoveries about cognition, brain function, and dysfunction. However, where do EEG signals come from and what do they mean? The purpose of this paper is to argue that we know shockingly little about the answer to this question, to highlight what we do know, how important the answers are, and how modern neuroscience technologies that allow us to measure and manipulate neural circuits with high spatiotemporal accuracy might finally bring us some answers. Neural oscillations are perhaps the best feature of EEG to use as anchors because oscillations are observed and are studied at multiple spatiotemporal scales of the brain, in multiple species, and are widely implicated in cognition and in neural computations.


An experimental and computational study into the crystallisation propensity of 2nd generation sulflower.
The crystallisation propensity of the newly synthesised molecule persulfurated coronene has been investigated through a number of experimental methods. Electrostatic potential calculations and multi-molecular optimisations show that face-face interactions are far more favorable than edge-face interactions, severely restricting the ability of the molecule to crystallise.


The His131Arg substitution in the FCGR2A gene (rs1801274) is not associated with the severity of influenza A(H1N1)pdm09 infection.
The virulence and pathogenicity of different influenza strains are responsible for a more or less severe disease. Recent studies have attempted to understand how host genetic factors may influence the clinical presentation of the disease. In the present study, the His131Arg (rs1801274) polymorphism was investigated in individuals from a Brazilian admixed population with a diagnosis of influenza A(H1N1)pdm09 infection. In the present study, the influence of the His131Arg (rs1801274) polymorphism, a variant of the FCGR2A gene, was investigated in 436 patients with a diagnosis of influenza A(H1N1)pdm09, evaluated at health services in the northern and northeastern regions of Brazil between June 2009 and August 2010. Patients were divided into a group of non-hospitalized patients (n = 192) and a group of hospitalized patients (n = 244; 100 of them died). No significant difference in the allele or genotype frequencies of the rs1801274 polymorphism was observed between groups (p = 0.952 and p = 0.388). Multinomial logistic regression showed no effect of the rs1801274 polymorphism on severity or death of patients from the Brazilian admixed population (p = 0.368 and p = 0.469). The rs1801274 polymorphism is not associated with severe disease in patients infected with influenza A(H1N1)pdm09.


Association between vitamin D/calcium intake and 25-hydroxyvitamin D and risk of ovarian cancer: a dose-response relationship meta-analysis.
The association between vitamin D/calcium and risk of ovarian cancer is still a debatable point. The aim of our study was to systematically investigate the association between vitamin D/calcium, and the risk of ovarian cancer and estimate their dose-response association quantitatively. PubMed, EMBASE, and Web of Science databases were searched to identify relevant observational studies. Two investigators screened citations and extracted data independently. Data were extracted and the association between vitamin D/calcium and ovarian cancer risk was estimated by calculating pooled relative risks (RRs). Subgroup analyses, publication bias estimation, and dose-response analyses were carried out as well. In total, 21 articles involving 980,008 participants were included in our present study. No significant association was observed between total vitamin D intake and ovarian cancer risk (RR: 1.02; 95% CI, 0.89-1.16, p = 0.81). Further subgroup analysis suggested that neither dietary vitamin D intake (RR: 0.80; 95% CI, 0.62-1.03, p = 0.09) nor supplementary vitamin D intake (RR: 0.98; 95% CI, 0.85-1.13, p = 0.80) was associated with the risk of ovarian cancer. As for calcium, total calcium intake was found to be statistically inversely associated with ovarian cancer risk in case-control studies (RR: 0.73; 95% CI, 0.63-0.86, p < 0.001) but not in cohort studies (RR: 1.05; 95% CI, 0.90-1.24, p = 0.52). Besides, supplementation with calcium plus vitamin D was not effective for the prevention of ovarian cancer (p = 0.98). Of note, dose-response analysis based on cohort studies suggested a potential inverse U-shape relationship between calcium intake (including total calcium and dietary calcium) and ovarian cancer risk, which indicated that low dose of calcium intake might reduce ovarian cancer risk while high dose of calcium intake might not. Taken together, vitamin D could not decrease the risk of ovarian cancer. The role of calcium intake was not proven for reducing ovarian cancer risk. Besides, no evidence showed combinative use of calcium and vitamin D have additional benefits for ovarian cancer prevention.


Trochodendron aralioides, the first chromosome-level draft genome in Trochodendrales and a valuable resource for basal eudicot research.
The wheel tree (Trochodendron aralioides) is one of only 2 species in the basal eudicot order Trochodendrales. Together with Tetracentron sinense, the family is unique in having secondary xylem without vessel elements, long considered to be a primitive character also found in Amborella and Winteraceae. Recent studies however have shown that Trochodendraceae belong to basal eudicots and demonstrate that this represents an evolutionary reversal for the group. Trochodendron aralioides is widespread in cultivation and popular for use in gardens and parks. We assembled the T. aralioides genome using a total of 679.56 Gb of clean reads that were generated using both Pacific Biosciences and Illumina short-reads in combination with 10XGenomics and Hi-C data. Nineteen scaffolds corresponding to 19 chromosomes were assembled to a final size of 1.614 Gb with a scaffold N50 of 73.37 Mb in addition to 1,534 contigs. Repeat sequences accounted for 64.226% of the genome, and 35,328 protein-coding genes with an average of 5.09 exons per gene were annotated using de novo, RNA-sequencing, and homology-based approaches. According to a phylogenetic analysis of protein-coding genes, T. aralioides diverged in a basal position relative to core eudicots, ∼121.8-125.8 million years ago. Trochodendron aralioides is the first chromosome-scale genome assembled in the order Trochodendrales. It represents the largest genome assembled to date in the basal eudicot grade, as well as the closest order relative to the core-eudicots, as the position of Buxales remains unresolved. This genome will support further studies of wood morphology and floral evolution, and will be an essential resource for understanding rapid changes that took place at the base of the Eudicot tree. Finally, it can further genome-assisted improvement for cultivation and conservation efforts of the wheel tree.


Synthesis and Preliminary Biological Evaluation of 1,3,5-Triazine Amino Acid Derivatives to Study Their MAO Inhibitors.
Three series of 4,6-dimethoxy-, 4,6-dipiperidino- and 4,6-dimorpholino-1,3,5-triazin-2-yl) amino acid derivatives were synthesized and characterized. A preliminary study for their monoamine oxidase inhibitory activity showed that compounds 7, 18, and 25 had MAO-A inhibition activity comparable to that of the standard clorgyline, with apparently more selective inhibitory activity toward MAO-A than MAO-B and no significant acute toxicity.


Controversy around parabens: Alternative strategies for preservative use in cosmetics and personal care products.
Parabens usage as preservatives in cosmetics and personal care products have been debated among scientists and consumers. Parabens are easy to production, effective and cheap, but its safety status remains controversial. Other popular cosmetics preservatives are formaldehyde, triclosan, methylisothiazolinone, methylchloroisothiazolinone, phenoxyethanol, benzyl alcohol and sodium benzoate. Although their high antimicrobial effectiveness, they also exhibit some adverse health effects. Lately, scientists have shown that natural substances such as essential oils and plant extracts present antimicrobial potential. However, their use in cosmetic is a challenge. The present review article is a comprehensive summary of the available methods to prevent microbial contamination of cosmetics and personal care products, which can allow reducing the use of parabens in these products.


Origin of descending afferents to the rostral part of dorsal cap of inferior olive which transfers contralateral optic activities to the flocculus. A horseradish peroxidase study.
Neurons in the ventromedial tegmental area that project to the rostral part of the dorsal cap of the ipsilateral inferior olive were labeled by the technique of retrograde transport of horseradish peroxidase (HRP). Following iontophoresis of HRP into the rostral part of the dorsal cap a cluster of labeled cells are found ipsilaterally in the area ventromedial to the red nucleus as well as in the area between the substantia nigra and the medial lemniscus. Following HRP injections into the medial accessory olive just beneath the dorsal cap, labeled cells are found exclusively contralaterally in the deep layers of the superior colliculus and in the adjacent reticular formation. These findings clearly show that neuronal groups in the ventromedial tegmental area are involved in the pathway which from the contralateral eye via the rostral half of the dorsal cap conveys impulses to the flocculus, recorded as climbing fiber activation.


The Children of Alcoholics Screening Test: relationship to sex, family environment, and social adjustment in adolescents.
The Children of Alcoholics Screening Test (CAST), the Family Environment Scale (relationship scales only), and the Social Maladjustment Scale were administered to 494 male and female adolescents with a mean age of 16.6 years. High CAST scores were found to be related significantly to low family cohesion, high family conflict, and low overall family support. CAST scores were not related significantly to family expressiveness or to social maladjustment. Internal consistency reliability estimates for the CAST for both males and females were in the mid .90s. Finally, CAST scores of male and female adolescents were found to differ significantly, which indicates the need for separate validation studies to determine screening cut-points for the two groups.


Adaptive evolution of wine yeast.
Alcoholic fermentation is one of the main phases in wine production. It is usually conducted by yeasts belonging to the species Saccharomyces cerevisiae. Industrial S. cerevisiae strains are highly specialized organisms, which have evolved to utilize to their full potential the different environments or ecological niches. So, during the alcoholic fermentation, the yeast has been adapted to different kinds of stress conditions; this adaptation is call "domestication". In this review, we describe the different mechanisms involved in the adaptive evolution of wine yeast strains.


Biodegradable copolymers carrying cell-adhesion peptide sequences.
Amphiphilic block copolymers are used to create bioactive surfaces on biodegradable polymer scaffolds for tissue engineering. Cell-selective biomaterials can be prepared using copolymers containing peptide sequences derived from extracellular-matrix proteins (ECM). Here we discuss alternative ways for preparation of amphiphilic block copolymers composed of hydrophobic polylactide (PLA) and hydrophilic poly(ethylene oxide) (PEO) blocks with cell-adhesion peptide sequences. Copolymers PLA-b-PEO were prepared by a living polymerisation of lactide in dioxane with tin(II)2-ethylhexanoate as a catalyst. The following approaches for incorporation of peptides into copolymers were elaborated. (a) First, a side-chain protected Gly-Arg-Gly-Asp-Ser-Gly (GRGDSG) peptide was prepared by solid-phase peptide synthesis (SPPS) and then coupled with delta-hydroxy-Z-amino-PEO in solution. In the second step, the PLA block was grafted to it via a controlled polymerisation of lactide initiated by the hydroxy end-groups of PEO in the side-chain-protected GRGDSG-PEO. Deprotection of the peptide yielded a GRGDSG-b-PEO-b-PLA copolymer, with the peptide attached through its C-end. (b) A protected GRGDSG peptide was built up on a polymer resin and coupled with Z-carboxy-PEO using a solid-phase approach. After cleavage of the delta-hydroxy-PEO-GRGDSG copolymer from the resin, polymerisation of lactide followed by deprotection of the peptide yielded a PLA-b-PEO-b-GRGDSG block copolymer, in which the peptide is linked through its N-terminus.


Effect of training on the scope of oral and maxillofacial surgery.
The relationships between training and qualifications and the scope of oral and maxillofacial surgical practice was investigated by a survey of all full members of the Australian and New Zealand Association of Oral and Maxillofacial surgeons. It was found that scope did correlate to length of training. Three were differences in scope for more recently trained surgeons and by practice location. The possession of medical qualification did not necessarily affect scope of practice but did affect attitudes.


Proton Pump Inhibitor Use and Efficacy of Nivolumab and Ipilimumab in Advanced Melanoma.
The impact of proton pump inhibitors (PPIs) on clinical outcomes with first-line immune checkpoint inhibitors (ICIs) in patients with metastatic melanoma was previously analyzed in the phase II study, CheckMate 069. This retrospective analysis utilized data from three phase II/III studies of first-line ICI therapy in untreated advanced melanoma: CheckMate 066, 067, and 069. All randomized patients with PPI use ≤ 30 days before initiating study treatment were included in the PPI-use subgroup. Possible associations between baseline PPI use and efficacy were evaluated within each treatment arm of each study using multivariable modeling. Approximately 20% of 1505 randomized patients across the studies reported baseline PPI use. The median follow-up was 52.6-58.5 months. Objective response rate (ORR), progression-free survival (PFS), and overall survival analyses provided insufficient evidence of a meaningful association between PPI use and efficacy outcomes with nivolumab-plus-ipilimumab, nivolumab, or ipilimumab therapy. In five of the six ICI treatment arms, 95% confidence intervals for odds ratios or hazard ratios traversed 1. Significant associations were observed in the CheckMate 069 combination arm between PPI use and poorer ORR and PFS. This multivariable analysis found insufficient evidence to support meaningful associations between PPI use and ICI efficacy in patients with advanced melanoma.


Motility disorders. Diagnosis and treatment for the pediatric patient.
Motility disorders are common in children and may affect any area of the GI tract. The past decade has brought significant advances in the understanding of motility disorders in pediatrics. More sophisticated testing techniques have helped to differentiate normal from abnormal motility in children of different ages. Manometry now may be used to clarify the pathophysiologic defect underlying chest pain, dysphagia, rumination, gastroparesis, chronic intestinal pseudo-obstruction, and colonic neuromuscular disorders. Motility testing also may be used to identify the motor defect responsible for persistence of symptoms after surgery for GER or HD. New investigational techniques and prokinetic agents likely to be available in the future also were discussed.


ICU psychosis and patient autonomy: some thoughts from the inside.
I shall draw on my experience of being an ICU patient to make some practical, ethical, and philosophical points about the care of the critically ill. The recurring theme in this paper is ICU psychosis. I suggest that discharged patients ought to be educated about it; I discuss the obstacles in the way of accurately measuring it; I argue that we must rethink autonomy in light of it; and I suggest that the self disintegrates in the face of it.


Sweet taste loss in myasthenia gravis: more than a coincidence?
Sweet dysgeusia, a rare taste disorder, may be encountered in severe anti-acetylcholine receptor antibody (AChRAb)-myasthenia gravis (MG). A 42 year-old man reported progressive loss of sweet taste evolving for almost 10 weeks, revealing an AChRAb-positive MG with thymoma. Improvement of sweet perception paralleled reduction of the MG composite score during the 15 months follow up period, with immunosuppressive and surgical treatments. We suggest that sweet dysgeusia is a non-motor manifestation of MG that may result from a thymoma-dependent autoimmune mechanism targeting gustducin-positive G-protein-coupled taste receptor cells, in line with recent data from MRL/MpJ-Fas lpr/ (MRL/lpr) transgenic mice with autoimmune disease.


Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors.
Within the bone marrow, stem cells differentiate and give rise to diverse blood cell types and functions. Currently, hematopoietic progenitors are defined using surface markers combined with functional assays that are not directly linked with in vivo differentiation potential or gene regulatory mechanisms. Here, we comprehensively map myeloid progenitor subpopulations by transcriptional sorting of single cells from the bone marrow. We describe multiple progenitor subgroups, showing unexpected transcriptional priming toward seven differentiation fates but no progenitors with a mixed state. Transcriptional differentiation is correlated with combinations of known and previously undefined transcription factors, suggesting that the process is tightly regulated. Histone maps and knockout assays are consistent with early transcriptional priming, while traditional transplantation experiments suggest that in vivo priming may still allow for plasticity given strong perturbations. These data establish a reference model and general framework for studying hematopoiesis at single-cell resolution.


School lunch waste among middle school students: nutrients consumed and costs.
The National School Lunch Program has been guided by modest nutrient standards, and the palatability of meals, which drives consumption, receives inadequate attention. School food waste can have important nutritional and cost implications for policymakers, students, and their families. Nutrient losses and economic costs associated with school meal waste were examined. The study also assessed if school foods served were valid proxies for foods consumed by students. Plate waste measurements were collected from middle school students in Boston attending two Chef Initiative schools (n=1609) and two control schools (n=1440) during a 2-year pilot study (2007-2009) in which a professional chef trained cafeteria staff to make healthier school meals. The costs associated with food waste were calculated and the percentage of foods consumed was compared with a gold standard of 85% consumption. Analyses were conducted in 2010-2011. Overall, students consumed less than the required/recommended levels of nutrients. An estimated $432,349 of food (26.1% of the total food budget) was discarded by middle school students annually at lunch in these Boston middle schools. For most meal components, substantially less than 85% was consumed. There is substantial food waste among middle school students in Boston. Overall, students' nutrient consumption levels were below school meal standards, and foods served were not valid proxies for foods consumed. The costs associated with discarded foods are high; if translated nationally for school lunches, roughly $1,238,846,400 annually is wasted. Students might benefit if additional focus were given to the quality and palatability of school meals.


Shock-wave lithotripsy of renal stones situated adjacent to electronic nerve stimulators.
Shock-wave lithotripsy is commonly employed for the treatment of nephrolithiasis in the pediatric patient population. This report describes such treatment of a patient with electronic nerve stimulators that were located in close proximity to bilateral renal pelvic stones. Precautions and considerations of shock-wave lithotripsy in this context are discussed.


Prevalence of diabetic retinopahty in India: Results from the National Survey 2015-19.
Diabetes mellitus (DM) and diabetic retinopathy (DR) contribute to ocular morbidity and are emerging as diseases with significant public health impact. Our aim was to assess the countrywide prevalence of DR and sight-threatening DR (STDR) among persons with diabetes and to evaluate the coverage of DR examinations among them. The present survey was planned to estimate the burden of DR in the population aged ≥50 years for assisting in the planning and prioritization of diabetic eye services. For this survey, 21 districts with a high prevalence of DM were selected among the 31 districts where the national blindness and visual impairment survey was conducted. The total sample size was 63,000 people aged 50 years and above. DR was assessed by dilated fundus examination with indirect ophthalmoscope and was graded according to Scottish DR grading. STDR included severe nonproliferative DR, proliferative DR, and clinically significant macular edema. The prevalence of diabetes in the surveyed population was 11.8%. Among them, one-third were newly diagnosed DM, that is, diagnosed at the time of the survey. The study revealed that the prevalence of DR among persons with diabetes was 16.9%, the prevalence of STDR was 3.6%, and the prevalence of mild retinopathy was 11.8%. Risk factors for DR in the current study were duration of diabetes (>10 years, OR 4.8, 95% CI: 3.3-6.9), poor glycemic control (≥200 mg/dL, OR: 1.5, 95% CI: 1.2-1.7) and insulin treatment (OR: 2.6, 95% CI: 1.7-4.1). The current study highlights the substantial burden of DM and DR in India and the critical need to adopt a coordinated and multisectoral approach to reduce their prevalence. There is a need for early identification of persons with diabetes and their routine screening for DR along with availability of treatment facilities.


Effect of insulin on sulfated proteoglycan synthesis in cultured smooth muscle cells from pig aorta.
The effect of insulin upon proteoglycan synthesis was studied in cultured smooth muscle cells from pig aorta blocked in the G0 phase by serum deprivation. Insulin enhanced [35S]sulfate incorporation into cell layer and medium-secreted proteoglycans. The increase in incorporation of the precursor was not due to a mitogenic response by smooth muscle cells to the hormone and the specific radioactivity of proteoglycans showed that the stimulation reflected a real increase in sulfated proteoglycan synthesis. Maximal stimulation was observed, for the cell layer as well as for the medium, 40 h after the addition of 1.7 x 10(-7) M insulin and reached respectively 65 and 53%. This stimulation was about 80 and 60% of the level achieved with 10% fetal calf serum for cell layer and medium-secreted proteoglycans, respectively. The half-maximal effect was attained, for both the cell layer and the medium, in the presence of 2.1 x 10(-9) M insulin. Proteoglycans secreted into the medium, in the presence of 1.7 x 10(-8) M insulin for 40 h, showed a higher proportion of complexes (24%) than those synthesized in control medium (11%) and at least 95% of the monomers from culture treated with insulin were characterized by a smaller hydrodynamic size than those synthesized by cells maintained in control medium. This decrease in the size of proteoglycans was partly due to a decrease in the size of their glycanic chains.


Potential relationship among three antioxidant enzymes in eliminating hydrogen peroxide in penaeid shrimp.
Antioxidant enzymes, such as glutathione peroxidase (GPx), catalase (CAT), and peroxiredoxin (Prx), are essential components in cells to eliminate excessive reactive oxygen species such as hydrogen peroxide (H(2)O(2)). GPx, CAT, and Prx genes have been reported in penaeid shrimp, and they showed different expression profiles at transcription or protein level when shrimps were challenged by microbes. In order to learn the relationship among the above three genes in their function, GPx, CAT, and Prx transcripts were analyzed, and the variation of GPx and CAT enzyme activity was detected when shrimp was injected with H(2)O(2) or one antioxidant enzyme gene was silenced in shrimp by double-strand RNA injection. The results indicated that there existed some relationships among three antioxidant enzyme genes, CAT, GPx, and Prx in shrimp at transcriptional level. The transcription of CAT and GPx could be directly induced by H(2)O(2) injection, while the transcription of Prx cannot be induced by H(2)O(2). Decreased transcription level of CAT or GPx could lead to increased transcription of the other two genes, which suggested that there existed some compensation among these three antioxidant enzyme genes. These data can help us to understand the roles of antioxidant enzymes in crustacean.


Zibotentan in systemic sclerosis-associated chronic kidney disease: a phase II randomised placebo-controlled trial.
We report results from a phase II randomised placebo-controlled trial assessing zibotentan, a highly selective endothelin receptor antagonist (ERA), in chronic kidney disease (CKD) secondary to systemic sclerosis (SSc). This trial included three sub-studies: ZEBRA 1-a randomised placebo-controlled, double-blind trial of zibotentan in SSc patients with CKD2 or CKD3 (and glomerular filtration rate (GFR) >45 ml/min) over 26 weeks; ZEBRA 2A-a 26-week placebo-controlled, single-blind trial of zibotentan in scleroderma renal crisis patients not requiring dialysis; and ZEBRA 2B-an open label pharmacokinetic study of zibotentan in patients on haemodialysis. Sixteen patients were screened for ZEBRA 1. Of these, 6 patients were randomised to zibotentan and 7 to placebo. In ZEBRA 1, there were 47 non-serious adverse events (AE) during the trial. Twenty-seven occurred in the placebo group and 20 in the zibotentan group. One serious adverse event (SAE) occurred during ZEBRA1, in the placebo arm. Descriptive statistics did not suggest an effect of study drug on serum sVCAM1. Estimated GFR numerically declined in patients treated with placebo at 26 weeks and 52 weeks. In contrast, average eGFR increased in zibotentan-treated cases. The 4 patients in ZEBRA 2A experienced 8 non-serious AEs, distributed equally between placebo and zibotentan. There was one SAE each in placebo and zibotentan groups, both unrelated to study medication. ZEBRA 2B recruited 8 patients, 6 completed first dosing, and 2 completed a second dosing visit. Pharmacokinetic analysis confirmed zibotentan levels within the therapeutic range. Three patients experienced 3 non-serious AEs. One SAE occurred and was unrelated to study drug. Zibotentan was generally well-tolerated. ZEBRA 1 did not show any effect of zibotentan on serum sVCAM-1 but was associated with numerical improvement in eGFR at 26 weeks that was more marked at 52 weeks. ZEBRA 2B suggested a feasible dose regimen for haemodialysis patients. EudraCT no: 2013-003200-39 (first posted January 28, 2014) ClinicalTrials.gov Identifier: NCT02047708 Sponsor protocol number: 13/0077.


Down-regulation of testicular androgen biosynthesis and LH receptor levels by an LHRH agonist: role of prolactin.
Inhibition of plasma prolactin levels by 2-bromo-alpha-ergocryptine (CB-154) caused a 60% decrease and potentiated the inhibitory effects of [D-Ala6,des-Gly-NH2(10)]LHRH ethylamide on testicular LH receptor levels. Animals treated with the LHRH agonist showed reduced plasma and testicular testosterone levels and elevated progesterone concentration. This progesterone rise was further increased in animals having high circulating prolactin levels but was prevented by CB-154. These data demonstrate that: (1) treatment with the LHRH agonist induces a blockage in the steroidogenic pathway at a step between progesterone and testosterone and (2) prolactin levels to an apparent accentuation of this blockage reflected by higher progesterone levels.


Comparison of hormonal and metabolic markers after a high-fat, Western meal versus a low-fat, high-fiber meal in women with polycystic ovary syndrome.
To determine the effect of meal composition on postprandial T levels in women with polycystic ovary syndrome (PCOS). Randomized, crossover design. Academic research center. Fifteen women with PCOS. We evaluated changes in T, sex hormone binding globulin (SHBG), DHEAS, cortisol, glucose, and insulin for 6 hours after a high-fat, Western meal (HIFAT) (62% fat, 24% carbohydrate, 1 g fiber) and an isocaloric low-fat, high-fiber meal (HIFIB) (6% fat, 81% carbohydrate, 27 g fiber). Change in T levels. Testosterone decreased 27% within 2 hours after both meals. However, T remained below premeal values for 4 hours after the HIFIB meal and 6 hours after the HIFAT meal. Insulin was twofold higher for 2 hours after the HIFIB meal compared with the HIFAT meal. Glucose was higher for 1 hour after the HIFIB meal compared with the HIFAT meal. DHEAS decreased 8%-10% within 2-3 hours after both meals, then increased during the remainder of the study period. Cortisol decreased during the 6-hour period after both meals. Diet plays a role in the regulation of T levels in women with PCOS. Further studies are needed to determine the role of diet composition in the treatment of PCOS.


Maternal anxiety predicts favourable treatment outcomes in anxiety-disordered adolescents.
To determine the differential impact of maternal and paternal internalizing psychopathology on cognitive-behavioural treatment (CBT) outcome of anxiety-disordered children and adolescents. Participants consisted of 127 children and 51 adolescents with a primary anxiety diagnosis. Children were randomly assigned to a standardized group CBT or individual CBT; adolescents received individual CBT. Parents received four training sessions. Participants were evaluated at pre- and post-treatment with a clinical interview and with self- and parent-reported questionnaires. Lifetime anxiety and mood disorders in parents were obtained with a clinical interview. For children, no associations were found between maternal and paternal anxiety or mood disorders and treatment outcome. For adolescents, however, maternal lifetime anxiety disorders were positively associated with pre-post-treatment improvement in clinician severity ratings and with treatment success. Lifetime maternal anxiety disorders were significantly associated with favourable treatment outcomes in adolescents. Paternal disorders were not associated with treatment response.


Familial pericentric inversion of chromosome 1 with a note on reproductive risks.
An inversion of chromosome 1 was found in three normal members of a two generation family. G- and C-banding studies revealed inv(1)(p13q23). The problems encountered in counseling such normal carriers are discussed.


Differential reactivity of anti-primate and anti-human secondary antibodies against human and monkey immunoglobulins: implications for determining the sensitivity of immunogenicity assays.
Development of immunogenicity assays for assessment of human antibodies to therapeutic proteins requires a quantitative determination of assay sensitivity. In the absence of true human positive controls, this is usually accomplished by utilizing affinity-purified antibodies from non-human primates or monoclonal antibodies. In the former case, it is generally considered that non-human primate antibodies will be recognized equally to human antibodies by secondary anti-human immunoglobulin reagents used in immunogenicity assays. We present results here demonstrating that this is not the case. In reality, anti-human immunoglobulin secondary antibodies do not recognize primate immunoglobulins as well as human immunoglobulins. As a result, the use of affinity purified primate antibodies to determine the sensitivity of an immunogenicity assay will likely result in the true sensitivity of the assay being underestimated.


Integrated Instillation Technology for the Synthesis of a pH-Responsive Sodium Alginate/Biomass Charcoal Soil Conditioner for Controlled Release of Humic Acid and Soil Remediation.
In this work, pH-responsive gel spheres for controlled release of humic acid (CSGCHs) were prepared by an integrated instillation technology using a composite material of sodium alginate (SA) and charcoal activated carbon (CAC) as a carrier, and their slow-release performance, pH-responsive performance, and soil amendment performance were investigated. The results showed that the prepared CSGCH was uniform in size with obvious base responsiveness. Soil remediation experiments revealed that CSGCH could play a good role in the remediation of different types of soils. After 50 days of remediation, the content of nutrients and organic matter in the soil increased significantly and the pH and salt content of saline soils decreased by 15.2 and 29.8%, respectively. The plant experiment showed that CSGCH could effectively promote the growth of crops. Therefore, the prepared soil conditioner has a great potential value for improving soil conditions and promoting crop growth in agricultural applications.


Hepatotoxicity associated with antiepileptic drugs.
Drug-induced liver injury associated with antiepileptic drugs (AED) is well recognized. The frequency of the most common AED is rare but the consequences can be very serious leading to death or liver transplantation due to acute liver failure induced by these drugs. Hypersensitivity features are found in more than 70% of patients with phenytoin-induced liver injury, whereas this is only observed in 30% of carbamazepine-associated hepatotoxicity and very rarely with valproate (VPA)-induced liver injury. The underlying mechanisms behind hepatotoxicity induced by AED are not clear. Reactive metabolites from AED can, in some cases, lead to direct cytotoxicity and liver cell necrosis, whereas in other cases this may lead to neoantigen formation inducing immunoallergic mechanisms. No specific therapy is of proved value in severe hepatotoxicity due to AED. However, N-acetylcystein is an appropriate treatment in patients with clinically significant liver injury due to phenytoin and carbamazepine. In patients with VPA-associated liver injury, carnitine that is an important co-factor in the mitochondrial beta-oxidation of fatty acids is the recommended treatment. Early referral of patients with severe liver reactions and coagulopathy to liver transplant centers before encephalopathy can be the difference between liver transplantation and death.


Correlation of flexural strength of coupons versus strength of crowns fabricated with different zirconia materials with and without aging.
The purpose of this study was to determine the presence of a correlation between flexural strength and simulated crown strength; a correlation between crown strength and mode of fracture; an effect of aging on the flexural strength; and an effect of aging on the crown strength. Two hundred forty zirconia specimens were fabricated with 2 different designs, fully contoured crown shape specimens (n = 120) and rectangular coupons (n = 120), to provide 10 specimens each of 6 brands of zirconia (Lava Plus High Translucency [3M ESPE], Argen HT [Argen Corp], Zirlux [Ardent], BruxZir [Glidewell Laboratories], ZenoStar [Wieland Dental], and DDBioZX(2) [Dental Direkt]). One-half of each sample type was given a severe, simulated low-temperature aging treatment. The coupons were tested by 3-point flexural strength, and crowns were tested after luting to metallic abutments using resin cement. Statistical significance was evaluated by 2-factor analysis of variance (P = .05). Aging increased the mean (standard deviation [SD]) flexural strength for the following groups: Argen HT (995 [140] megapascals versus 677 [121] MPa before aging), Zirlux (939 [101] MPa versus 826 [169] MPa before aging), and ZenoStar (954 [81] MPa versus 764 [77] MPa before aging). There were statistical differences for the mean (SD) crown strengths for the following aged crowns: DDBioZX(2) had higher magnitudes (9,755 [1,095] MPa) than ZenoStar (8,864 [976] MPa), whereas Lava Plus High Translucency crowns had higher magnitudes (9,871 [942] MPa) than ZenoStar (8,864 [976] MPa). There was no effect of aging on the crown strength. There were statistical differences in the mode of fracture for the zirconia crowns between the following groups: nonaged and aged BruxZir (P = .014), nonaged and aged ZenoStar (P = .0226), and nonaged and aged Lava Plus High Translucency (P < .0001). There was no correlation between flexural strength and crown strength. There was no direct correlation between ranking of flexural strength and crown strength in the range of properties exhibited by these dental zirconias. Flexural strength does not predict simulated clinical strengths for crowns.


Correction: A Flare for the Unexpected: Bone Flare as Response to Tyrosine Kinase Inhibitor Treatment in a Lung Cancer Patient.
[This corrects the article DOI: 10.5334/jbsr.1907.].


Incidence, outcomes and guideline compliance of out-of-hospital maternal cardiac arrest resuscitations: A population-based cohort study.
Incidence and survival rates after cardiac arrest among pregnant women are reported for in-hospital cardiac arrests; the incidence and outcomes of maternal out-of-hospital cardiac arrest (OHCA) are unknown. Current cardiopulmonary resuscitation guidelines contain recommendations specific to this population; compliance with these has not been investigated. To report maternal OHCA incidence, outcomes, and compliance with recommended treatment guidelines. A population-based cohort study of consecutive maternal OHCAs from 2010 to 2014. Census data of all women of childbearing age provided the comparison. Resuscitation performance was measured against the 2010 American Heart Association (AHA) Guidelines. Six maternal OHCAs were identified among 1085 OHCAs occurring in females of child bearing age (15-49) years; Incidence 1.71 per 100,000 pregnant women (95% CI 0.21 to 6.18) vs. 20.18 OHCAs per 100,000 females of child bearing age (95% CI, 18 to 22.62) p < 0.0001. Survival to hospital discharge was 16.7% (95% CI 3.0, 56.4%) after maternal OHCA vs. 6.8% (95% CI 5.4, 8.4) p < 0.0001 after OHCA in all females of childbearing age, and neonatal survival was 33.3% (95% CI 9.7, 70%). CPR quality metric compliance averaged 83% (range 75% to 100%); compliance with pregnancy-specific resuscitation guidelines ranged from 0% (uterine displacement) to 100% (intravenous line insertion above diaphragm and prehospital maternal team activation). The incidence of maternal OHCA was 1.71:100,000. Survival was higher after maternal OHCA than after OHCA of non-pregnant females of childbearing age. Pregnancy-specific guideline compliance was low suggesting a need for training and better documentation to improve outcomes in these rare events.


Electrophoresis karyotype and chromosome-length polymorphism of Histoplasma capsulatum clinical isolates from Latin America.
Intact chromosomes of 19 clinical isolates of Histoplasma capsulatum recently obtained in Argentina, Mexico and Guatemala and the laboratory reference strain G186B from Panama were analyzed using pulsed-field gel electrophoresis. Chromosomal banding patterns of the human isolates revealed 5-7 bands, ranging from 1.3 to 10 Mbp in size. Strain G186B showed five bands of approximately 1.1, 2.8, 3.3, 5.4 and 9.7 Mbp. Thirteen different electrokaryotypes were identified, indicating that the genome of H. capsulatum varies widely in nature, as observed previously in laboratory strains. No definite association was found between electrokaryotype and geographical or clinical source.


Infiltrating immune cells and gene mutations in pancreatic ductal adenocarcinoma.
The aim of this study was to assess the immune profile within the microenvironment of pancreatic ductal adenocarcinoma (PDAC), and to investigate the prognostic value of intratumoral infiltrating immune/inflammatory cells (IICs) in patients after surgery. Eighteen phenotypic markers representing 11 types of IIC and the protein products of genes TP53, CDKN2A/p16 and SMAD4/DPC4 were assessed by immunohistochemistry of specimens from patients with pancreatic cancer. The expression of IICs and the mutational status of the genes were correlated with tumour recurrence and survival, and results were validated in an independent cohort. CD15+ neutrophils, CD20+ B cells and CD206+ tumour-associated macrophages were seen frequently in tumours, and their presence was associated with reduced survival in a cohort of 79 patients. Expression of CD4+ T helper cells, CD8+ cytotoxic T lymphocytes and CD117+ mast cells was associated with a favourable prognosis. A weighted Cox regression recurrence-predictive model was constructed that showed good correlation of IICs and gene mutations. A combination of CD15, CD206, CD117 and Smad4 expression was independently associated with overall (hazard ratio (HR) 3·63, 95 per cent c.i. 2·18 to 6·04; P < 0·001) and recurrence-free (HR 2·93, 1·81 to 4·75; P < 0·001) survival. These findings were validated in an independent cohort (151 patients) and in 54 tissue samples obtained by preoperative endoscopic ultrasound-guided fine-needle aspiration. PDAC has a unique immunosuppressive phenotype that is associated with characteristic gene mutations, disease recurrence and survival after pancreatectomy. Surgical relevance The immune microenvironment plays a critical role in the development of pancreatic ductal adenocarcinoma (PDAC). PDAC is associated with mutations in major driver genes, including KRAS, TP53, CDKN2A/p16 and SMAD4/DPC4. This study shows that the microenvironment of PDAC has a unique immunosuppressive phenotype, which may be driven by oncogene mutations. Patients with PDAC with a highly immunosuppressive profile tended to have poor postoperative survival. A model including three intratumoral infiltrating immune markers (CD15+, CD206+ and CD117+) and a SMAD4 mutation can be used to predict recurrence and survival in patients after surgery for PDAC.


[Carcinoma of the breast: introduction (author's transl)].
In the German Federal Republic, carcinoma of the breast and colon lie close together as the second und third most tumors. We owe to our surgical forefathers of 100 years ago, Dieffenbach, Rotter, and Halsted, the decisive therapeutic advance whereby as a result of a better understanding of the anatomy of lymphatic drainage, excision of axillary glands and pectoralis muscle was first undertaken. Neither increasing the extent of the operation (superradical excision) nor reducing it (enucleation, partial mastectomy) has so far with any certainly proved as effective as radical mastectomy. The prevalence of various operations used in the western world was ascertained from a survey of about 1000 surgical clinics. With less extensive operations (enucleation) there is the special danger that the understandable desire to strive for a cosmetic result may vitiate the chance of cure.


Biochemical analysis of meiosis in the male mouse. I. Separation of DNA labelling of specific spermatogenic stages.
Spermatogenic cells of the mouse have been separated by gravity sedimentation using a modification of a previously published method. Details are given for the collection of purified samples of specific meiotic stages and for the collection of labelled cell fractions following injection of 3H-thymidine. Suppression of semi-conservative meiotic DNA synthesis, essential to the biochemical analysis of pachytene DNA metabolism, has been achieved by in vivo administration of 1 M hydroxyurea.


Hypertrophic cardiomyopathy with longevity to 90 years or older.
Hypertrophic cardiomyopathy (HC) is the most common cause of sudden death in the young, but survival to particularly advanced age is less well appreciated. The investigators report the prevalence, clinical features, and demographics of patients with HC surviving to ≥90 years of age. Of 1,297 patients with HC in the Hypertrophic Cardiomyopathy Center database (Minneapolis Heart Institute Foundation), 26 (2.0%) were identified who had achieved the age of ≥90 years; 18 (69%) were women. HC diagnosis came late in life, at 61 to 92 years (mean 80 ± 8; ≥75 years in 21 patients), recognized fortuitously by the detection of a heart murmur or during family screening (n = 6) or after onset of new symptoms (n = 20). At most recent evaluation (or death) patients were aged 90 to 96.7 years (mean 92.2 ± 2), with 6 presently alive at 91 to 96 years of age; HC did not appear to be the primary cause of death in any patient. Left ventricular wall thicknesses were 15 to 31 mm (mean 20 ± 3); 8 patients (31%) had obstruction to left ventricular outflow at rest (peak instantaneous gradients, 38 to 135 mm Hg). Significant HC-related complications occurred in 13 patients (50%), including progressive heart failure symptoms, atrial fibrillation, and nonfatal embolic stroke. Although no patient died suddenly, 13 (50%) nevertheless carried conventional HC risk markers. A greater proportion of cohort patients reached ≥90 years of age (2.0%) than expected in the general population (0.8%) (p <0.001). In conclusion, HC may be unrecognized until late in life and is consistent with survival to particularly advanced age into the 10th decade of life without the need for major HC-related treatment interventions, and with demise ultimately largely unrelated to this disease. This principle regarding the natural history of HC can afford a measure of reassurance to many patients.


Structure-based protein engineering for thermostable and alkaliphilic enhancement of endo-β-1,4-xylanase for applications in pulp bleaching.
In the pulp bleaching industry, enzymes with robust activity at high pH and temperatures are desirable for facilitating the pre-bleaching process with simplified processing and minimal use of chlorinated compounds. To engineer an enzyme for this purpose, we determined the crystal structure of the Xyn12.2 xylanase, a xylan-hydrolyzing enzyme derived from the termite gut symbiont metagenome, as the basis for structure-based protein engineering to improve Xyn12.2 stability in high heat and alkaline conditions. Engineered cysteine pairs that generated exterior disulfide bonds increased the kcat of Xyn12.2 variants and melting temperature at all tested conditions. These improvements led to up to 4.2-fold increases in catalytic efficiency at pH 9.0, 50°C for 1h and up to 3-fold increases at 60°C. The most effective variants, XynTT and XynTTTE, exhibited 2-3-fold increases in bagasse hydrolysis at pH 9.0 and 60°C compared to the wild-type enzyme. Overall, engineering arginines and phenylalanines for increased pKa and hydrogen bonding improved enzyme catalytic efficiency at high stringency conditions. These modifications were the keys to enhancing thermostability and alkaliphilicity in our enzyme variants, with XynTT and XynTTTE being especially promising for their application to the pulp and paper industry.


Prognostic value of consolidation-to-tumor ratio on computed tomography in NSCLC: a meta-analysis.
Although several studies have confirmed the prognostic value of the consolidation to tumor ratio (CTR) in non-small cell lung cancer (NSCLC), there still remains controversial about it. We systematically searched the PubMed, Embase, and Web of Science databases from inception to April, 2022 for eligible studies that reported the correlation between CTR and prognosis in NSCLC. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were extracted and pooled to assess the overall effects. Heterogeneity was estimated by I2 statistics. Subgroup analysis based on the cut-off value of CTR, country, source of HR and histology type was conducted to detect the sources of heterogeneity. Statistical analyses were performed using STATA version 12.0. A total of 29 studies published between 2001 and 2022 with 10,347 patients were enrolled. The pooled results demonstrated that elevated CTR was associated with poorer overall survival (HR = 1.88, 95% CI 1.42-2.50, P < 0.01) and disease-free survival (DFS)/recurrence-free survival (RFS)/progression-free survival (PFS) (HR = 1.42, 95% CI 1.27-1.59, P < 0.01) in NSCLC. According to subgroup analysis by the cut-off value of CTR and histology type, both lung adenocarcinoma and NSCLC patients who had a higher CTR showed worse survival. Subgroup analysis stratified by country revealed that CTR was a prognostic factor for OS and DFS/RFS/PFS in Chinese, Japanese, and Turkish patients. In NSCLC patients with high CTR, the prognosis was worse than that with low CTR, indicating that CTR may be a prognostic factor.


Learning from the COVID-19 pandemic in Italy to advance multi-hazard disaster risk management.
COVID-19 challenged all national emergency management systems worldwide overlapping with other natural hazards. We framed a 'parallel phases' Disaster Risk Management (DRM) model to overcome the limitations of the existing models when dealing with complex multi-hazard risk conditions. We supported the limitations analysing Italian Red Cross data on past and ongoing emergencies including COVID-19 and we outlined three guidelines for advancing multi-hazard DRM: (i) exploiting the low emergency intensity of slow-onset hazards for preparedness actions; (ii) increasing the internal resources and making them available for international support; (iii) implementing multi-hazard seasonal impact-based forecasts to foster the planning of anticipatory actions.


Miles to go: an introduction to the 5 Million Lives Campaign.
The Institute for Healthcare Improvement (IHI)'s 5 Million Lives Campaign targets a reduction of five million instances of harm from December 2006 through December 2008. The campaign continues the six interventions of the 100,000 Lives Campaign and adds six more. The campaign's aim is to support the reduction of medical harm, so defined: "Unintended physical injury resulting from or contributed to by medical care (including the absence of indicated medical treatment), that requires additional monitoring, treatment, or hospitalization, or that results in death." The goal of a reduction of five million incidents of harm in two years is based on an estimate that 40 to 50 incidents occur per 100 admissions, for a total of 15 million incidents of medical harm each year in the United States. THE 5 MILLION LIVES CAMPAIGN'S "PLATFORM": This campaign's six new interventions address the prevention of pressure ulcers, reduction of methicillin-resistant Staphylococcus aureus (MRSA) infection, prevention of harm from high-alert medications, reduction of surgical complications, delivery of reliable and evidence-based care for congestive heart failure, and getting hospitals' boards of directors on board. Together with complementary partner initiatives, the 5 Million Lives Campaign is intended to act as a major driver of national improvement.


Cytomegalovirus and rubella seroprevalence in pregnant women in Izmir/Turkey: follow-up and results of pregnancy outcome.
It is aimed to determine the Rubella and CMV prevalence in the pregnant women in Izmir and to research the effect of these infections on the course of pregnancy in the pregnant women exposed to infection during pregnancy. The pregnant women applied to pregnancy outpatient department during 2001-2008 have been examined with enzyme-linked fluorescent assay (VIDAS; bioMérieux) method in terms of Rubella and CMV IgM and IgG antibodies and CMV IgG avidity test. Totally 5,959 pregnant women were included in the study. The seropositivity rates for Rubella and CMV were found as 97.8 and 98.3 %, IgM positivity rates were found as 0.37 and 0.18 %, respectively. Curettage was recommended to the pregnant women in which Rubella IgM positivity was detected in the first trimester of the pregnancy. Eight of the pregnant women in which IgM was found as positive after the 20th week of pregnancy were examined and three intrauterine growth retardation, one hypospadias and three normal deliveries were seen in these pregnant women. Any congenital anomaly finding was not detected in the pregnant women with positive CMV IgM. Seroprevalence values are high for Rubella and CMV in our region. It can be recommended not to check the pregnant women routinely for this purpose with the good implementation of Rubella vaccine programs.


[Role of PI3K/AKT pathways in mitomycin-mediated apoptosis of WB-F344 cells].
To investigate the role of p38MAPK and PI3K/AKT pathways in mitomycin (MMC)-induced apoptosis in the liver stem-like cell line WB-F344. WB-F344 cells were exposed to MMC and apoptosis was evaluated by flow cytometry and DNA fragmentation. Phospho-MAPK and phospho-PI3K/AKT were detected by western blotting. MMC induced apoptosis in WB-F344 cells at 6h after addition of MMC; the maximum level of apoptosis was reached at 24h after MMC exposure. The apoptosis effects of MMC were concentration dependent and inhibited when the PI3K pathway was abolished by the specific inhibitor LY294002, but not inhibited when the p38MAPK pathway was abolished by inhibitor SB203508. Apoptosis of WB-F344 cells can be induced by MMC.Although MMC can activate both the PI3K/AKT and p38MAPK pathways, the apoptosis effect of MMC occurs via a PI3K pathway and is not dependent on the p38MAPK pathway.


Acetone-dependent regulation of cytochromes P4502E1 and P4502B1 in rat nasal mucosa.
The inducibility and molecular regulation of cytochrome P4502E1 (CYP2E1) has been examined in nasal mucosa of rats after acetone treatment and compared to that of cytochrome P4502B1 (CYP2B1). Twenty-four hours following treatment with acetone (5 mL/kg) for 2 days, the amount of CYP2E1 as well as the rate of microsomal 4-nitrophenol hydroxylase activity had increased by a factor of 2-3, in microsomes isolated from nasal mucosa. The increase in CYP2E1 was accompanied by a corresponding increase of CYP2E1 mRNA, as determined by northern and slot blot analyses. In contrast, hepatic and renal CYP2E1 mRNA, studied in the same rats, did not increase, despite the fact that the amount of CYP2E1 was increased 3- and 5-fold, respectively. The amount of CYP2B1, an isozyme known as acetone-inducible in other tissues, decreased significantly by acetone, as detected by immunoblot analysis. After 48 hr, the amount of CYP2E1 enzyme, the level of CYP2E1 mRNA and the rate of 4-nitrophenol hydroxylase activity had returned to normal levels, whereas in liver and kidneys the immunoreactive protein remained 3-4-fold higher than control. The results indicate that acetone does not regulate CYP2E1 in nasal mucosa by post-translational mechanisms, in contrast to the situation observed in liver and kidneys. This indicates a tissue-specific expression of post-translational regulatory systems responsible for P450 stabilization. Furthermore, nasal CYP2B1 also seems to be regulated in a tissue-specific manner by acetone.


Pulmonary histoplasmosis in a Japanese male: report of a case.
A case of pulmonary histoplasmosis, which is rare in Japan, is reported herein. A 43-year-old man who had worked in Mexico for 2 years and had come back to Japan 3 months earlier, presented at our hospital because of an abnormal shadow on his chest roentogenogram with no symptoms. His chest roentogenogram as well as chest computed tomograms revealed a 2-cm-diameter nodule in the anterior basal segment of his right lung and an enlargement of the subcarinal lymph node. Although these pictures seemed to indicate an advanced lung cancer, no malignant cells were found based on the brushing cytology findings after bronchoscopy. An exploratory thoracoscopic tumor resection and biopsy of the enlarged lymph node led to a histological diagnosis of an abscess due to histoplasma. The hospital course was uneventful. Postoperatively, amphotericin B was administered for 1 year. This is the eighth case of pulmonary histoplasmosis reported in Japan. A pulmonary nodule together with mediastinal lymphoadenopathy seems to be characteristic in these patients. Histoplasmosis should therefore be considered in the differential diagnosis, since overseas travel has now become common-place for the Japanese.


Oncogene profile of papillary thyroid carcinoma.
Our purpose was to study the expression of multiple oncogenes in papillary thyroid cancer for possible interactions and prognostic significance. Twenty papillary thyroid carcinomas were studied for expression/mutation of 3 oncogenes: ras, ret/PTC, and erbB-2/neu. H, N, and K ras codons were examined by polymerase chain reaction (PCR), single-stranded conformation polymorphism, and sequencing. The thyroid oncogene ret/PTC was identified by reverse transcription (RT)-PCR. Gene amplification of erbB-2/neu was analyzed by differential PCR. The transmembrane domain of erbB-2/neu was sequenced for activating mutations. Quantitation of erbB-2/neu mRNA was evaluated by competitive RT-PCR, and protein expression was determined by immunohistochemistry. Among 20 tumors, 3 had insular/anaplastic dedifferentiation, 13 were intrathyroidal, and 7 were metastatic to cervical lymph nodes (6) or lung (1). An H-ras 13 mutation was found in 1 metastatic tumor and an N-ras 61 mutation in 1 intrathyroidal tumor. ret/PTC was identified in 3 intrathyroidal and 5 metastatic tumors. No erbB-2/neu DNA amplification or mutations were identified, although 4 tumors had elevated erbB-2/neu mRNA levels. Three of 20 patients had abnormalities detected in multiple oncogenes; 2 had elevated erbB-2/neu mRNA and ret/PTC rearrangements, and 1 of these had pulmonary metastasis. An intrathyroidal papillary cancer had an N61 ras mutation and a ret/PTC gene rearrangement. ret/PTC rearrangements are present in 40% of papillary thyroid carcinomas and may play a role in metastatic behavior. In contrast, ras mutations are rare (10%). erbB-2/neu gene amplification and activating mutations are not detected, although elevated mRNA levels were found in 20% of papillary carcinomas. The lack of correlation among the 3 oncogenes in 17 of 20 (85%) papillary thyroid carcinomas suggests that they were not cumulative factors in the pathogenesis of these tumors.