Rationale and design of a randomized clinical study to investigate the effect of ezetimibe, a cholesterol absorption inhibitor, on the regression of intracoronary plaque evaluated by non-obstructive angioscopy and ultrasound: The ZIPANGU study.
It is well recognized that low-density lipoprotein cholesterol (LDL-C)-lowering therapy is effective for primary and secondary prevention of cerebrovascular/cardiovascular disease. Ezetimibe, an inhibitor of the Niemann-Pick C1-Like 1 cholesterol transporter, is a relatively new drug for LDL-C-lowering therapy in addition to statins. However, comparison between an aggressive LDL-C-lowering therapy with a combination of statin and ezetimibe versus a standard LDL-C-lowering therapy with statin alone is still unclear in terms of their effects on stabilization and volume regression of coronary plaque. The ZIPANGU (Ezetimibe clinical investigation for the regression of intracoronary plaque evaluated by angioscopy and ultrasound) study is aimed at comparing these two types of therapy based on indices of plaque characteristics using non-obstructive coronary angioscopy and intravascular ultrasound. The study is a multi-center, prospective, randomized, open-label, blinded-endpoint trial. Through a centralized enrollment method, patients will be allocated to either monotherapy with atorvastatin alone or to combination therapy with atorvastatin (maximum: 20mg/day) and ezetimibe (10mg/day). The target LDL-C level will be <100mg/dL for the monotherapy group and <70mg/dL for the combination therapy group. At the baseline and the follow-up period of 9 months, non-obstructive coronary angioscopy and intravascular ultrasound will be performed to compare the changes in plaque color and volume between the two groups. The ZIPANGU study will clarify whether combination therapy with statins and ezetimibe is better for stabilizing coronary plaque as secondary prevention than monotherapy by statins alone. The study will give new insights into lipid-lowering guidelines in Japan.


Soft-templated mesoporous carbon-modified glassy carbon electrode for sensitive and selective detection of aristolochic acids.
In this study, ordered mesoporous carbon (OMC) was synthesized by applying a soft template method, and its mesoporous structure was characterized by scanning electron microscopy, transmission electron microscopy, and nitrogen adsorption-desorption techniques. X-ray diffraction and Raman spectroscopic analyses were conducted to demonstrate the high graphitization and topological defects at the sample surface. An electrochemical sensor based on an OMC-modified glassy carbon electrode (OMC/GCE) was constructed to detect aristolochic acids (AAs) using cyclic voltammetry and linear sweep voltammetry. The dependence of the experimental parameters including solution pH, scan rate, and accumulation time were examined and optimized. Under the optimal conditions, the response of OMC/GCE was linear over wide concentration ranges of AAs (0.6-10 μM and 10-50 μM), with sensitivities of -1.77 and -0.31 μA/μM, respectively. The limit of detection was calculated to be 0.186 μM (at S/N = 3). Furthermore, the proposed OMC/GCE was applied to detect AAs in Asarum sieboldini and the content of AAs was calculated to be 8.9 μg/g with high accuracy and precision. In addition, the modified electrode also exhibited good selectivity, reproducibility, and stability. Therefore, the OMC/GCE can be used as a platform for the determination of AAs.


The impact of gender, race, socioeconomic status, and treatment on outcomes in esophageal cancer: A population-based analysis.
African Americans and Hispanics are reported to have higher mortality from esophageal cancer (EC) than Caucasians. In this study, we analyzed the independent effects of race, gender, treatment, and socioeconomic status (SES) on overall survival (OS). Data for all EC cases between 2004 and 2010 with follow-up through 2012 were obtained from the California Cancer Registry. We conducted descriptive analyses of clinical variables and survival analyses by Kaplan-Meier and Cox proportional hazards methods. African Americans and Hispanics were more likely to be in the lower SES strata and less likely to receive surgery than Caucasians in this cohort. The proportion of patients receiving chemotherapy and radiotherapy was similar across different racial/ethnic groups. After adjustment for stage, grade, histology, treatments, and SES in multivariate analyses, the mortality risk in African Americans (hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.85-1.07) and Hispanics (HR 0.96, 95% CI 0.89-1.07) did not differ from Caucasians (HR = 1.00, referent), with histology, SES, and surgery largely accounting for unadjusted OS differences. We also observed that African American men had higher adjusted risk of death relative to Caucasian men (HR 1.24, 95% CI 1.07-1.42), but this effect was not observed for African American women compared to Caucasian women (HR 1.12, 95% CI 0.94-1.35). Race is not an independent risk factor for OS in our population-based analysis of EC cases. Rather, observed differences in OS by race/ethnicity result from differences in cancer histology, SES, surgery, and gender. Our findings support further health disparities research for this disease.


Stress and associated factors among dentists.
Studies have shown that dentists are experiencing stress at work and it might have an impact on general health. Dental students have reported negative effect of stress starting in undergraduate studies period. The various predisposing factors have been identified and determined. The aim of our study was to determine and compare stress among dentists of different specializations. A cross-sectional study was conducted in March-September 2016 among 317 dentists. 151 (48%) form public and 166 (52%) from private clinics. All participants were dental practitioners working in Kaunas, Lithuania. A modified version of Occupational stress questionnaire (Institute of Health, Helsinki, Finland, 1992) was used. Chi-square, Kolmogorov-Smirnov test Mann-Whitney U tests, Student's (t) criterion and logistic regression analysis model served for statistical analysis. Majority of dentists were women (85%) and 61.8% of all participants were general practitioners. More general practitioners and paediatric dentists specialists were working in public clinics. The most stressful factors were: restrictions, work tension, and responsibility, while least stressful were value of work, work and life satisfaction (p<0.05). The intensive stress (>3) was indicated mostly by general practitioners, pediatric dentists and periodontologists. Stress is more experienced by dentists working in public clinic being as a general practitioner or having specialization of periodontologist or pediatric dentist. Dentists should be encouraged to take stress management course to cope with.


[Modulation of the neutrophil died process-mechanisms of the flap protection from ischemia-reperfusion with dexamethasone].
To study the modulation of neutrophil apoptosis and necrosis, elucidate the protecton mechanisms of dexamethasone. 50 rats were divided into 5 groups. I: normal island flap. II: artery occlusion for 8 hours, saline given into peritoneal. III: venous occlusion for 8 hours, saline given into peritoneal. IV: artery occlusion for 8 hours, dexamethasone injected through peritoneal. V: venous occlusion for 8 hours, dexamethasone injected through peritoneal. Flap survived areas were measured, neutrophil apoptosis and necrosis values were ananlyzed with FCM. Their morphology were observed with light microscopy. The swallows of apoptotic neutrophil by mascrophages were studied with transmission electron microscopy. Flap survived areas I, IV and V groups were higher than that in II and III groups, which in I, IV, V had no significant values. Apoptotic neutrophils values in II and III groups on 1, 3 days were less than that in, but on 6 days, higher than that in I, IV and V. Necrotic neutrophils showed another tendency postoperatively when compared with its apoptotic values. There were more swallows of apoptotic neutrophils in flaps of IV, V groups than that in II, III flaps. Dexamethasone's flap protection results from modulating of neutrophils apoptosis, decreasing it's necrosis, increasing swallowings values of apoptotic neutrophils by macrophages.


Mycobacterium marinum infections of the hand.
Fifteen patients had culture proven Mycobacterium marinum infections of the hand; 11 had injured their hands while fishing in water around Long Island. No patient had type I lesions (verrucal), six patients had type II lesions (subcutaneous granulomas), and nine patients had type III lesions (deep). Histologic examination showed noncaseating granulomas in all cases. A specific defect in the patients' lymphocytes ability to respond to M. marinum antigens was identified. A combination of surgery and tetracycline provided effective treatment. Follow-up averaged 2 1/2 years.


What learning-disabled readers fail to retrieve on verbal dichotic tests: a problem of encoding, retrieval, or storage?
Three theoretical models were assessed as a framework for capturing learning-disabled readers' faulty word retrieval. To this end, learning-disabled and skilled readers were compared on verbal dichotic listening tasks for free recall and cued recall of word lists organized by semantic, phonemic, and structural features. The results indicated that disabled readers were comparable on free recall but were inferior to skilled readers on cued recall. No ability group differences were found for categorical and noncategorical recall intrusions during the cued recall phase. Cued recall performance was further analyzed for individual differences in memory trace structure (via the Tulving & Watkins, 1975, reduction method), ear asymmetry, and the allocation of attention to word features prior to cuing. Results indicated that during the cued recall phase, disabled readers' memory traces were inferior in structure to those of skilled readers, even though the two ability groups produced comparable symmetrical recall patterns for the ear presentations. Further, disabled readers had lower selective attention scores for the interhemispheric processing of information prior to cuing than did skilled readers. Taken together, the results suggest that, prior to cued recall, disabled readers suffer from attentional difficulties during interhemispheric processing, which in turn influences the structural formation of their memory trace.


Preimplantation genetic screening in a case of recurrent trisomy 21 offspring.
To describe a unique case of recurrent aneuploidy and the use of preimplantation genetic screening (PGS). Case report. Midwest academic medical center. A 36-year-old woman with two trisomy 21 offspring. Preimplantation genetic screening. Karyotype of embryos, liveborn eukaryotic infant. Preimplantation genetic screening was performed on three cryopreserved embryos, followed by a two-embryo transfer yielding a eukaryotic infant. Preimplantation genetic screening may prove to be useful as a diagnostic tool to help ensure a euploid pregnancy when termination is not a viable option for a couple.


Poly(ADP-ribosylation) of P-TEFb by PARP1 disrupts phase separation to inhibit global transcription after DNA damage.
DNA damage shuts down genome-wide transcription to prevent transcriptional mutagenesis and to initiate repair signalling, but the mechanism to stall elongating RNA polymerase II (Pol II) is not fully understood. Central to the DNA damage response, poly(ADP-ribose) polymerase 1 (PARP1) initiates DNA repair by translocating to the lesions where it catalyses protein poly(ADP-ribosylation). Here we report that PARP1 inhibits Pol II elongation by inactivating the transcription elongation factor P-TEFb, a CDK9-cyclin T1 (CycT1) heterodimer. After sensing damage, the activated PARP1 binds to transcriptionally engaged P-TEFb and modifies CycT1 at multiple positions, including histidine residues that are rarely used as an acceptor site. This prevents CycT1 from undergoing liquid-liquid phase separation that is required for CDK9 to hyperphosphorylate Pol II and to stimulate elongation. Functionally, poly(ADP-ribosylation) of CycT1 promotes DNA repair and cell survival. Thus, the P-TEFb-PARP1 signalling plays a protective role in transcription quality control and genomic stability maintenance after DNA damage.


Combined drug therapy in the management of granulomatous amoebic encephalitis due to Acanthamoeba spp., and Balamuthia mandrillaris.
Granulomatous amoebic encephalitis (GAE) is caused by two protist pathogens, Acanthamoeba spp., and Balamuthia mandrillaris. Although rare, it almost always results in death. In the present study, amoebae were treated with various combinations of clinically-approved drugs, targeting vital cellular receptors and biochemical pathways. The results revealed that among the seven different combinations tested, three proved highly effective against both Acanthamoeba castellanii as well as B. mandrillaris at a concentration of 100μM. These combinations included (i) prochlorperazine plus loperamide; (ii) prochlorperazine plus apomorphine; and (iii) procyclidine plus loperamide. In viability assays, none of the drug-treated amoebae emerged as viable trophozoites, suggesting irreversible amoebicidal effects. Four combinations of drugs tested showed varied potency against A. castellanii and B. mandrillaris at 100μM. The combination of haloperidol and loperamide was highly effective against A. castellanii at 100μM, but potent effects against B. mandrillaris were observed only at 250μM. Digoxin and amlodipine were effective against A. castellanii and B. mandrillaris at 100μM and 250μM, respectively. In contrast, the combination of apomorphine and haloperidol was effective against B. mandrillaris and A. castellanii at 100μM and 250μM, respectively. At 100μM, the combination of procyclidine and amiodarone was effective against neither A. castellanii nor B. mandrillaris. In this case, amoebicidal properties were observed at 750μM for A. castellanii, and 950μM for B. mandrillaris. As these drugs are used clinically against non-communicable diseases, the findings reported here have the potential to be tested in a clinical setting against amoebic encephalitis caused by A. castellanii and B. mandrillaris.


[Escherichia coli K-12 mutants with increased resistance to ionizing radiation. V. The effect of mutations on spontaneous and radiation mutagenesis].
The frequencies of spontaneous mutations (reversions his-4----His+ and forward mutations to rifampicin-, nalidixic acid- or valine-resistance) in radiation-resistant mutants Gamr444 and Gamr445 are much lower than in the wild-type strain AB1157. His+ revertants and rifampicin-resistant mutants Rifr are induced by low doses of gamma-rays more efficiently than in the wild-type. Low doses of UV light only enhanced mutagenic activity in Gamr strains for induction of His+ reversions but not for Rifr mutations. For the wild-type strain the frequencies of His+ and Rifr mutations increase proportionally to the square of dose both of UV light and gamma-rays. For the most radioresistant Gamr444 mutant the frequencies of UV- and gamma-rays-induced Rifr mutations and of gamma-rays-induced reversions increase linearly with the dose. Possible reasons for these anomalies of radiation-induced mutagenesis in Gamr mutants are discussed.


Non-differential measurement error does not always bias diagnostic likelihood ratios towards the null.
Diagnostic test evaluations are susceptible to random and systematic error. Simulated non-differential random error for six different error distributions was evaluated for its effect on measures of diagnostic accuracy for a brucellosis competitive ELISA. Test results were divided into four categories: < 0.25, 0.25-0.349, 0.35-0.499, and > or = 0.50 proportions inhibition for calculation of likelihood ratios and diagnostic odds ratios. Larger variance components of the error structure resulted in larger accuracy attenuations as measured by the area under the receiver-operating characteristic curve and systematic components appeared to cause little bias. Added error caused point estimates of likelihood ratios to be biased towards the null value (1.0) for all categories except 0.25-0.349. Results for the 0.35-0.499 category also extended beyond the null value for some error structures. Diagnostic odds ratios were consistently biased towards the null when the < 0.25 category was considered the reference level. Non-differential measurement error can lead to biased results in the quantitative evaluation of ELISA and the direction is not always towards the null value.


Paediatric surgical oncology. 5--Nephroblastoma. International Society of Paediatric Oncology (SIOP) Nephroblastoma Trial & Study Committee.
The favourable results from the treatment of Wilms' tumour are an example of the success of multimodal therapy in paediatric oncology. The epidemiology, methods of diagnosis, benefits of pre-operative chemotherapy, basic principles of surgery and post-operative treatment modalities are presented. The approach to the management of Wilms' tumour considered in this paper is mainly that of the International Society of Paediatric Oncology.


Development and validation of a risk score (CHANGE) for cognitive impairment after ischemic stroke.
Post-stroke cognitive impairment (PSCI) warrants early detection and management. We sought to develop a risk score for screening patients at bedside for risk of delayed PSCI. Ischemic stroke survivors with PSCI and no cognitive impairments (NCI) 3-6 months post-stroke were studied to identify candidate variables predictive of PSCI. These variables were used to develop a risk score using regression models. The score, and the best identified clinical cutoff point, underwent development, stability testing, and internal and external validation in three independent cohorts from Singapore and Hong Kong. Across 1,088 subjects, the risk score, dubbed CHANGE, had areas under the receiver operating characteristics curve (AUROC) from 0.74 to 0.82 in detecting significant risk for PSCI, and had predicted values following actual prevalence. In validation data 3-6 and 12-18 months post-stroke, subjects with low, medium, and high scores had PSCI prevalence of 7-23%, 25-58%, and 67-82%. CHANGE was effective in screening ischemic stroke survivors for significant risk of developing PSCI up to 18 months post-stroke. CHANGE used readily available and reliable clinical data, and may be useful in identifying at-risk patients for PSCI.


The impact of oral health on prognosis of older multimorbid inpatients: the 6-month follow up MPI oral health study (MPIOH).
There is clear evidence for an association between oral health and systemic illnesses, geriatric syndromes, and mortality. Frail and multimorbid older people often suffer from insufficient oral health care, but standardized dental examinations are not routinely performed in clinical settings. The aim of this study was to verify the practicability of in-hospital oral health examinations and to identify their association with patients' prognosis as assessed by means of the Comprehensive Geriatric Assessment (CGA)-based Multidimensional Prognostic Index (MPI). One hundred hospitalized patients aged 65 years and older (mean age 76.9 years (SD 6.4); 58.2% male, 41.8% female) underwent a CGA-based MPI calculation at discharge with subdivision into three mortality risk groups (MPI-1, low risk, score 0-0.33; MPI-2, moderate risk, score 0.34-0.66; MPI-3, high risk, score 0.67-1). To identify the current oral health status and the Oral Health-related Quality of Life (OHRQoL), three oral health examinations were performed. Information on survival, the incidence of oral diseases, dental appointments, and treatments up to 6 months after discharge were collected. All oral health examinations were feasible during hospitalization and were associated with MPI prognosis, even though they were not associated with 6-month mortality. The MPI could not predict the use of dental health care or treatment, as, irrespective of MPI and oral health examinations, dental services were underutilized during follow up. Besides MPI evaluation, oral health examinations should be implemented into an inhospital course to improve clinical decision-making as well as secondary and tertiary prevention of oral health- and related systemic diseases. German Clinical Trials Register: DRKS00013607 (07.02.2019, retrospectively registered).


Fat Grafting for Treatment of Secondary Facial Deformity.
Craniofacial deformities represent a great challenge for the patient and the plastic surgeon. Fat grafting has allowed a shift in paradigm for craniofacial reconstruction by providing a less invasive and safer alternative than traditional reconstructive options. Increasing evidence supports its use with optimal results. This article examines the evidence and practical aspects involved in the decision making and technique of fat grafting to treat secondary craniofacial deformities.


Simultaneous determination of l-ascorbic acid, ascorbic acid-2-phosphate magnesium salt, and ascorbic acid-6-palmitate in commercial cosmetics by micellar electrokinetic capillary electrophoresis.
L-ascorbic acid (LAA) can be used as a whitening agent in cosmetics. Because of its instability, some more stable derivatives have been developed to control melanin production, such as ascorbic acid-2-phosphate magnesium salt (AAPM) and ascorbic acid-6-palmitate (AA6P). To assess the quality of cosmetics, a micellar electrokinetic capillary electrophoresis technique (MEKC) was established for simultaneous analysis of AA and its two derivatives. Separation was performed with 10mM borate (pH 9.5) containing 50 mM sodium dodecyl sulfate (SDS) at 20 kV. The detection wavelength was 265 nm. Several parameters, including borate concentration, buffer pH, and SDS level, were investigated. On method validation, calibration curves were linear over a concentration range of 150.0-1000.0 microM for LAA and 200.0-1000.0 microM for AAPM and AA6P. For intraday and interday analysis, relative standard deviation and relative errors were all less than 3%. Limits of detection were 70 microM for AAPM and AA6P, and 50 microM for LAA. All recoveries were greater than 95%. This method was applied to quality control of commercial cosmetics.


Peripheral retinal ischemia in a young Indian woman with neurofibromatosis type 1.
Neurofibromatosis type 1 (NF-1) is an autosomal dominantly inherited disease characterized by café-au-lait spots, neurofibromas, axillary freckling, Lisch nodules of iris, gliomas and various systemic vascular ischemic manifestations mainly in the aorta, brain and kidney. Retinal vascular manifestations in patients with NF-1 are usually representative of retinal capillary hemangiomatosis. Few cases of NF-1 with retinal vascular occlusive disease have been described. We describe a young Indian woman with NF-1 with unilateral peripheral retinal ischemia but no vascular abnormality at the posterior pole.


Megalourethra and bladder foreign body in a female patient.
Undiagnosed female megalourethra can be a cause of iatrogenic bladder foreign body. Foreign bodies in the urinary bladder are relatively rare. Female megalourethra is an extremely rare congenital disorder which is usually associated with Müllerian anomalies. We describe a case of an iatrogenic bladder foreign body and a megalourethra in a young woman with normal gynecological organs.


[A knowledge, attitude and practice survey on SARS in a rural area].
To learn the knowledge, attitude and practice (KAP) of rural people towards Severe Acute Respiratory Syndrome (SARS), and to quickly provide the informations to decision-making department. The observation, interview via telephone, personal in-depth interview and structured questionnaire methods were conducted to survey the KAP level about SARS. From May 5th to 7th in 2003, 118 people in Pinggu County, Beijing China were investigated. 97.7% of them knew SARS was one infectious disease, 73.0% of them knew it spread via saliva, 94.4% of them knew fever was the early symptom, 86.8% of them thought the best prevalent method was opening the windows and respiring fresh air, 90.0% of them thought it could be cured. 92.4% of people received all above knowledge about SARS via television. There was the condition to avoid the SARS to diffuse and extend in the rural area as Pinggu.


Genetically encoding latent bioreactive amino acids and the development of covalent protein drugs.
As natural proteins generally do not bind targets in a covalent mode, the therapeutic potential of covalent protein drugs remains largely unexplored. Recently, latent bioreactive amino acids have been incorporated into proteins through genetic code expansion, which selectively react with nearby natural residues via proximity-enabled reactivity, generating diverse covalent linkages for proteins in vitro and in cells. These new covalent linkages provide novel avenues for protein research and engineering. In addition, a general platform technology, proximity-enabled reactive therapeutics (PERx), has been established for the development of covalent protein drugs. The first covalent protein drug demonstrates advantageous features in cancer immunotherapy in mice. Selective introduction of covalent bonds into proteins will advance biological studies, synthetic biology, and biotherapeutics with the power of biocompatible covalent chemistries.


Air-jet spun tissue engineering scaffolds incorporated with diamond nanosheets with improved mechanical strength and biocompatibility.
The development of highly porous cell supportive polymeric scaffolds with sufficient mechanical strength has always been a challenging task in tissue engineering. The widely used nanofiber fabrication methods like electrospinning are time consuming and the obtained nanofibrous scaffolds are generally consist of compactly packed fibers, which affect proper cell penetration. On the other hand, air-jet spinning is an upcoming, less explored alternative approach for generating loosely arranged nanofibrous scaffolds within short time. However, air-jet spun scaffolds show inferior mechanical properties due to loosely organized fibers. Herein, we report the fabrication and detailed characterization of polycaprolactone (PCL) tissue engineering scaffolds loaded with diamond nanosheets (DNS) by air-jet spinning. Our results showed that the inclusion of DNS could improve the mechanical strength of the scaffolds. In vitro biocompatibility, and in vivo implantation studies demonstrated that PCL-DNS scaffolds are highly biocompatible and are suitable for tissue engineering applications. Our studies showed that mammalian cells can proliferate well in the presence of PCL-DNS scaffolds and the nanocomposite scaffolds implanted in rats did not show any considerable adverse effects. Overall, the findings show that the developed novel air-jet spun PCL-DNS nanocomposite scaffolds can be used as cell supportive scaffolds for various tissue engineering applications.


Binding of serotonin and dopamine to 'serotonin binding proteins' in bovine frontal cortex: evidence for iron-induced oxidative mechanisms.
Binding of [3H]serotonin and of [3H]dopamine to serotonin binding proteins (SBP) from soluble extracts of bovine frontal cortex is increased by Fe2+ but not by Fe3+. It was generally believed that Fe2+ first binds to sulfhydryl groups of SBP and that the monoamines form coordination bonds with the trapped iron. We report two series of findings that are incompatible with this mechanism. First, the binding of both radioligands is an irreversible process since it is not diminished when a large excess (1 mM) of serotonin or dopamine is added to a pre-equilibrated mixture of SBP, 0.1 mM Fe2+ and 0.2 microM radioligand. Once formed, binding is not impaired by chelating agents such as ethyleneglycoltetraacetic acid and desferal. Second, the Fe(2+)-stimulated binding is inhibited by reducing agents (sodium ascorbate, vitamin E, sodium metabisulfite) and by agents which deplete superoxide radicals (superoxide dismutase and hydrogen peroxide). Moreover, the effect of Fe2+ can be mimicked by oxidants (sodium periodate, potassium superoxide) and by the generation of superoxide radicals by the xanthine oxidase-catalysed oxidation of xanthine. To integrate these findings, we formulate the hypothesis that Fe2+ reacts with dissolved molecular oxygen to produce superoxide radicals, that these radicals oxidise [3H]serotonin and [3H]dopamine, and that the formed oxidation products bind covalently to cysteine residues of SBP. This alternative mechanism is also based on the ability of reagents which contain or modify sulfhydryl groups to decrease the binding and on the inability of hydroxyl radical scavengers (dimethyl sulfoxide, mannitol, ethanol and thiourea) to do so. Fe2+ is also able to irreversibly inactivate part of the binding sites on SBP (81% of the specific binding of [3H]serotonin, and 61% for [3H]dopamine). This Fe(2+)-mediated inactivation, as well as the covalent nature of the binding, preclude the interpretation of saturation and competition binding data in terms of reversible bimolecular interactions. Yet, such experiments indicate that, at the same concentration, [3H]dopamine binds to 2 to 3 times more sites than [3H]serotonin. Unlabelled dopamine acts also as a potent competitor at all the [3H]serotonin binding sites, whereas unlabelled serotonin only acts as a potent competitor at part (30%) of the [3H]dopamine binding sites. SBP were initially proposed to be involved in the storage, protection and/or transport of serotonin, and recently also of catecholamines. However, these potential functions of SBP can hardly be reconciled with the molecular mechanism of the binding. Moreover, it is conceivable that this binding actually represents an in vitro model for neurodegeneration.


[Pulmonary alveolar microlithiasis: A report on two familial cases in Morocco].
Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive disease. The majority of patients are asymptomatic. The disease is often diagnosed on routine radiological examination. We report two familial cases of PAM. A 17-year-old girl with a chest X-ray showing an alveolar syndrome, especially on the right side, a bronchointerstitial syndrome, and diffuse calcifications. The thoracic CT scan showed calcified micro- and macronodules with pleural and pericardial calcifications. Respiratory function tests showed restrictive syndrome and normal blood gas values suggestive if PAM, which was confirmed by the presence of microliths in bronchoalveolar lavage (BAL). Family investigation led to chest radiograph of a 14-year-old sister who was asymptomatic but presented with an aspect of "sandstorm" calcifications. PAM is known to be radio-clinically dissociative. In typical cases, radiology can suggest the diagnosis, which is often confirmed by SLC34A2 mutation or microliths in BAL or sputum. The prognosis is compromised in the long-term. The only effective treatment nowadays is lung transplantation.


[Secure app usage-Evaluation benchmarks for medical apps : Quality aspects for health apps based on 9 key criteria].
Smartphones and health apps are an integral part of everyday life. They are increasingly being used for medical purposes. However, there is no fundamental basis or consensus on the evidence on which decisions are made towards a unified digital strategy. Consequently, the understanding of the quality of health apps is only inconsistent and fuzzily defined. The 9 quality criteria presented by the Association of Medical Societies (AWMF)-transparency, appropriateness, risk appropriateness, ethical harmlessness, legal conformity, content validity, technical appropriateness, usability, resource efficiency-serve as a guide for individual and institutionalized quality assessment. The principles are based on a comprehensive compilation of existing (inter-) national standards and evaluation benchmarks. Analogously to usual medical practice, it is also obligatory to conduct one's own research for a suitable app and to weigh up the risks and benefits when using an app.


Ultrasound imaging of the axilla.
Axilla is a pyramidal-in-shape "virtual cavity" housing multiple anatomical structures and connecting the upper limb with the trunk. To the best of our knowledge, in the pertinent literature, a detailed sonographic protocol to comprehensively assess the axillary region in daily practice is lacking. In this sense, the authors have briefly described the anatomical architecture of the axilla-also using cadaveric specimens-to propose a layer-by-layer sonographic approach to this challenging district. The most common sonographic pathological findings-for each and every anatomical compartment of the axilla-have been accurately reported and compared with the corresponding histopathological features. This ultrasound approach could be considered a ready-to-use educational guidance for the assessment of the axillary region. CRITICAL RELEVANCE STATEMENT: Axilla is a pyramidal-in-shape "virtual cavity" housing multiple anatomical structures and connecting the upper limb with the trunk. The aim of this review article was to describe the anatomical architecture of the axilla, also using cadaveric specimens, in order to propose a layer-by-layer sonographic approach to this challenging district.


The efficacy of influenza vaccine in elderly persons. A meta-analysis and review of the literature.
To quantify the protective efficacy of influenza vaccine in elderly persons. A MEDLINE search was done using the index terms influenza vaccine, vaccine efficacy, elderly, mortality, hospitalized, and pneumonia. Appropriate references in the initially selected articles were also reviewed. Only cohort observational studies with mortality assessment were included in the meta-analysis. In addition, 3 recent case-control studies, 2 cost-effectiveness studies, and 1 randomized, double-blind, placebo-controlled trial were reviewed. Vaccine and epidemic virus strains, age and sex of patients, severity of illness, patient status, and study design were recorded. Upper respiratory illness, hospitalization, pneumonia, and mortality were used as outcome measures. In a meta-analysis of 20 cohort studies, the pooled estimates of vaccine efficacy (1-odds ratio) were 56% (95% Cl, 39% to 68%) for preventing respiratory illness, 53% (Cl, 35% to 66%) for preventing pneumonia, 50% (Cl, 28% to 65%) for preventing hospitalization, and 68% (Cl, 56% to 76%) for preventing death. Vaccine efficacy in the case-control studies ranged from 32% to 45% for preventing hospitalization for pneumonia, from 31% to 65% for preventing hospital deaths from pneumonia and influenza, from 43% to 50% for preventing hospital deaths from all respiratory conditions, and from 27% to 30% for preventing deaths from all causes. The randomized, double-blind, placebo-controlled trial showed a 50% or greater reduction in influenza-related illness. Recent cost-effectiveness studies confirm the efficacy of influenza vaccine in reducing influenza-related morbidity and mortality and show that vaccine provides important cost savings per year per vaccinated person. Despite the paucity of randomized trials, many studies confirm that influenza vaccine reduces the risks for pneumonia, hospitalization, and death in elderly persons during an influenza epidemic if the vaccine strain is identical or similar to the epidemic strain. Influenza immunization is an indispensable part of the care of persons 65 years of age and older. Annual vaccine administration requires the attention of all physicians and public health organizations.


Effects of age and sex on hexachloro-1,3-butadiene toxicity in the Fischer 344 rat.
Effects of age and sex on hexachloro-1,3-butadiene (HCBD) nephrotoxicity were determined 24 hours after a single dose (0, 25, 50, 100 or 200 mg/kg) in 28- and 63-day-old Fischer 344 rats. HCBD treatment significantly increased the kidney to body weight ratio but had little effect on the liver to body weight ratio. The 28-day-old rats were more susceptible to HCBD nephrotoxicity judged by elevated blood urea nitrogen, decreased renal cortical accumulation of p-aminohippurate and tetraethylammonium. Adult female rats (63-day-old) appeared to be more susceptible to HCBD nephrotoxicity than males at the low dose (50 mg/kg).


Peripapillary intrachoroidal cavitation in high myopia: reappraisal.
To evaluate optical coherence tomography (OCT) and clinical findings of a peripapillary lesion in high myopia recently named peripapillary detachment in pathologic myopia (PDPM) or intrachoroidal cavitation. Observational case report by chart review, analysis of colour fundus photography, fluorescein angiography, and OCT in 16 eyes of 12 patients with myopic degeneration and the presence of a slightly elevated, patchy peripapillary, yellow-orange lesion on the fundus. Patients were mean age 53.1+/-10.7 years, with a spherical-equivalent refractive error of -10.99+/-3.33 D and mean axial length of 27.34+/-1.44 mm. The mean best-corrected visual acuity was log MAR 0.3+/-0.2 (between 20/100 and 20/20). Six eyes also showed myopic maculopathy. In 13 eyes, OCT showed an intrachoroidal hyporeflective space located below the normal plane of the retinal pigment epithelium. Six of these 13 eyes were found to have apparent communication between the intrachoroidal cavity and the vitreous space at the junction of the lesion and the myopic conus. In three eyes, OCT revealed intrachoroidal splitting. The fluorescein angiogram showed early hypofluorescence, without pooling or staining in late phase. The yellow-orange elevated patchy lesions adjacent to the peripapillary conus in high myopic eyes may represent either intrachoroidal cavitation or choroidal schisis, which may be different stages of one disease spectrum. Vitreous fluid may be the source of the disruption of choroid and fluid accumulation.


VATS in complicated COVID-19 patients: case series.
Common complications of coronavirus disease 2019 (COVID-19) related ARDS and ventilation are barotrauma-induced pneumothorax, pneumatocele and/or empyema. We analysed indications and results of video-assisted thoracoscopic surgery (VATS) in complicated COVID-19 patients. This is a retrospective single-institution study analysing a case series of patients treated by VATS for secondary spontaneous pneumothorax (SSP), pneumatocele and empyema complicating COVID-19, not responding to drainage in Lodi Maggiore Hospital between February 2020 and May 2021. Out of 2076 patients hospitalized in Lodi Maggiore Hospital with COVID-19, nine Males (0,43%; mean age 58,1-33-81) were treated by VATS for complications of pneumonia (6 SSP and 3 empyema; 1 case complicated by haemothorax). 7 patients (77%) had CPAP before surgery for 21.3 days mean (4-38). Mean Operative time was 80.9 min (38-154). Conversion rate was 0%. 3 (33%) patients were admitted to ICU before VATS. Treatments were: bullectomy in six patients (66%), drainage of the pleural space in all patients, pleural decortication and fluid aspiration in five cases (55%). two patients (22%) needed surgery interruption and bilateral ventilation to restore adequate oxygenation. Mortality was 1/9 (11%) due to respiratory failure for persistent pneumonia. In one patient (11%) redo surgery was performed for bleeding. Mean postop Length of Stay (LOS) was 37.9 days (10-77). Our report shows that VATS can be considered an extreme, but effective treatment for COVID-19 patients with SSP, pneumatocele or empyema, for patients who can tolerate general anaesthesia. Attention must be paid to the aerosol-generation of infected droplets.


Neonatal medical trainee doctors' perceptions and parents' self-reported needs and stressors in a surgical neonatal intensive care unit: An individualised approach.
As more infants survive surgery in the newborn period for major congenital anomalies, the focus has shifted to the quality of care for parents as well as infants. In contemporary neonatal intensive care units (NICUs), doctors are encouraged to practice family-centred care and partner with parents in their infant's care. This study explored doctors' perceptions and parents' self-reported needs and stressors in a surgical NICU. From January 2014 to September 2015, parents of infants admitted for general surgery for a major congenital anomaly who were present in the NICU between 48 and 72 h of admission and doctors caring for their infant at the time of data collection were invited to participate. Matched data were provided using the Neonatal Family Needs Inventory and the Parental Stressor Scale:NICU. Matched data for 12 doctor-parent dyads showed that doctors (neonatal medical trainees) consistently under-rated the importance of parents' needs and identified fewer of mothers' than fathers' most important needs. Doctors also consistently under-rated parents' stressors. They perceived few of fathers', but all of mothers', greatest stressors. Thematic analysis revealed four themes: infant pain management; parental autonomy; empathy; and communicating reassurance and education to parents. The findings suggest incongruences between doctors' perceptions and parents' self-reported needs and stressors. While there is hesitation in making recommendations with this sample size, the findings highlight issues that may inform further research and contribute to a dialogue regarding the role of doctors in family-centred relationship-based models of care in the NICU.


Association study of polymorphisms in the alpha 7 nicotinic acetylcholine receptor subunit and catechol-o-methyl transferase genes with sensory gating in first-episode schizophrenia.
The purpose of the current study was to explore the association of auditory P50 sensory gating (P50) and prepulse inhibition (PPI) of schizophrenia with polymorphisms in the CHRNA7 and COMT genes. One hundred and fourty patients with schizophrenia participated in this study. They were administered the tests P50 and PPI. Moreover, three single nucleotide polymorphisms (SNPs) (rs2337980, rs1909884 and rs883473) in CHRNA7 and three SNPs (rs4680, rs737865 and rs165599) in COMT were selected to be genotyped by polyacrylamide gel microarray techniques. P50 index showed significant reduction in S2 amplitude between wild-type and mutation groups in the COMT rs4680. S1 amplitude of mutation group in the COMT rs737865 was also lower compared to wild-type group. PPI index revealed a shorter pulse latency of mutation group in the rs4680. The suppression ratio of mutation group was lower in COMT rs165599. Negative findings were shown between comparisons in all the CHRNA7 SNPs. We find that P50 and PPI may be influenced by COMT rs4680 polymorphisms in schizophrenia; more excitingly, we find that P50 might be influenced by COMT rs737865 polymorphisms and PPI may be influenced by COMT rs165599 polymorphisms in schizophrenia, and their mutations are associated with the reduction of the risk of P50 or PPI defects in schizophrenia. Futher studies with a larger number of subjects are needed to verify the present findings.


Cell cycle control by timer and sizer in Chlamydomonas.
Conservation of cell cycle control mechanisms is indicated by the presence of functionally homologous division control genes in unrelated yeasts and by the nonspecific action of oncogenes, but it remains uncertain what property of a growing cell results in the initiation of events leading to division. Response to a critical size is indicated by the longer growth period of smaller cells prior to division, which is consistent with deferment of division events until a minimum size is attained; however, in the same cell types faster growing cells are larger and this is more easily explained if division follows a timed period during which faster growing cells grow more, as is postulated for mammalian cells. Therefore, either time- or size-dependent controls might be the sole significant mechanism; we report here, however, that both controls do function in Chlamydomonas since cycle duration is under timer control and cell size determines the number of division rounds committed at the end of each cycle, and hence whether 2, 4, 8 or 16 daughter cells are formed.


Contractility, ATP, and creatine phosphate during myocardial ischaemia and reperfusion: the effects of adenosine and inhibition of adenosine catabolism in the dog heart.
Provision of AMP or adenosine to heart cells during recovery from episodes of myocardial ischaemia accelerates physiological, biochemical, and structural recovery. Inhibition of adenosine loss from the tissue during ischaemia should have a similar effect. This hypothesis was tested in dog heart by infusion of adenosine and inhibitors of adenosine catabolism prior to, during, and following ischaemia. Post-ischaemic recovery of ATP and contractile function was accelerated significantly by adenosine and by inhibitors of adenosine catabolism both singly and in combination. Contractility and ATP levels during ischaemia were also increased by these inhibitors.


Prediction of tumor response to experimental radioimmunotherapy with 90Y in nude mice.
To identify those factors that predict variability in tumor response to 90Y-radioimmunotherapy based on measurement of incorporated activity and physical dimensions of individual tumors and to apply the concept of effective dose to radioimmunotherapy. Human colon carcinoma xenografts growing in nude mice were treated with anti-CEA antibodies labeled with 90Y directly or through a bispecific antibody/labeled hapten system. Tumor response was measured as the delay in growth to eight times the treatment volume. Noninvasive activity (based on bremsstrahlung radiation) and dimension measurements were made in these animals at several times after label injection. The following parameters were compared for their ability to predict individual tumor response: (a) injected activity, (b) injected activity times a factor based on average uptake as a function of volume, (c) in vivo activity per volume measured in each animal at a single time, (d) the integral over time of in vivo activity per volume in each animal, and (e) the minimum dose for each animal in a uniformly active ellipsoid whose total activity and dimensions varied over time the same as the tumor. After correcting for differences in injected activity, two parameters account for much of the variability in tumor response. One of these is the general trend of larger tumors to take up less activity per volume. Additional variability can be accounted for by the in vivo activity per volume measurements. The minimum dose as introduced here is likely to be useful in estimating the biologically effective dose delivered by each treatment.


Evolution and Single-Droplet Analysis of Fuel-Driven Compartments by Droplet-Based Microfluidics.
Active droplets are a great model for membraneless organelles. However, the analysis of these systems remains challenging and is often limited due to the short timescales of their kinetics. We used droplet-based microfluidics to encapsulate a fuel-driven cycle that drives phase separation into coacervate-based droplets to overcome this challenge. This approach enables the analysis of every coacervate-based droplet in the reaction container throughout its lifetime. We discovered that the fuel concentration dictates the formation of the coacervate-based droplets and their properties. We observed that coacervate-based droplets grow through fusion, decay simultaneously independent of their volume, and shrinkage rate scales with their initial volume. This method helps to further understand the regulation of membraneless organelles, and we believe the analysis of individual coacervate-based droplets enables future selection- or evolution-based studies.


Evidence of Inverse Hall-Petch Behavior and Low Friction and Wear in High Entropy Alloys.
We present evidence of inverse Hall-Petch behavior for a single-phase high entropy alloy (CoCrFeMnNi) in ultra-high vacuum and show that it is associated with low friction coefficients (~0.3). Grain size measurements by STEM validate a recently proposed dynamic amorphization model that accurately predicts grain size-dependent shear strength in the inverse Hall-Petch regime. Wear rates in the initially soft (coarse grained) material were shown to be remarkably low (~10-6 mm3/N-m), the lowest for any HEA tested in an inert environment where oxidation and the formation of mixed metal-oxide films is mitigated. The combined high wear resistance and low friction are linked to the formation of an ultra-nanocrystalline near-surface layer. The dynamic amorphization model was also used to predict an average high angle grain boundary energy (0.87 J/m2). This value was used to explain cavitation-induced nanoporosity found in the highly deformed surface layer, a phenomenon that has been linked to superplasticity.


Application of the PM6 method to modeling the solid state.
The applicability of the recently developed PM6 method for modeling various properties of a wide range of organic and inorganic crystalline solids has been investigated. Although the geometries of most systems examined were reproduced with good accuracy, severe errors were found in the predicted structures of a small number of solids. The origin of these errors was investigated, and a strategy for improving the method proposed.


Computed tomography (CT)-guided versus laparoscopic radiofrequency ablation: a single-institution comparison of morbidity rates and hospital costs.
Computed tomography (CT)-guided radiofrequency ablation (RFA) is presumed to be less morbid and less costly than laparoscopic RFA. This analysis investigates the 30-day morbidity, hospital cost, and reimbursement for CT-guided RFA versus laparoscopic RFA used to manage hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM). A retrospective review was performed for all patients with CRLM or HCC who underwent CT-guided RFA or laparoscopic RFA between January 2002 and August 2008. Demographics, risk stratification, and procedural data were analyzed. Hospital financial data were queried for total cost, reimbursement, and itemized departmental charges. The CRLM and HCC patients were evaluated separately. The study analyzed 18 RFA procedures for the treatment of HCC (8 CT-guided RFA; 10 laparoscopic RFA) and 25 RFA procedures for the treatment of CRLM (6 CT-guided RFA; 19 laparoscopic RFA). Immediate local failures were reported for 33.3% and 12.5% of the CT-guided RFA procedures for CRLM and HCC and for 5.2% and 0.0% of the laparoscopic RFA procedures for CRLM and HCC, respectively. The mean hospital cost was higher for the patients who underwent laparoscopic RFA ($11,808.70 ± $7,238.90 for HCC vs $9,882.40 ± $1,926.90 for CRLM) than for those who underwent CT-guided RFA ($7,186.10 ± $3,899.60 for HCC vs $5,767.50 ± $2,869.00 for CRLM). The mean reimbursement was lower than the mean hospital cost for the patients who underwent CT-guided RFA for CRLM ($4,329.10 vs $5,767.50). Although CT-guided RFA is less expensive, it is poorly reimbursed. Also, CT-guided RFA is associated with a higher immediate local failure rate for both CRLM and HCC and a higher complication rate for patients with CRLM. For patients with HCC, CT-guided RFA is associated with a lower complication rate. Our data suggest that laparoscopic RFA should be used for most patients with CRLM and only selectively for patients with HCC.


Unbalanced regulation of Sec22b and Ykt6 blocks autophagosome axonal retrograde flux in neuronal ischemia-reperfusion injury.
Cerebral ischemia-reperfusion injury in ischemic penumbra is accountable for poor outcome of ischemic stroke patients receiving recanalization therapy. Compelling evidence previously demonstrated a dual role of autophagy in stroke. This study aimed to understand the traits of autophagy in the ischemic penumbra and the potential mechanism that switches the dual role of autophagy. We found that autophagy induction by rapamycin and lithium carbonate performed before ischemia reduced neurological deficits and infarction, while autophagy induction after reperfusion had the opposite effect in the male murine middle cerebral artery occlusion/reperfusion model, both of which were eliminated in mice lacking autophagy (Atg7flox/flox; Nestin-Cre). Autophagic flux determination showed that reperfusion led to a blockage of axonal autophagosome retrograde transport in neurons, which then led to autophagic flux damage. Then, we found that ischemia-reperfusion induced changes in the protein levels of Sec22b and Ykt6 in neurons, two autophagosome transport-related factors, in which Sec22b significantly increased and Ykt6 significantly decreased. In the absence of exogenous autophagy induction, Sec22b knockdown and Ykt6 overexpression significantly alleviated autophagic flux damage, infarction, and neurological deficits in neurons or murine exposed to cerebral ischemia-reperfusion in an autophagy-dependent manner. Furthermore, Sec22b knockdown and Ykt6 overexpression switched the outcome of rapamycin post-treatment from deterioration to neuroprotection. Thus, Sec22b and Ykt6 play key roles in neuronal autophagic flux, and modest regulation of Sec22b and Ykt6 may help to reverse the failure of targeting autophagy induction to improve the prognosis of ischemic stroke.Significance Statement:The highly polarized architecture of neurons with neurites presents challenges for material transport, such as autophagosomes, which form at the neurite tip and need to be transported to the cell soma for degradation. Here, we demonstrate that Sec22b and Ykt6 act as autophagosome porters and play an important role in maintaining the integrity of neuronal autophagic flux. Ischemia-reperfusion-induced excess Sec22b and loss of Ykt6 in neurons lead to axonal autophagosome retrograde trafficking failure, autophagic flux damage, and finally neuronal injury. Facilitated axonal autophagosome retrograde transport by Sec22b knockdown and Ykt6 overexpression may reduce ischemia-reperfusion-induced neuron injury and extend the therapeutic window of pharmacological autophagy induction for neuroprotection.


Intermittent Letrozole Administration as Adjuvant Endocrine Therapy for Postmenopausal Women With Hormone Receptor-Positive Early Breast Cancer: A Biologic Study.
Letrozole withdrawal for 3 months might permit estrogenic stimulation in residual resistant breast cancer disease susceptible to letrozole reintroduction. We investigated the impact of a 3-month letrozole-free interval on serum estradiol levels in patients with early stage breast cancer. Postmenopausal women with estrogen receptor- and/or progesterone receptor-positive (> 10% of immunoreactive cells), node-negative early breast cancer were eligible. Patients received letrozole for 5 years with a 3-month treatment-free interval after the first year of therapy. The primary end point was to evaluate the increase in serum estradiol levels after a 3-month treatment-free interval. The secondary end points were the evaluations of other biologic markers (eg, follicle-stimulating hormone, luteinizing hormone, cholesterol, high-density lipoprotein, triglycerides, osteocalcin). From November 2007 to February 2012, 130 evaluable patients were enrolled. The median age was 61 years. Mean values of estradiol levels at time of discontinuation were 5.6 pg/mL (standard deviation 1.7). Estradiol levels increased after a 3-month treatment-free interval by a mean of 3.3 pg/mL (66%; P < .0001). Follicle-stimulating hormone and luteinizing hormone levels decreased from baseline by a mean of 7.5 mU/mL (P < .0001), and 1.4 mU/mL (P = .0062), respectively. Triglycerides decreased from baseline by a mean of 8.6 mg/dL (P = .036), and osteocalcin increased by a mean of 2.8 ng/mL (P = .013). Intermittent letrozole significantly affects estradiol levels.


Modification of the radiation induced damage by 2-deoxy-D-glucose in organ cultures of human cerebral gliomas.
Effects of a glucose antimetabolite, 2-deoxy-D-glucose (2-DG), on the gamma ray induced radiation damage have been studied in organ cultures of human cerebral gliomas. Percentage of cells with micronuclei (M-fraction) was used to assay the radiation damage. Experimental data indicate the following results. Untreated cerebral gliomas show considerable spatial heterogeneity in M-fraction; In spite of this heterogeneity, increases in M-fraction induced by gamma rays can be clearly observed, if multiple and randomly selected explants are analyzed for each group; The radiation induced M-fraction in different gliomas varies over a wide range; Presence of 2-DG (5 mM) for 4 h after irradiation leads to an increase in the radiation induced M-fraction in the majority of tumors, while in a smaller number (congruent to 25%) a decrease is observed under similar conditions. These results can be explained on the basis of a model postulating differential effects of 2-DG on the energy linked modulations of the processes of repair and fixation of DNA damage, which competitively influence the formation of micronuclei.


The impact of discrete compartments of a multi-compartment collagen-GAG scaffold on overall construct biophysical properties.
Orthopedic interfaces such as the tendon-bone junction (TBJ) present unique challenges for biomaterials development. Here we describe a multi-compartment collagen-GAG scaffold fabricated via lyophilization that contains discrete mineralized (CGCaP) and non-mineralized (CG) regions joined by a continuous interface. Modifying CGCaP preparation approaches, we demonstrated scaffold variants of increasing mineral content (40 vs. 80wt% CaP). We report the impact of fabrication parameters on microstructure, composition, elastic modulus, and permeability of the entire multi-compartment scaffold as well as discrete mineralized and non-mineralized compartments. Notably, individual mineralized and non-mineralized compartments differentially impacted the global properties of the multi-compartment composite. Of particular interest for the development of mechanically-loaded multi-compartment composites, the elastic modulus and permeability of the entire construct were governed primarily by the non-mineralized and mineralized compartments, respectively. Based on these results we hypothesize spatial variations in scaffold structural, compositional, and mechanical properties may be an important design parameter in orthopedic interface repair.


Non-linear uptake and hormesis effects of selenium in red-winged blackbirds (Agelaius phoeniceus).
Effects of selenium on reproductive success were assessed in red-winged blackbirds (Agelaius phoeniceus). Mean egg selenium (MES) ranged from 2.96 to 21.7 mg/kg dry weight with individual eggs up to 40 mg/kg. Uptake was non-linear: increments in MES declined as aqueous selenium increased; the asymptote was approximately 23 mg/kg. Eggs were heavier and more were laid in 2004 compared to 2005, a year of record rainfall and below-normal temperatures. Mortality of embryos that were incubated to full term was low (2.6% in 2004 and 3.2% in 2005), as was the prevalence of embryonic defects (2.7% in 2004 and 5.1% in 2005). Abnormalities in nestlings were also rare. Egg mortality was caused by predation, weather, and parental abandonment. Nestlings died from predation, starvation, and hypothermia associated with rain and cold, drowning, and bacterial infections. Nestling liver concentrations reached 81 mg/kg dry wt. selenium and were highest at the most highly selenium-exposed sites. Blood glutathione peroxidase (a selenium-dependent enzyme indicative of selenium exposure) was unrelated to liver selenium concentrations, egg selenium, or ambient selenium exposure. The selenium concentration in prey that parents fed to nestlings was higher at the selenium-exposed sites (up to 37 mg/kg dry wt. Se) compared to reference sites. Aqueous selenate:selenite ratios were related to redox differences and were much higher at the site with the highest MES, liver selenium, and prey item selenium concentrations. Hatchability showed U-shaped, or hormesis, relationships with MES: productivity increased with selenium concentrations at low exposures and decreased at high exposures. The effects threshold was approximately 22 mg/kg dry wt. MES.


A model for estimating the number of glass fragments transferred when breaking a pane: experiments with firearms and hammer.
Numerous publications have shown the importance of transfer in the interpretation of glass evidence. As this phenomenon is also highly variable, it was decided to test the hypothesis that there exists a means to predict the number of fragments recovered at time t = 0. Panes of float glass-of different types and thickness-were broken using either a firearm or a hammer. It was decided to choose a firearm as the main breaking device, as it allowed not only to have more reproducible conditions but also to acquire knowledge in a field where little has been published. Despite the inherent variation in the breaking process, the results show that using a statistical model it is possible to predict the number of fragments transferred onto a garment from the number of fragments transferred to the ground. This research also indicates the size and number of particles transferred onto a person, when breaking window panes of different types (float, laminated or toughened) with different breaking procedures.


A novel stop mutation in the EDNRB gene in a family with Hirschsprung's disease associated with multiple sclerosis.
We identified a girl with Hirschsprung's disease (HSCR) whose mother and grandmother had HSCR associated with multiple sclerosis (MS). The aim of this study was to outline mutations in HSCR-related genes and MS susceptibility alleles in these three individuals. The phenotypes were reviewed based on medical records. The three subjects had rectosigmoid HSCR verified with histopathology. The mother and grandmother fulfilled the McDonald criteria for MS. DNA was isolated from EDTA-preserved blood according to standard procedures. Exome sequencing aiming mainly at analyzing HSCR associated genes as well as Sanger sequencing for confirmation was performed. All affected individuals carry a novel heterozygous nonsense mutation in the EDNRB gene (c.C397T,p.R133X,refNM_000115), changing an arginine at position 133 into a premature stop codon. None of the subjects were homozygous for the HLA risk alleles for MS. We report a novel non-sense EDNRB gene mutation in a girl with HSCR and her mother and grandmother with HSCR and MS. We propose that this EDNRB gene mutation plays a role in the etiology of HSCR and also makes the subjects susceptible to MS.


Vascular smooth muscle cell response on thin films of collagen.
Vascular smooth muscle cells (vSMC) cultured on gels of fibrillar type I collagen or denatured collagen (gelatin) comprise a model system that has been widely used for studying the role of the extracellular matrix in vascular diseases such as hypertension, restenosis and athrosclerosis. Despite the wide use of this model system, there are several disadvantages to using collagen gels for cellular studies. These include poor optical characteristics for microscopy, difficulty in verifying that the properties of the preparations are identical from experiment to experiment, heterogeneity within the gels, and difficulty in handling the gels because they are fragile. Previously, we developed an alternative collagen matrix by forming thin films of native fibrillar collagen or denatured collagen on self-assembled monolayers of alkanethiols [Elliott, J.T., Tona, A., Woodward, J., Jones,P., Plant, A., 2003a. Thin films of collagen affect smooth muscle cell morphology. Langmuir 19, 1506-1514.]. These substrates are robust and can be characterized by surface analytical techniques that allow both verification of the reproducibility of the preparation and high-resolution analysis of collagen structure. In addition, they have excellent optical properties that allow more details of the cell-matrix interactions to be observed by microscopy. In this study, we performed a side-by-side structural and functional comparison of collagen gels with thin films of collagen. Our results indicate that vSMC on thin films of collagen are nearly identical to vSMC on thick gels as determined by morphology, proliferation rate, integrin ligation, tenascin-C expression and intracellular signaling events. These results suggest that the features of collagen gels that direct the observed vSMC responses are adequately reconstituted in the thin films of collagen. These thin films will be useful for elucidating the features of the collagen matrix that regulate vSMC response and may be applicable to high content screening.


Ruthenium(II) carbonyl complexes bearing quinoline-based NNO tridentate ligands as catalyst for one-pot conversion of aldehydes to amides and o-allylation of phenols.
Six new octahedral ruthenium(II) carbonyl complexes having the general molecular formula [RuCl(CO)(B)L(1-2)] (B = PPh3, AsPh3 or py; L(1-2) = quinoline based NNO ligand) were synthesized. The quinoline based ligands behave as monoanionic tridentate donor and coordinated to ruthenium via ketoenolate oxygen, azomethine nitrogen and quinoline nitrogen. The composition of the complexes has been established by elemental analysis and spectral methods (FT-IR, electronic, (1)H NMR, (13)C NMR, (31)P NMR and ESI-Mass). The complexes were used as efficient catalysts for one-pot conversion of various aldehydes to their corresponding primary amides in presence of NH2OH · HCl and NaHCO3. The effect of catalyst loading and reaction temperature on catalytic activity of the ruthenium(II) carbonyl complexes were also investigated. The synthesized complexes also possess good catalytic activity for the o-allylation of phenols in the presence of K2CO3 under mild conditions. The complexes afforded branched allyl aryl ethers according to a regioselective reaction.


Using topic modeling to detect cellular crosstalk in scRNA-seq.
Cell-cell interactions are vital for numerous biological processes including development, differentiation, and response to inflammation. Currently, most methods for studying interactions on scRNA-seq level are based on curated databases of ligands and receptors. While those methods are useful, they are limited to our current biological knowledge. Recent advances in single cell protocols have allowed for physically interacting cells to be captured, and as such we have the potential to study interactions in a complemantary way without relying on prior knowledge. We introduce a new method based on Latent Dirichlet Allocation (LDA) for detecting genes that change as a result of interaction. We apply our method to synthetic datasets to demonstrate its ability to detect genes that change in an interacting population compared to a reference population. Next, we apply our approach to two datasets of physically interacting cells to identify the genes that change as a result of interaction, examples include adhesion and co-stimulatory molecules which confirm physical interaction between cells. For each dataset we produce a ranking of genes that are changing in subpopulations of the interacting cells. In addition to the genes discussed in the original publications, we highlight further candidates for interaction in the top 100 and 300 ranked genes. Lastly, we apply our method to a dataset generated by a standard droplet-based protocol not designed to capture interacting cells, and discuss its suitability for analysing interactions. We present a method that streamlines detection of interactions and does not require prior clustering and generation of synthetic reference profiles to detect changes in expression.


Effects of TGF-β signaling in clear cell renal cell carcinoma cells.
Clear cell renal cell carcinoma (ccRCC) is by far the most common type of kidney cancer and is characterized by loss of the tumor suppressor gene von Hippel-Lindau (VHL). ccRCC patients with metastatic disease has poor prognosis and today's therapy is insufficient. The cytokine Transforming Growth Factor-β (TGF-β) has been extensively studied in tumor biology and is believed to serve a variety of functions in tumor progression. We have previously shown that inhibition of NOTCH signaling causes a reduced migratory and invasive capacity of ccRCC cells, at least partly by a cross-talk with the TGF-β pathway. In the present study we aimed to further clarify the role of TGF-β signaling in ccRCC. We investigated the effects of TGF-β pathway modulation and showed that TGF-β inhibition attenuates the invasive capacity of ccRCC cells. By performing expression profiling we obtained a gene signature of the TGF-β induced response in ccRCC cells. The expression analyses revealed an extensive overlap between the TGF-β response and genes regulated by the hypoxia inducible factor (HIF). The link between the hypoxic and the TGF-β pathways was further corroborated by functional experiments, which demonstrated that TGF-β pathway activity was attenuated upon reintroduction of functional VHL in ccRCC.


Levels, distribution, and sources of organophosphate flame retardants and plasticizers in urban soils of Shenyang, China.
Seventy-four soil samples from the road greenbelts, residential areas, drylands, waste grasslands, education lands, industrial areas, city parks, and rural homesteads of Shenyang city, China, were collected and analyzed for 13 organophosphate esters (OPEs). OPEs were detected in all analyzed soil samples, which indicate that OPEs are ubiquitously environmental contaminants. The ∑13OPEs concentrations ranged from 0.039 to 0.95 mg/kg dry weight (dw), with the mean and median concentrations of 0.23 and 0.16 mg/kg dw, respectively. The pollution levels of OPEs in different land use types were different; the concentrations of OPEs in dryland soils were maximum and in city park soils were minimum. Of 13 OPEs, tri-iso-butyl phosphate (TiBP), tris-(1-chloro-2-propyl) phosphate (TCPP), tri-butoxyethyl phosphate (TBEP), and tris[2-chloro-1-(chloromethyl) ethyl] phosphate (TDCP) were the most abundant OPEs, contributing 42.0 ± 12.8, 12.4 ± 2.32, 6.31 ± 1.88, and 5.76 ± 1.86% of ∑13OPEs, respectively. Principal component analysis (PCA) and absolute principal component score-multiple linear regression (APCS-MLR) suggested that OPE pollution in soils may be derived from atmospheric deposition, road runoff and vehicular traffic emission, and wastewater/reclaimed water irrigation and sludge application, their contributions were accounting for 62.4, 17.6, and 20.0%, respectively. As compared to the results from other studies, the pollution of OPEs in the urban soils of Shenyang is relatively serious.


Levels of soluble VCAM-1, soluble ICAM-1, and soluble E-selectin in patients with tuberculous pleuritis.
Tuberculosis is characterized by the presence of activated mononuclear cells both in the peripheral circulation and in pleural fluid. Expression and up-regulation of adhesion molecules is the basis of cell-cell adhesion in granuloma formation and in leukocyte migration to the inflammatory site. Soluble isoforms of adhesion molecules have been described, and their expression at high levels indicated an activated state. The purpose of this study was to evaluate levels of soluble adhesion molecules in serum and pleural fluid from patients with tuberculous pleural effusions, compared with non-tuberculous pleural effusions. We analysed levels of soluble vascular cell adhesion molecule-1 (s.VCAM-1), soluble intercellular adhesion molecule-1 (s.ICAM-1), and soluble E-selectin (sE-selectin) in serum and pleural fluid from patients with tuberculous pleuritis, by sandwich ELISA. Serum levels of s.ICAM-1 and s.VCAM-1 in patients with tuberculosis were higher than those in healthy controls (p < 0.001). Levels of sE-selectin levels were in the normal range compared with control groups. In pleural fluid, levels of s.VCAM-1 and s.ICAM-1 were increased in pleural effusions. Patients with tuberculous pleural effusion exhibited high levels of s.ICAM-1 compared with patients with neoplastic pleural involvement. Up-regulation of s.VCAM-1 and s.ICAM-1 in serum, along with increased levels of sE-selectin in pleural effusions from tuberculous patients, may result in transmigration of activated inflammatory cells inducing pleural damage, which may contribute to the pathological processes involved.


Policies to mitigate nonmedical use of prescription medications: how should emerging evidence of gabapentin misuse be addressed?
Over the past decade, increased prescription supply has facilitated an epidemic of nonmedical use of controlled substances, including predominantly opioids, as well as benzodiazepines, z-hypnotics, and stimulants. Areas covered: More recently, misuse of noncontrolled prescriptions, such as gabapentin, has been detected. Gabapentin misuse has been associated with drug-related harm and increased healthcare service utilization in a few studies, including a recent large-sample analysis of commercially insured enrollees in the United States (U.S.) Responding to this emerging base of evidence, a small number of U.S. states have acted to prevent or detect gabapentin misuse by requiring the inclusion of gabapentin utilization in reporting to local Prescription Drug Monitoring Programs (PDMPs) and/or imposing other restrictions on gabapentin prescribing (e.g., classification as a controlled substance, quantity limits). These efforts may result in unintentional harm by (1) encouraging 'doctor shopping' across state lines to seek lenient regulatory policies and (2) placing the burden for mitigating misuse on individual practitioners. Expert opinion: We call for a unified national approach, comprising federal regulation and enhanced PDMP reporting to address gabapentin misuse, while laying the groundwork for management of new medications of abuse that the healthcare industry may encounter in the future.


Uneven distribution of repetitive trinucleotide motifs in human immunoglobulin heavy variable genes.
Insertions and deletions of entire codons have recently been discovered as a mechanism by which B cells, in addition to conventional base substitution, evolve the antibodies produced by their immunoglobulin genes. These events frequently seem to involve repetitive sequence motifs in the antibody-encoding genes, and it has been suggested that they occur through polymerase slippage. In order to better understand the process of codon deletion, we have analyzed the human immunoglobulin heavy variable (IGHV) germline gene repertoire for the presence of trinucleotide repeats. Such repeats would ensure that the reading frame is maintained in the case of a deletional event, as slippage over multiples of three bases would be favored. We demonstrate here that IGHV genes specifically carry repetitive trinucleotide motifs in the complementarity-determining regions (CDR) 1 and 2, thus making these parts of the genes that encode highly flexible structures particularly prone to functional deletions. We propose that the human IGHV repertoire carries inherent motifs that allow an antibody response to develop efficiently by targeting codon deletion events to the parts of the molecule that are likely to be able to harbor such modifications.


Electron paramagnetic resonance and optical absorption spectral studies on covellite mineral.
A covellite mineral sample from Coquimbo region, Chile is used in the present study. An electron paramagnetic resonance (EPR) study on powdered sample confirms the presence of Mn(II) and Cu(II). Optical absorption spectrum indicates that Fe(II) and Cu(II) impurities are present in octahedral structure. Bands in the near-infrared from 7,000 to 5,000 cm(-1) result from the overtones of the first fundamental OH-stretching modes.


[The significance of individual sensitivity to hypoxia for the duration of severe compression trauma].
In the experiments on rats was shown that individual differences in sensitivity to hypoxia were significant for subsequences of long-term immobilization stress and severe compression trauma. In these conditions, low resistant rats were more sensitive to hypoxia compared with high resistant animals. The low resistant rats had got more significant changes of the main functional systems and acid-alkaline buffer state.


Antidepressant-like effects of BU10119, a novel buprenorphine analogue with mixed κ/μ receptor antagonist properties, in mice.
The κ receptor antagonists have potential for treating neuropsychiatric disorders. We have investigated the in vivo pharmacology of a novel buprenorphine analogue, BU10119, for the first time. To determine the opioid pharmacology of BU10119 (0.3-3 mg·kg-1 , i.p.) in vivo, the warm-water tail-withdrawal assay was applied in adult male CD1 mice. A range of behavioural paradigms was used to investigate the locomotor effects, rewarding properties and antidepressant or anxiolytic potential of BU10119. Additional groups of mice were exposed to a single (1 × 2 h) or repeated restraint stress (3× daily 2 h) to determine the ability of BU10119 to block stress-induced analgesia. BU10119 alone was without any antinociceptive activity. BU10119 (1 mg·kg-1 ) was able to block U50,488, buprenorphine and morphine-induced antinociception. The κ antagonist effects of BU10119 in the tail-withdrawal assay reversed between 24 and 48 h. BU10119 was without significant locomotor or rewarding effects. BU10119 (1 mg·kg-1 ) significantly reduced the latency to feed in the novelty-induced hypophagia task and reduced immobility time in the forced swim test, compared to saline-treated animals. There were no significant effects of BU10119 in either the elevated plus maze or the light-dark box. Both acute and repeated restraint stress-induced analgesia were blocked by pretreatment with BU10119 (1 mg·kg-1 ). Parallel stress-induced increases in plasma corticosterone were not affected. BU10119 is a mixed κ/μ receptor antagonist with relatively short-duration κ antagonist activity. Based on these preclinical data, BU10119 has therapeutic potential for the treatment of depression and other stress-induced conditions. This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.


A cross-sectional study of the impact of COVID-19 pandemic on the physical activity of Jordanian population.
Since the declaration of the COVID-19 pandemic on 11th March 2020, the public health recommendations have applied lockdowns and restrictions to limit the spread of the disease. These measures determined outdoor activities and access to many forms of exercise. The primary objective of this study was to examine the impact of the COVID-19 pandemic on the physical activity (PA) of the Jordanian population. A cross-sectional online survey was designed using Google Forms services and distributed on social media platforms during the first two weeks of November 2020 to evaluate the exercise activity changes during the COVID-19 pandemic in the study population. In this research, we included those who perform any form of physical activity (n = 1103). The data collected were analyzed using the Statistical Package for the Social Sciences (SPSS) version 26 (IBM SPSS Corp, SPSS Statistics ver. 26, USA). The categorical variables were summarized as frequencies and proportions and were compared using the Chi-square. For all analyses, P-value less than 0.05 was considered statistically significant. A total of 1103 out of 2,511 (43.9%) respondents who participated in the survey were physically exercising during the COVID-19 pandemic. 41.8% were exercising at an irregular frequency, while 21.5% were exercising daily, 16.8% were exercising three to five times a week, and 19.9% were exercising once or twice a week. Moreover, 282 (25.6%) respondents started doing some form of exercise during the pandemic. Those significantly were less than 18-year-old, male gender, were single, were non-smokers, and had a diploma or bachelor's degree in a health-related major. These changes in the level of exercise have been attributed by 57.8% of respondents to the health aspects where they realized the importance of exercising in strengthening the immune system against diseases, including COVID-19. The current study showed that lockdown, due to the COVID-19 pandemic, had a positive impact on the healthy lifestyle of the Jordanian population which was attributed to their feeling of the importance of sports practice on the immune system and the availability of time for those activities. However, the younger and individuals were more aware of the importance of these practices which highlights the importance of considering other age groups in future studies of healthy behaviors.


A synonymous mutation in SPINK5 exon 11 causes Netherton syndrome by altering exonic splicing regulatory elements.
Netherton syndrome (NS) is a rare, life-threatening ichthyosiform syndrome caused by recessive loss-of-function mutations in SPINK5 gene encoding lymphoepithelial Kazal-type-related inhibitor (LEKTI), a serine protease inhibitor expressed in the most differentiated epidermal layers and crucial for skin barrier function. We report the functional characterization of a previously unrecognized synonymous variant, c.891C>T (p.Cys297Cys), identified in the SPINK5 exon 11 of an NS patient. We demonstrated that the c.891C>T mutation is associated with abnormal pre-mRNA splicing and residual LEKTI expression in the patient's keratinocytes. Subsequent minigene splicing assays and in silico predictions confirmed the direct role of the synonymous mutation in inhibiting exon 11 inclusion by a mechanism that involves the activity of exonic regulatory sequences, namely splicing enhancer and silencer. However, this deleterious effect was not complete and a residual amount of normal mRNA and LEKTI protein could be detected, correlating with the relatively mild patient's phenotype. Our study represents the first identification of a disease-causing SPINK5 mutation that alters splicing without affecting canonical splice sites.


A nuclear pore sub-complex restricts the propagation of Ty retrotransposons by limiting their transcription.
Beyond their canonical function in nucleocytoplasmic exchanges, nuclear pore complexes (NPCs) regulate the expression of protein-coding genes. Here, we have implemented transcriptomic and molecular methods to specifically address the impact of the NPC on retroelements, which are present in multiple copies in genomes. We report a novel function for the Nup84 complex, a core NPC building block, in specifically restricting the transcription of LTR-retrotransposons in yeast. Nup84 complex-dependent repression impacts both Copia and Gypsy Ty LTR-retrotransposons, all over the S. cerevisiae genome. Mechanistically, the Nup84 complex restricts the transcription of Ty1, the most active yeast retrotransposon, through the tethering of the SUMO-deconjugating enzyme Ulp1 to NPCs. Strikingly, the modest accumulation of Ty1 RNAs caused by Nup84 complex loss-of-function is sufficient to trigger an important increase of Ty1 cDNA levels, resulting in massive Ty1 retrotransposition. Altogether, our study expands our understanding of the complex interactions between retrotransposons and the NPC, and highlights the importance for the cells to keep retrotransposons under tight transcriptional control.


Generation of In Vitro Model of Epithelial Mesenchymal Transition (EMT) Via the Expression of a Cytoplasmic Mutant Form of Promylocytic Leukemia Protein (PML).
Epithelial Mesenchymal Transition (EMT) is a key event in cancer progression. During this event, epithelial cancer cells undergo molecular and cellular changes leading to their trans-differentiation into mesenchymal cancer cells that are capable of migration, invasion, and metastasis to other tissues and organs. Here, we present a method for in vitro induction of EMT in prostate cancer cell lines using lentiviral expression of a PMLI isoform mutant construct.


Dexamethasone-induced gastric mucosal damage in the rat: possible role of platelet-activating factor.
1. The aim of the present experiments was to study the possible role of platelet-activating factor (PAF) in mediating gastric mucosal damage induced by dexamethasone in the rat by measuring gastric tissue levels of PAF during dexamethasone-treatment and by investigating the effects of specific PAF receptor antagonists on dexamethasone-induced gastric lesions. PAF-like bioactivity extracted from the rat glandular stomach was determined by a platelet aggregation assay. 2. Dexamethasone treatment (0.4-4 mg kg-1, daily for 1-6 days) produced time- and dose-dependent damage to the glandular mucosa of the stomach as characterized by extensive, uniform hyperaemia with multiple, focal petechiae and erosions. 3. These changes were accompanied by a time-, and dose-dependent increase in PAF content of the glandular stomach. Control rat stomach contained small amounts of PAF (0.14 +/- 0.04 ng per g wet weight), which increased over 40 fold in response to dexamethasone treatment (4 mg kg-1, daily for 6 consecutive days). The presence of PAF-like material in the stomach extract was ascertained by thin-layer chromatography, high performance liquid chromatography and by alkaline hydrolysis. 4. Pretreatment of the animals with one or other of the structurally unrelated PAF receptor antagonists, BN 52021 (10 mg kg-1, i.p.) or BN 50727 (1 mg kg-1, i.p.) significantly reduced dexamethasone-induced gastric damage. In these animals neither petechiae nor erosions were observed. 5. These observations suggest that PAF is a likely endogenous mediator of glucocorticoid-induced gastric mucosal damage in the rat.


The impact of the coronavirus disease 2019 pandemic on elective urological procedures in Australia.
To investigate the changes in elective private urological procedures in Australia during the coronavirus disease 2019 pandemic. Data were extracted from publicly available datasets from Medicare Benefits Schedule using item numbers assigned to each commonly performed urological intervention. These procedures were divided into three groups: Oncological therapeutic, diagnostic, and non-oncological therapeutic procedures. A smoothing model, based on the historic procedure numbers from 2017 to 2019, was used to forecast monthly number of procedures performed in each category between January 2020 and June 2020. These forecasted models were compared with reported figures. A total of 108 169 procedures were performed between January 2020 and June 2020 based on the Medicare Benefits Schedule item numbers listed. There was a significant reduction (percentage change) in total procedures performed in April 2020 (-22.6%, 95% confidence interval [CI]: -28.7% to -15.4%) and May 2020 (-33.2%, 95% CI: -37.5% to -28.3%). There was a significant reduction in oncological therapeutic, non-oncological therapeutic, and diagnostic procedures performed in April 2020 and May 2020 (p<0.05). These numbers did not include procedures performed in public sector. There was a significant reduction in total urological procedures (including diagnostic, oncological, and non-oncological) performed in months of April 2020 and May 2020 during time of federal restrictions. Both public and private healthcare sectors need to be supported in the upcoming months to prevent further delays in treatment and poorer clinical outcomes.


The influence of temperature and resource level on the fecundity of a predatory planktonic mite, Piona exigua Viets.
Piona exigua Viets is a predaceous freshwater mite that can potentially affect the population densities of its cladoceran prey. As part of a study of the effect of Piona exigua on its prey populations we measured the effects of water temperature and prey density on the lifespan, age at first reproduction and per capita egg production of adult female mites. Mites were raised in the laboratory at five prey (Ceriodaphnia, Daphnia) densities (5, 15, 30, 60, 120/l) at 15° C and at four temperatures (10, 15, 18, 22° C) at c. 60 prey/l. In response to increased food level, mites increased the number of eggs laid to reach a maximum at 60 prey/l, the rate at which they were laid increased and the pre-reproductive period was shorter. Low temperatures prolonged the pre-reproductive period. At temperatures above 10° C, food level and temperature had more influence on the timing of reproductive events (growth rate, oviposition rate, age at first reproduction) than on the size of females at first reproduction. When temperatures exceed 10° C and food levels exceed 5 prey/l the major scope for reproductive plasticity in Piona lies in the timing and duration of egg production.


An assessment of gas emanation hazard using a geographic information system and geostatistics.
This paper describes the use of geostatistical analysis and GIS techniques to assess gas emanation hazards. The Mt. Vulsini volcanic district was selected for this study because of the wide range of natural phenomena locally present that affect gas migration in the near surface. In addition, soil gas samples that were collected in this area should allow for a calibration between the generated risk/hazard models and the measured distribution of toxic gas species at surface. The approach used during this study consisted of three general stages. First data were digitally organized into thematic layers, then software functions in the GIS program "ArcView" were used to compare and correlate these various layers, and then finally the produced "potential-risk" map was compared with radon soil gas data in order to validate the model and/or to select zones for further, more-detailed soil gas investigations.


[The role of glycosaminoglycans in regulation of medullary hematopoiesis in stress].
The role of the constituents of hematopoiesis inducing bone marrow microenvironment in myelopoiesis regulation was studied. It was found that during the development of the general adaptation syndrome the functional activity of stroma cells and granulomonocytopoiesis precursor cells intensifies and the content of acid glycosaminoglycans in the bone marrow increases. It is shown that acid glycosaminoglycans produce an effect on the myelokaryocytes in intimate interrelationship with the prostaglandin system, changing the level of intracellular calcium and cAMP in the hematopoietic cells.


Hormonal activities of new brominated flame retardants.
After the phase-out of two commercial mixtures of brominated flame retardants, an increasing number of alternative flame retardants have been introduced in commercial applications. None of them, however, has been thoroughly tested for its hormonal activity. We used two yeast reporter-gene assays to determine the potential of eleven compounds to interfere with estrogenic and androgenic pathways. Our data demonstrate the ability of 2,4,6-tribromophenol to lower the transcriptional activity of human estrogen and androgen receptors. A nominal IC(50) value of 14.1 μM for anti-estrogenic and 3.9 μM for anti-androgenic activity was obtained using the luciferase reporter. An IC(50) value of 9.2 μM was calculated for the anti-estrogenic activity measured by the β-galactosidase assay. Of the tested chemicals, this study highlights the endocrine disrupting effects of 2,4,6-tribromophenol whose occurrence in the environment should be monitored.


A comparison of the technological effectiveness of dairy wastewater treatment in anaerobic UASB reactor and anaerobic reactor with an innovative design.
The present research was an investigation of the influence of an innovative design of reactor filled with polyethylene (PE) granulate on model dairy wastewater treatment efficiency under anaerobic conditions compared to that obtained in a typical UASB reactor. The experiment was conducted at laboratory scale. An innovative reactor was designed with the reaction chamber inclined 30 degrees in relation to the ground with upward waste flow and was filled with PE granular material. Raw model dairy wastewater was fed to two anaerobic reactors of different design at the organic loading rate of 4 kg COD m(-3)d(-1). Throughout the experiment, a higher removal efficiency of organic compounds was observed in the reactor with an innovative design and it was higher by 7.1% on average than in the UASB reactor. The total suspended solids was lower in the wastewater treated in the anaerobic reactor with the innovative design. Applying a PE granulated filling in the chamber of the innovative reactor contributed to an even distribution of sludge biomass in the reactor, reducing washout of anaerobic sludge biomass from the reaction chamber and giving a higher organic compounds removal efficiency.


Prospects of transcript profiling for mRNAs and MicroRNAs using formalin-fixed and paraffin-embedded dissected autoptic multiple sclerosis lesions.
The elaboration of novel pathogenic aspects of multiple sclerosis (MS) requires the analysis of well-defined stages of lesion development. However, specimens of certain stages and lesion types are either present in small brain biopsies, insufficient in size for further molecular studies or available as formalin-fixed and paraffin-embedded (FFPE) material only. Therefore, application of current molecular biology techniques to FFPE tissue is warranted. We compared FFPE and frozen tissue by using quantitative polymerase chain reaction and report: (1) FFPE material is highly heterogeneous regarding the utility for transcript profiling of mRNAs; well-preserved FFPE samples had about a 100-fold reduced sensitivity compared with frozen tissue, but gave similar results for genes of sufficient abundance; (2) FFPE samples not suitable for mRNA analysis are still highly valuable for miRNA quantification; (3) the length of tissue fixation greatly affects utility for mRNA but not for miRNA analysis; (4) FFPE samples can be processed via a hot water bath for dissection of defined lesion areas; and (5) in situ hybridization for proteolipid protein (PLP) helps to identify samples not suitable for mRNA amplification. In summary, we present a detailed protocol how to use autoptic FFPE tissue for transcript profiling in dissected tissue areas.


Potent vasoconstrictor responses to endogenous digitalis-like factor of isolated, perfused dog intermediate auricular arteries.
Endogenous digitalis-like factor obtained from urine of hypertensive patients caused a vasoconstriction in a dose-related manner in isolated, perfused dog intermediate auricular arteries. The constriction was not modified by alpha-adrenoceptor blockade.


Butorphanol agonist effects and acute physical dependence in opioid abusers: comparison with morphine.
This study compared the direct effects and acute physical dependence of butorphanol and morphine, opioids with differing actions at mu versus kappa receptors. Six non-dependent heroin-using volunteers were exposed to six conditions in a within-subject, Latin square design using double-blind procedures. In each session, agonist effects of single i.m. injections of butorphanol (3 and 6 mg/70 kg), morphine (15 and 30 mg/70 kg), lorazepam (4 mg/70 kg) or saline were evaluated. Butorphanol and morphine produced effects of comparable magnitude on miosis and reports of 'any drug effect'. Volunteers reported dysphoria, confusion and sedation after butorphanol, subjective effects that overlapped with those of lorazepam, whereas morphine produced euphoria and stimulation. Acute physical dependence (i.e. precipitated withdrawal responses to naloxone 10 mg/70 kg i.m. administered 6 h after each treatment) significantly increased after 30 mg/70 kg morphine but not after butorphanol treatments. These differences in naloxone sensitivity are likely due to differences in opioid receptor (mu versus kappa) activity, affinity and efficacy of these compounds. Pharmacological ramifications of these results are discussed.


Depression of liver drug metabolism in sarcoma-bearing mice. Evidence for a circulating factor and dissociation from lipolytic activity.
Mice bearing the S-180 sarcoma displayed a depression of liver catalase and cytochrome P-450-dependent enzymes (ethoxycoumarin deethylase, ED) from day 6 following tumor implantation. Injection of serum obtained from tumor-bearing mice into normal mice caused depression of liver ED suggesting that a circulating factor was involved. Tumor-bearing mice did not show any significant change in serum triglycerides and food intake. By contrast, injection of endotoxin, interleukin-1 (IL-1) or tumor necrosis factor (TNF) caused not only a depression in liver ED but also a marked increase in serum triglycerides. To study the possible analogies between cancer-associated circulating factor and monokines, we studied the effect of dexamethasone (a known inhibitor of monokine synthesis) on liver ED activity in tumor-bearing mice. Dexamethasone (DEX) treatment increased (up to 60%) liver ED activity in tumor-bearing mice. We conclude that: (i) a circulating factor is involved in cancer-associated ED depression; (ii) that this mediator is not necessarily identical to TNF or IL-1 and (iii) that DEX reverses the depression of liver ED in cancer, possibly by inhibiting the synthesis, or the effects, of this factor.