M1-derived extracellular vesicles enhance photodynamic therapy and promote immunological memory in preclinical models of colon cancer.
Extracellular vesicles (EVs) are promising drug carriers of photosensitizers for photodynamic therapy (PDT) in cancer treatment, due to their ability to circulate in blood and enter cells efficiently. The therapeutic potential of EVs has been suggested to depend on the type and physiological state of their cell of origin. However, the effects of deriving EVs from various cells in different physiological states on their antitumor capacity are rarely evaluated. In the present study, we compared the antitumor efficacy of EV-mediated PDT by incorporating the photosensitizer Zinc Phthalocyanine (ZnPc) into EVs from multiple cells sources. ZnPc was incorporated by a direct incubation strategy into EVs derived from immune cells (M1-like macrophages and M2-like macrophages), cancer cells (B16F10 melanoma cancer cells) and external sources (milk). Our data show that all EVs are suitable carriers for ZnPc and enable efficient PDT in vitro in co-culture models and in vivo. We observed that EV-mediated PDT initiates immunogenic cell death through the release and exposure of damage associated molecular patterns (DAMPs) on cancer cells, which subsequently induced dendritic cell (DC) maturation. Importantly, of all ZnPc-EVs tested, in absence of light only M1-ZnPc displayed toxicity to MC38, but not to DC, in monoculture and in co-culture, indicating specificity for cancer over immune cells. In MC38 tumor-bearing mice, only M1-ZnPc induced a tumor growth delay compared to control in absence of light. Interestingly, M1- but not M2-mediated PDT, induced complete responses against MC38 tumors in murine models (100% versus 38% of cases, respectively), with survival of all animals up to at least 60 days post inoculation. Finally, we show that all cured animals are protected from a rechallenge with MC38 cells, suggesting the induction of immunological memory after EV-mediated PDT. Together, our data show the importance of the cell type from which the EVs are obtained and highlight the impact of the immunological state of these cells on the antitumor efficacy of EV-mediated PDT.


Can we do it all? Reflections on the development of a collaborative, three day a week internal medicine rounding experience.
Interdisciplinary training is a critical part of pharmacy education, and often much of the interdisciplinary participation occurs during the advanced practice experiences of the final professional year of pharmacy education. Creation and maintenance of these experiences can be difficult for faculty members, especially faculty at community hospitals or those with multiple roles and responsibilities at their practice site. The purpose of this article is to reflect on the development process and student acceptance of a collaborative, three-day a week internal medicine rounding student experience. Instead of a traditional five-day a week rounding schedule with a single, primary faculty preceptor, students participated in a three-day a week internal medicine rounding experience where their primary faculty preceptor had a faculty partner who functioned as a substitute. The student activities on the other days were adapted by each faculty preceptor based on their internal medicine subspecialty duties and needs of the practice site. Results from a seven-question, anonymous survey to students who participated in the three-day a week internal medicine rounds found high impact on their reported confidence and knowledge. Those responding "positive impact" or "extreme positive impact" ranged from 67% to 100%. In addition, 78% indicated comfort with the substitute faculty preceptor. This collaborative, three-day a week rounding experience was well received by pharmacy students. Non-traditional rounding may be an option that could help decrease pharmacy student and faculty burnout, while still providing a positive learning experience for students.


Genetic and developmental basis of cichlid trophic diversity.
Cichlids have undergone extensive evolutionary modifications of their feeding apparatus, making them an ideal model to study the factors that underlie craniofacial diversity. Recent studies have provided critical insights into the molecular mechanisms that have contributed to the origin and maintenance of cichlid trophic diversity. We review this body of work, which shows that the cichlid jaw is regulated by a few genes of major additive effect, and is composed of modules that have evolved under strong divergent selection. Adaptive variation in cichlid jaw shape is evident early in development and is associated with allelic variation in and expression of bmp4. Modulating this growth factor in the experimentally tractable zebrafish model reproduces natural variation in cichlid jaw shape, supporting a role for bmp4 in craniofacial evolution. These data demonstrate the utility of the cichlid jaw as a model for studying the genetic and developmental basis of evolutionary changes in craniofacial morphology.


Three-dimensional modeling of EXAFS spectral mixtures by combining Monte Carlo simulations and target transformation factor analysis.
We have developed a new method for the three-dimensional modeling of extended X-ray absorption fine structure (EXAFS) spectra which enables the extraction of the local structure of aqueous metal complexes from spectral mixtures of several components. The new method combines two techniques: Monte Carlo simulation and target transformation factor analysis (TFA). Monte Carlo simulation is used to create random arrangements between the X-ray absorbing metal ion and the ligand atoms, and to calculate the theoretical EXAFS spectrum of each arrangement. The theoretical EXAFS spectrum is then introduced as test spectrum in the TFA procedure, to test whether or not the test spectrum is likely to be a component of the spectral mixtures. This coupled procedure is repeated until the error in the test spectrum is minimized. The new method can thus be used to isolate and refine the structure of complexes from spectral mixtures and to determine their relative concentrations, solely on the basis of an estimate of a ligand structure. The performance of the proposed method is validated using uranium Liii-edge EXAFS spectra of binary mixtures of two uranium(VI) 3,4-dihydroxybenzoic acid complexes.


Challenges in Metabolomics-Based Tests, Biomarkers Revealed by Metabolomic Analysis, and the Promise of the Application of Metabolomics in Precision Medicine.
Metabolomics helps identify metabolites to characterize/refine perturbations of biological pathways in living organisms. Pre-analytical, analytical, and post-analytical limitations that have hampered a wide implementation of metabolomics have been addressed. Several potential biomarkers originating from current targeted metabolomics-based approaches have been discovered. Precision medicine argues for algorithms to classify individuals based on susceptibility to disease, and/or by response to specific treatments. It also argues for a prevention-based health system. Because of its ability to explore gene-environment interactions, metabolomics is expected to be critical to personalize diagnosis and treatment. Stringent guidelines have been applied from the very beginning to design studies to acquire the information currently employed in precision medicine and precision prevention approaches. Large, prospective, expensive and time-consuming studies are now mandatory to validate old, and discover new, metabolomics-based biomarkers with high chances of translation into precision medicine. Metabolites from studies on saliva, sweat, breath, semen, feces, amniotic, cerebrospinal, and broncho-alveolar fluid are predicted to be needed to refine information from plasma and serum metabolome. In addition, a multi-omics data analysis system is predicted to be needed for omics-based precision medicine approaches. Omics-based approaches for the progress of precision medicine and prevention are expected to raise ethical issues.


MCL-DTI: using drug multimodal information and bi-directional cross-attention learning method for predicting drug-target interaction.
Prediction of drug-target interaction (DTI) is an essential step for drug discovery and drug reposition. Traditional methods are mostly time-consuming and labor-intensive, and deep learning-based methods address these limitations and are applied to engineering. Most of the current deep learning methods employ representation learning of unimodal information such as SMILES sequences, molecular graphs, or molecular images of drugs. In addition, most methods focus on feature extraction from drug and target alone without fusion learning from drug-target interacting parties, which may lead to insufficient feature representation. In order to capture more comprehensive drug features, we utilize both molecular image and chemical features of drugs. The image of the drug mainly has the structural information and spatial features of the drug, while the chemical information includes its functions and properties, which can complement each other, making drug representation more effective and complete. Meanwhile, to enhance the interactive feature learning of drug and target, we introduce a bidirectional multi-head attention mechanism to improve the performance of DTI. To enhance feature learning between drugs and targets, we propose a novel model based on deep learning for DTI task called MCL-DTI which uses multimodal information of drug and learn the representation of drug-target interaction for drug-target prediction. In order to further explore a more comprehensive representation of drug features, this paper first exploits two multimodal information of drugs, molecular image and chemical text, to represent the drug. We also introduce to use bi-rectional multi-head corss attention (MCA) method to learn the interrelationships between drugs and targets. Thus, we build two decoders, which include an multi-head self attention (MSA) block and an MCA block, for cross-information learning. We use a decoder for the drug and target separately to obtain the interaction feature maps. Finally, we feed these feature maps generated by decoders into a fusion block for feature extraction and output the prediction results. MCL-DTI achieves the best results in all the three datasets: Human, C. elegans and Davis, including the balanced datasets and an unbalanced dataset. The results on the drug-drug interaction (DDI) task show that MCL-DTI has a strong generalization capability and can be easily applied to other tasks.


Pulmonary rehabilitation in clinical routine: a follow-up study.
The effect of rehabilitation for chronic obstructive pulmonary disease has been well-documented in randomized controlled trials. Evidence-based guidelines support rehabilitation programmes for chronic obstructive pulmonary disease, but knowledge of their outcome in clinical practice is limited. The aim of this study was to assess the outcome of a clinical routine rehabilitation programme for chronic obstructive pulmonary disease implemented by a Danish regional hospital. Changes in walk-distance (6-min walk-distance test; 6MWD), dyspnoea (Medical Research Council dyspnoea scale; MRC) and health-related quality of life (Short-Form 36; SF-36) were compared between and within completers and non-completers from baseline to the end of clinical routine rehabilitation, and at 6 and 12 months. The 8-week clinical routine rehabilitation comprised bi-weekly 90-min sessions of patient education and physical training. The hospital treated 521 patients during the study period. Of these, 175 were invited to join the study, 148 participated at baseline, and 98 at the 12-month follow-up. Completers' 6MWD was sustained from baseline to the end of clinical routine rehabilitation, but had declined by 12 months. Dyspnoea and health-related quality of life did not change. Seventy-five percent of completers felt better or much better after rehabilitation. The failure of completers to achieve expected outcomes shows a need for a stronger implementation effort and continuous quality control. Successful implementation in clinical routine requires targeted recruitment and overall programme improvement in general, and a stronger focus on physical training and staff competences.


The relationship between executive function and verbal memory in Parkinson's disease.
A growing body of evidence suggests that the various cognitive symptoms found in Parkinson's disease (PD) are secondary to executive dysfunction. Studies addressing this possibility for memory impairment specifically have not included measures of working memory nor have they ruled-out potential mediating variables such as overall level of cognitive impairment or depression. The purpose of this study was to include measures of these variables in determining the relationship between multiple aspects of executive function and delayed verbal recall in 32 idiopathic PD patients. Results were consistent with the original hypothesis and further suggest that working memory is a key factor in recall memory and may mediate the relationship between other executive measures and recall in PD.


Reconstruction of crimes by infrared photography.
Whenever blunt or sharp forces are used in a crime, analysis of bloodstain pattern distribution may provide important information for the reconstruction of happenings. Thereby, attention should be paid to both the crime scene and the clothes of everyone involved in the crime. On dark textiles, though, it is difficult or even impossible for the human eye to detect bloodstains because of the low contrast to the background. However, in the near infrared wavelength range, contrast is considerably higher. Many textiles reflect light beyond a wavelength of 830 nm and thus appear light-colored, whereas blood absorbs the light and appears dark. In our studies, a D7000 NIKON reflex camera modified for infrared photography produced high-resolution photographs visualizing even very small spatter stains on dark textiles. The equipment can be used at any crime scene or lab and provides immediately available and interpretable images. Thus, important findings can be obtained at an early stage of police investigations, as two examples (homicide and attempted homicide) illustrate.


Configurational assignment of rhizopodin, an actin-binding macrolide from the myxobacterium Myxococcus stipitatus.
The relative and absolute stereochemistry of the 38-membered myxobacterial polyketide rhizopodin, a potent actin-binding macrolide, was determined by J-based configurational analysis in combination with molecular modeling and chemical derivatization.


Facial Expression Stereotypes of Male and Female Adults and Children: Do Facial Expression Stereotypes of Adults Apply to Children?
This study explored the facial expression stereotypes of adult men and women within the Chinese cultural context and investigated whether adult participants had facial expression stereotypes of children aged 6 and 10 years old. Three experiments were conducted with 156 adult Chinese university student participants. Experiment 1 explored whether adult participants had facial expression stereotypes of adult men and women. In Experiment 1a, the participants imagined a happy or angry adult face and stated the gender of the imagined face. In Experiment 1b, the participants were asked to quickly judge the gender of happy or angry adult faces, and their response time was recorded. Experiments 2 and 3 explored whether adults apply the stereotypes of adult men and women to 10-year-old and 6-year-old children. Experiment 1 revealed that the participants associated angry facial expressions with men and happy facial expressions with women. Experiment 2 showed that the participants associated angry facial expressions with 10-year-old boys and happy expressions with 10-year-old girls. Finally, Experiment 3 revealed that the participants associated happy facial expressions with 6-year-old girls but did not associate angry facial expressions with 6-year-old boys. These results showed that, within the Chinese cultural context, adults had gender-based facial expression stereotypes of adults and 10-year-old children; however, the adult participants did not have gender-based facial expression stereotypes of 6-year-old male children. This study has important implications for future research, as adults' perceptions of children is an important aspect in the study of social cognition in children.


Prevention of Aflatoxin contamination through some commercial chemical products and plant extracts in groundnut.
The effect of rock salts, NaCI, propionic acid, NCP.75, plant products - asafoetida, turmeric powder and aqueous leaf extracts ofAzadirachta indica, Lawsonia alba, Pongamia glabra andTridax procumbens on seed colonization and aflatoxin production byAspergillus flavus (NRRL-3000) was studied in two Spanish bunch groundnut varieties (J-11 and JL-24). All these treatments inhibited seed colonization and aflatoxin production to varying degrees. Inhibition of seed colonization with chemicals, plant products and aqueous leaf extracts was observed to range between 17 to 96%, 27 to 100%, and 8 to 75% while inhibition of aflatoxin production ranged from 14 to 74%, 42 to 71%, and 6 to 64%, respectively. In general, salts (20g/L), propionic acid (10mL/L), asafoetida (pure Ig/L and impure 20g/L), andAzadirachta indica aqueous leaf extract (20 g/L) are better in preventing aflatoxin contamination in both the groundnut varieties.


Lysine-ketoglutarate reductase in human tissues.
Lysine-ketoglutarate reductase (saccharopine dehydrogenase (NADP+, lysine-forming) EC 220.127.116.11) from human liver has been partially purified and characterized. A spectrophotometric assay is described. The Michaelis constants have been determined for lysine (1.5-10-3 M), alpha-ketoglutarate (1-10-3 M) and NADPH (8-10-5 M). The pH optimum is 7.8. The enzyme is product inhibited. The specificity of the enzyme, response to inhibitors, pH and thermal stability are reported. Lysine-ketoglutarate reductase is present in high concentration in liver and heart, to a lesser degree in kidney and skin and in trace amounts in several other tissues. Saccharopine dehydrogenase (saccharopine dehydrogenase (NAD+, L-glutamate-forming) EC 18.104.22.168) was demonstrable only in liver and kidney. Lysine-ketoglutarate reductase reacts effectively with delta-hydroxylysine.


Combining the strength of genomics, nanoparticle technology, and direct intraductal delivery for breast cancer treatment.
A large number of genes are altered in cancer cells. Often, reversal or inhibition of just one of these alterations leads to death of the cancer cells. Technological advances in multiple areas are necessary to potentiate clinical translation of these findings. In a recent article, Brock and colleagues reported that overexpressed HOXA1 is a critical event in tumor progression in a mouse mammary tumor model. They developed HOXA1-small interfering RNA nanoparticles and achieved effective therapeutic doses by delivering them intraductally through the nipple to the site of the tumor and at the same time circumvented the systemic immune response. This study strengthens the concept of targeting overexpressed genes by using small interfering RNA and bypassing systemic immunity through local intraductal delivery.


Gene expression in dopamine and GABA systems in an animal model of schizophrenia: effects of antipsychotic drugs.
We used in situ hybridization histochemistry to assess expression of dopamine receptors (D1R, D2R and D3R), neurotensin, proenkephalin and glutamate decarboxylase-67 (GAD67) in the prefrontal cortex, striatum, and/or nucleus accumbens in adult rats with neonatal ventral hippocampal (VH) lesions and in control animals after acute and chronic treatment with antipsychotic drugs clozapine and haloperidol. We also acquired these measures in a separate cohort of treatment-naïve sham and neonatally VH-lesioned rats used as an animal model of schizophrenia. Our results indicate that the neonatal VH lesion did not alter expression of D1R, D3R, neurotensin or proenkephalin expression in any brain region examined. However, D2R mRNA expression was down-regulated in the striatum, GAD67 mRNA was down-regulated in the prefrontal cortex and prodynorphin mRNA was up-regulated in the striatum of the VH-lesioned rats as compared with sham controls. Antipsychotic drugs did not alter expression of D1R, D2R or D3R receptor mRNAs but elevated neurotensin and proenkephalin expression in both groups of rats; patterns of changes were dependent on the duration of treatment and brain area examined. GAD67 mRNA was up-regulated by chronic antispychotics in the nucleus accumbens and the striatum and by chronic haloperidol in the prefrontal cortex in both sham and lesioned rats. These results indicate that the developmental VH lesion changed the striatal expression of D2R and prodynorphin and robustly compromised prefrontal GAD67 expression but did not modify drug-induced expression of any genes examined in this study.


Towards eco-friendly marine antifouling biocides - Nature inspired tetrasubstituted 2,5-diketopiperazines.
Marine biofouling plagues all maritime industries at vast economic and environmental cost. Previous and most current methods to control biofouling have employed highly persistent toxins and heavy metals, including tin, copper, and zinc. These toxic methods are resulting in unacceptable environmental harm and are coming under immense regulatory pressure. Eco-friendly alternatives are urgently required to effectively mitigate the negative consequence of biofouling without causing collateral harm. Amphiphilic micropeptides have recently been shown to exhibit excellent broad-spectrum antifouling activity, with a non-toxic mode of action and innate biodegradability. The present work focused on incorporating the pharmacophore derived from amphiphilic micropeptides into a 2,5-diketopiperazine (DKP) scaffold. This privileged structure is present in a vast number of natural products, including marine natural product antifoulants, and provides advantages of synthetic accessibility and adaptability. A novel route to symmetrical tetrasubstituted DKPs was developed and a library of amphiphilic 2,5-DKPs were subsequently synthesised. These biodegradable compounds were demonstrated to be potent marine antifoulants displaying broad-spectrum activity in the low micromolar range against a range of common marine fouling organisms. The outcome of planned coating and field trials will dictate the future development of the lead compounds.


Cytokines in relapsing experimental autoimmune encephalomyelitis in DA rats: persistent mRNA expression of proinflammatory cytokines and absent expression of interleukin-10 and transforming growth factor-beta.
Experimental autoimmune encephalomyelitis (EAE) in rats is typically a brief and monophasic disease with sparse demyelination. However, inbred DA rats develop a demyelinating, prolonged and relapsing encephalomyelitis after immunization with rat spinal cord in incomplete Freund's adjuvant. This model enables studies of mechanisms related to chronicity and demyelination, two hallmarks of multiple sclerosis (MS). Here we have investigated, in situ, the dynamics of cytokine mRNA expression in the central nervous system (CNS) and peripheral lymphoid organs (lymph node cells and splenocytes) of diseased DA rats. We demonstrate that peripheral lymphoid cells stimulated in vitro with encephalitogenic peptides 69-87 and 87-101 of myelin basic protein responded with high mRNA expression for proinflammatory cytokines; interferon-gamma, interleukin-12 (IL-12), tumour necrosis factors alpha and beta, IL-1 beta and cytolysin. A high expression of mRNA for these proinflammatory cytokines was also observed in the CNS where it was accompanied by classical signs of inflammation such as expression of major histocompatibility complex class I and II, CD4, CD8 and IL-2 receptor. The expression of mRNA for proinflammatory cytokines was remarkably long-lasting in DA rats as compared to LEW rats which display a brief and monophasic EAE. Furthermore, mRNAs for putative immunodownmodulatory cytokines, i.e. transforming growth factor-beta (TGF-beta), IL-10 and IL-4 were almost absent in DA rats, in both the CNS and in vitro stimulated peripheral lymphoid cells, while their levels were elevated in the CNS of LEW rats during the recovery phase. We conclude that the MS-like prolonged and relapsing EAE in DA rats is associated with a prolonged production of proinflammatory cytokines and/or low or absent production of immunodownmodulatory cytokines.


Cinchona-based zwitterionic stationary phases: Exploring retention and enantioseparation mechanisms in supercritical fluid chromatography with a fragmentation approach.
Chiralpak ZWIX(+) and ZWIX(-), are brush-type bonded-silica chiral stationary phases (CSPs), based on complex diastereomeric Cinchona alkaloids derivatives bearing both a positive and a negative charge. In the present study, we aimed to improve the understanding of retention and enantioseparation mechanisms of these CSPs employed in supercritical fluid chromatography (SFC). For this purpose, 9 other stationary phases were used as comparison systems: two of them are commercially available and bear only a positive charge (Chiralpak QN-AX and QD-AX) and the 7 others were designed purposely to be structurally similar to the parent ZWIX phases, but miss some portion of the complex ligand. First, cluster analysis was employed to identify similar and dissimilar behavior among the 11 stationary phases, where ionic interactions appeared to dominate the observed differences. Secondly, the stationary phases were characterized with linear solvation energy relationships (LSER) based on the SFC analysis of 161 achiral analytes and a modified version of the solvation parameter model to include ionic interactions. This served to compare the interaction capabilities for the 11 stationary phases and showed in particular the contribution of attractive and repulsive ionic interactions. Then the ZWIX phases were characterized for their enantioseparation capabilities with a set of 58 racemic probes. Discriminant analysis was applied to explore the molecular structural features that are useful to successful enantioseparation on the ZWIX phases. In particular, it appeared that the presence of positive charges in the analyte is causing increased retention but is not necessarily a favorable feature to enantiorecognition. On the opposite, the presence of negative charges in the analyte favors early elution and enantiorecognition. Finally, a smaller set of 30 pairs of enantiomers, selected by their structural diversity and different enantioseparation values on the ZWIX phases, were analyzed on all chiral phases to observe the contribution of each structural fragment of the chiral ligand on enantioselectivity. Molecular modelling of the ligands also helped in understanding the three-dimensional arrangement of each ligand, notably the intra-molecular hydrogen bonding or the possible contribution of ionic interactions. In the end, each structural element in the ZWIX phases appeared to be a significant contributor to successful enantioresolution, whether they contribute as direct interaction groups (ion-exchange functions) or as steric constraints to orientate the interacting groups towards the analytes.


[Hypercholesterolemia and cardiovascular risk].
Pharmacological reduction of LDL-cholesterol (LDL-C) is a major treatment strategy in limiting atherosclerotic cardiovascular (ASCVD) risk. Statins remain the primary therapeutic cornerstone in ASCVD prevention. Furthermore, ezetimibe, bempedoic acid, and PCSK9 inhibition have recently also shown to reduce cardiovascular risk. Unfortunately, a treatment gap remains between guideline-recommended LDL-C goals and what is achieved in real-world practice. An important reason for this is the limited use of novel and effective non-statin lipid-lowering therapies. In order to achieve LDL-C treatment goals and, ultimately, reduction of cardiovascular events, a combination lipid-lowering therapy needs to be considered as the standard of care for patients at very high cardiovascular risk.


Diversity Oriented Synthesis: Concise Entry to Novel Derivatives of Yohimbine and Corynanthe Alkaloids.
A novel MCAP-cycloaddition sequence has been applied to the facile synthesis of β-carboline intermediates to gain rapid access to novel derivatives of yohimbine-like and corynanthe-like compounds that may be easily diversified by cross-coupling reactions and N-derivatizations to generate small compound libraries.


Factors contributing to milk yield variation among cows in a cow-calf contact system in early lactation.
The conventional dairy production system involves separation of the cow and calf at around 24 h after birth. Due to public concerns regarding this early separation, a few farmers are taking up the cow-calf contact system. However, some farmers have cited great variation in milk yield delivered to the parlor by cows in this sytem, with this being detrimental because it leads to low farm returns. The main objective of this study was to determine the source of variation in milk delivered to the parlor among cows in a cow-calf contact system. The study examined milk yield records for the first 28 d of lactation for 110 fall- and spring-calving cows from a farm running a full-time cow-calf contact system to investigate factors leading to variation among cows in milk delivered to the parlor. We observed great individual variation in milk yield delivered to the parlor among cows, with the range between the highest and lowest average being 22 L/d. The sex of the calf had an effect on the average milk yield delivered to the parlor: cows with female calves had higher average milk yield (Wald = 5.61, df = 1). Additionally, the lactation number of the dam affected average milk yield delivered to the parlor, with cows in their third lactation and above having the highest milk yield average (Wald = 20.90, df = 2). From the results of this study, we conclude that sex of the calf and lactation number of the dam affect milk yield delivered to the milking parlor in a cow-calf contact system.


Management of hemorrhagic stroke.
Fifty thousand Americans suffer an intracerebral hemorrhage (ICH) annually, one third of whom die as a result. Poorly controlled hypertension is the most important risk factor for ICH. Over time it results in pathologic changes to small intracranial vessels, leading to their rupture. All stroke patients, including those with suspected ICH, require emergent evaluation. Surgical intervention is appropriate for some ICH patients, although intensive medical management of intracranial pressure and the systemic consequences of ICH can reduce morbidity in all. Innovative medical and surgical therapeutic approaches hold promise for improved treatment in the future, but prevention is the key for reducing morbidity in the short term.


Job quality differences among younger and older workers in Europe: The role of institutions.
We compare non-wage aspects of job quality of younger and older workers across European countries and relate the differences between them to the prevailing institutional settings. Microdata from the European Union Labour Force Survey are used to carry out the measurement of a job quality index during the period 2005-2015, while aggregate indicators are used to approximate a set of labour market institutions. Our findings support the notion that the institutional framework affects the age gap in job quality. Among other results, we find that older workers fare better than younger workers, that the employment quality is higher for employees working in countries where the wage-bargaining system is more coordinated/centralized and the employment protection for regular workers is stricter and that these institutions tend to favour the job quality of older workers over younger ones.


Efficacy of infliximab in the treatment of uveitis that is resistant to treatment with the combination of azathioprine, cyclosporine, and corticosteroids in Behçet's disease: an open-label trial.
To investigate the effect of infliximab on the frequency of uveitis attacks and the visual prognosis in male patients with Behçet's disease in whom uveitis was resistant to combination therapy with corticosteroids, azathioprine, and cyclosporine. The study group comprised patients who were receiving combination therapy but experienced at least 2 attacks of posterior uveitis/panuveitis or retinal vasculitis during the 6-month period prior to enrollment. Infliximab infusions (5 mg/kg) were administered at weeks 0, 2, 6, and 14. Weeks 0-22 were defined as the infusion period, and weeks 23-54 were defined as the observation period. Patients continued to receive azathioprine and corticosteroids, but cyclosporine was discontinued after the screening visit. The primary outcome measures were the absence of uveitis attacks during the infusion period (remission), and the absence of uveitis attacks throughout the study period (sustained remission). Thirteen patients were enrolled in the study. Thirty-two uveitis attacks involving the posterior segment occurred during the previous-treatment period. During the infusion period, 4 patients (30.8%) remained attack-free, and 9 patients had a total of 13 uveitis attacks. Ten of these attacks (76.9%) occurred at either week 14 or week 22. One of 13 patients fulfilled the definition of sustained remission, and the remaining 12 patients had a total of 36 uveitis attacks during the observation period. The mean number of uveitis attacks and daily corticosteroid doses were significantly lower during the infusion period than during the previous-treatment period or the observation period. Although potential visual acuity was regained following infliximab infusion, this beneficial effect was not preserved until week 54. None of the patients experienced a serious adverse event. The results of this trial suggest that infliximab is effective in suppressing the occurrence of uveitis attacks, has a corticosteroid-sparing effect, and has favorable implications for the visual prognosis of patients with resistant Behçet's uveitis.


Evaluation of the Stability of a Novel Lateral Plate Internal Fixation: An In Vitro Biomechanical Study.
This study aims to evaluate the biomechanical stability of a novel lateral plate (NLP) that can be used in oblique lateral lumbar fusion (OLIF). In vitro biomechanical tests were performed on 6 fresh calf lumbar vertebrae specimens. The surgical segment was set at L3-L4. Each specimen was tested in the following order: intact state (INT); OLIF cage only/stand-alone (SA); cage supplemented with lateral screw-rod (LSR); cage supplemented with novel lateral plate (NLP); and cage supplemented with unilateral or bilateral pedicle screw-rod (UPS or BPS). A pure moment of ±7.5 Nm was applied to the specimen to produce 6 different motion directions, including flexion and extension, lateral bending, and axial rotation, and the range of motion (ROM) of L3-L4 in each direction was recorded. In addition to flexion-extension, NLP reduced the ROM of SA (P < 0.05). In flexion-extension, the ROM of NLP was similar to those of SA and LSR (P > 0.05); compared to pedicle screw-rod (PSD), the ROM of NLP was higher (P < 0.05). In lateral bending, the ROM of NLP was close to that of LSR and PSD (P > 0.05). In axial rotation, the ROM of NLP was higher than that of PSD (P < 0.05), and close to that of LSR (P > 0.05). NLP can enhance surgical segment stability in all directions of motion, similar to LSR, but weaker than UPS and BPS in flexion-extension and rotation.


AlMe3-promoted oxidative cyclization of eta2-alkene and eta2-ketone on nickel(0). Observation of intermediate in methyl transfer process.
AlMe3 can promote the oxidative cyclization of eta2-alkene and eta2-ketone on nickel(0) to give an intriguing nickel-aluminum dinuclear complex having a bridging methyl group, which might be an intermediate for the nickel-catalyzed cycloisomerization of o-allylacetophenone or o-allylbenzophenone.


The structure of emotional symptoms in the postpartum period: is it unique?
In perinatal mental health there is a lack of consensus as to whether postpartum emotional disorders are unique in their aetiology and clinical presentation. If the clinical presentation is unique, then the factor structure should be different in a postpartum sample. Admission and discharge scores on the Depression Anxiety Stress Scales (DASS; Lovibond and Lovibond, 1995b) scores were collected for 527 inpatients admitted to a Psychiatric Mother and Baby Unit. Reliability and validity of the DASS were examined, and confirmatory factor analysis evaluated the fit of a series of models of the DASS. The DASS had sound reliability and validity in the postpartum inpatient sample. The optimal fitting factor solution for the DASS was a revised three-factor model previously supported in studies of other clinical and non-clinical populations. The factor structure was invariant across admission and discharge. The sample consisted of postpartum inpatients and the generalisability of results to other postpartum samples is not known. Postpartum emotional symptoms have the same factor structure previously observed in non-postpartum populations, consistent with the hypothesis that postpartum emotional disorders are similar to those occurring at other times. The present study provides support for the reliability and validity of the DASS in the postpartum period.


Investigating ESIPT and donor-acceptor substituent effects on the photophysical and electrochemical properties of fluorescent 3,5-diaryl-substituted 1-phenyl-2-pyrazolines.
This paper describes the synthesis, structural study, and evaluation of electrochemical and photophysical properties by UV-Vis absorption and fluorescence emission analysis (solution and solid-state) of a series of eight 3,5-aryl-substituted 1-phenyl-2-pyrazolines (5), where 3-aryl = 2-OH-C6H4 (5a-g) or Ph (5h), and 5-aryl = Ph (a, h), 1-naphthyl (b), 4-Br-C6H4 (c), 4-F-C6H4 (d), 4-OCH3-C6H4(e), 4-NO2-C6H4 (f), 4-(N(CH3)2)-C6H4(g). The UV-Vis absorption properties of 2-pyrazolines were evaluated in DCM, MeCN, AcOEt, EtOH, and DMSO as the solvent and showed a fluorescence shift for the polar aprotic solvents. The steady-state fluorescence emission exhibited a band in the blue region when excited at the least energetic transition of each compound, although the excited-state intramolecular proton (ESIPT) effect was not detected. In the solid state, compounds presented similar behavior regarding absorption and emission properties compared to the solution assays. With the electrochemical analyses performed for the synthesized 2-pyrazolines, it was possible to conclude that the redox potentials were influenced by the electronic and steric effects of the substituents on the aryl rings and, according to the electronic nature of the substituents, which electron-donating groups were favored. Finally, the TD-DFT analyses revealed that all compounds had delocalized electron density throughout the 2-pyrazolines unit and were not influenced by the substituent bonded at C-5. Nonetheless, LUMO orbital analysis showed that only derivatives 5b and 5f have this localized density over the substituents.


Influence of intron and exon splicing enhancers on mammalian cell expression of a truncated spike protein of SARS-CoV and its implication for subunit vaccine development.
The spike (S) protein of severe acute respiratory syndrome coronavirus (SARS-CoV) is important for vaccine development. A truncated S protein of the TW1 strain, STR2 (88 kDa), carrying three S fragments (S74-253, S294-739, and S1129-1255) was investigated to study the influences of intron and exon splicing enhancers to improve STR2 protein expression in mammalian cells. Our results showed that STR2 protein expression with the use of an 138 base-pair intron addition increased by 1.9-, 2.5-, and 4.1-fold in Vero E6, QBI-293A cells, and CHO/dhFr- cells (dihydrofolate reductase [dhfr] gene deficient CHO cells), respectively. Using the exon splicing enhancers, including a bidirectional splicing enhancer (BSE) or an exon splicing enhancer derived from the EDA alternative exon of the fibronectin gene (EDA ESE), were also found to increase STR2 protein expression in CHO/dhFr- cells by 1.7- and 2.6-fold. Nevertheless, combination of the intron and the exon splicing enhancers resulted in suppressing the intron-enhancing e STR2 protein expression in in CHO/dhFr- cells. Our studies also demonstrated the STR2 protein was mainly as the Endo H-sensitive glycoprotein (115 kDa) expressed in Vero E6, QBI-293A, and CHO/dhFr- cells. However, only a minor form of the Endo H-resistant glycoproteins ( approximately 130 kDa) was detected in CHO/dhFr- cells. Taken together, our results indicated that intron had a better enhancing effect on STR2 protein expression than exon splicing enhancers, and the expression of approximately 130 kDa STR2 glycoprotein was enhanced by the intron addition into the expression vector construct. Results of the present study can provide an optimal strategy to enhance SARS-CoV S protein expression in mammalian cells and may contribute to the development of SARS-CoV subunit vaccine.


A non-inferiority test for diagnostic accuracy based on the paired partial areas under ROC curves.
Non-inferiority is a reasonable approach to assessing the diagnostic accuracy of a new diagnostic test if it provides an easier administration or reduces the cost. The area under the receiver operating characteristic (ROC) curve is one of the common measures for the overall diagnostic accuracy. However, it may not differentiate the various shapes of the ROC curves with different diagnostic significances. The partial area under the ROC curve (PAUROC) may present an alternative that can provide additional and complimentary information for some diagnostic tests which require false-positive rate that does not exceed a certain level. Non-parametric and maximum likelihood methods can be used for the non-inferiority tests based on the difference in paired PAUROCs. However, their performance has not been investigated in finite samples. We propose to use the concept of generalized p-value to construct a non-inferiority test for diagnostic accuracy based on the difference in paired PAUROCs. Simulation results show that the proposed non-inferiority test not only adequately controls the size at the nominal level but also is uniformly more powerful than the non-parametric methods. The proposed method is illustrated with a numerical example using published data.


Method for testing adherence of Haemophilus influenzae to human buccal epithelial cells.
A method for testing adherence of Haemophilus influenzae strains to buccal mucosal cells is described. Bacteria grown in broth for 4 h were mixed with buccal mucosal cells. After elimination of unattached bacteria by repeated cycles of centrifugation and resuspension in PBS, the number of attached bacteria was counted microscopically. Optimal results were obtained with an early log-phase bacterial culture at a concentration of 10(9) bacteria/ml mixed with 2 X 10(4) cells/ml and incubated at 37 degrees C for 60 min. This assay showed an at least ten times higher rate of adherence for Haemophilus influenzae than previous studies. Nontypeable strains attached in higher numbers than strains with the type b capsule. Adherence was related to the frequency of nontypeable strains rather than to the site of isolation or type of infection. Thus all the isolates from middle ear fluid were nontypeable, and all but one adhered. The results suggest a difference in virulence mechanisms between type b and nontypeable Haemophilus influenzae strains.


Fore-period effect and stop-signal reaction time.
The effect of response readiness on the stop-signal reaction time (SSRT) in a stop-signal task was examined, with the stop-signal delay updated following a staircase procedure. We computed SSRT on the basis of a horse race model. A fore-period effect was computed, which described subjects' readiness to respond to the GO signal. The results showed that the fore-period effect correlated positively with SSRT, providing evidence of the effect of response prepotency on stop signal processing. This finding suggests that response readiness needs to be accounted for in examining response inhibition in a stop-signal task.


Cost-effectiveness of hepatic resection versus percutaneous radiofrequency ablation for early hepatocellular carcinoma.
Both hepatic resection and radiofrequency ablation (RFA) are considered curative treatments for hepatocellular carcinoma (HCC), but their economic impact still remains not determined. Aim of the present study was to analyze the cost-effectiveness (CE) of these two strategies in early stage HCC (Milan criteria). As first step, a meta-analysis of the pertinent literature of the last decade was performed. Seventeen studies fulfilled the inclusion criteria: 3996 patients underwent resection and 4424 underwent RFA for early HCC. Data obtained from the meta-analysis were used to construct a Markov model. Costs were assessed from the health care provider perspective. A Monte Carlo probabilistic sensitivity analysis was used to estimate outcomes with distribution samples of 1000 patients for each treatment arm. In a 10-year perspective, for very early HCC (single nodule <2 cm) in Child-Pugh class A patients, RFA provided similar life-expectancy and quality-adjusted life-expectancy at a lower cost than resection and was the most cost-effective therapeutic strategy. For single HCCs of 3-5 cm, resection provided better life-expectancy and was more cost-effective than RFA, at a willingness-to-pay above €4200 per quality-adjusted life-year. In the presence of two or three nodules ≤3 cm, life-expectancy and quality-adjusted life-expectancy were very similar between the two treatments, but cost-effectiveness was again in favour of RFA. For very early HCC and in the presence of two or three nodules ≤3 cm, RFA is more cost-effective than resection; for single larger early stage HCCs, surgical resection remains the best strategy to adopt as a result of better survival rates at an acceptable increase in cost.


Emergency Caesarean Section in Obese Parturients: Is a 30-Minute Decision-to-Incision Interval Feasible?
To determine the effect of obesity on decision-to-incision and decision-to-delivery time intervals in emergency Caesarean section. We performed a retrospective study of emergency Caesarean sections performed between 2005 and 2009. Indications for emergency Caesarean section were defined as those posing an immediate threat to the life of the mother or fetus. The primary outcomes were the time intervals from decision for emergency delivery to skin incision, and decision to delivery of the infant. The secondary outcome was a composite of poor neonatal outcomes comprising umbilical cord artery pH lt; 7.20, Apgar score lt; 7 at five minutes, admission to NICU, or neonatal death. A total of 232 women underwent emergency Caesarean section, and 140 of these met the inclusion criteria. At the time of delivery, 78/140 (55.7%) patients were categorized as obese (BMI ≥ 30kg/m2). The median decision-to-incision and decision-to-delivery intervals were significantly longer in the obese group, with a median delay of 4.5 minutes in both time intervals. Time-to-event analysis demonstrated prolongation of the decision-to-incision interval in the obese group (hazard ratio 0.71, P lt; 0.05). There was no difference in the neonatal composite outcome, but there was a significant reduction in median five-minute Apgar score in the obese group (P = 0.02). Obesity is associated with prolonged decision-to-incision and decision-to-delivery intervals, without associated neonatal morbidity, in a tertiary hospital setting. Further studies are required to assess the specific factors limiting expedient delivery in this population.


Insights on the mechanism of bleomycin to induce lung injury and associated in vivo models: A review.
Acute lung injury leads to the development of chronic conditions such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), asthma as well as alveolar sarcoma. Various investigations are being performed worldwide to understand the pathophysiology of these diseases, develop novel bioactive compounds and inhibitors to target the ailment. Generally, in vivo models are used to understand the disease outcome and therapeutic suppressing effects for which the animals are chemically or physically induced to mimic the onset of definite disease conditions. Amongst the chemical inducing agents, Bleomycin (BLM) is the most successful inducer. It is reported to target various receptors and activate inflammatory pathways, cellular apoptosis, epithelial mesenchymal transition leading to the release of inflammatory cytokines, and proteases. Mice is one of the most widely used animal model for BLM induced pulmonary associated studies apart from rat, rabbit, sheep, pig, and monkey. Although, there is considerable variation amongst in vivo studies for BLM induction which suggests a detailed study on the same to understand the mechanism of action of BLM at molecular level. Hence, herein we have reviewed various chemical inducers, mechanism of action of BLM in inducing lung injury in vivo, its advantages and disadvantages. Further, we have also discussed the rationale behind various in vivo models and recent development in BLM induction for various animals.


Direct effects of ovarian hormones on antidepressant binding sites.
Tricyclic antidepressants such as imipramine interact with a membrane binding site associated with the uptake of serotonin. Ovarian hormones estradiol and progesterone were found to affect the concentration and affinity of imipramine binding sites in the hypothalamus but not the cortex of female rats. In vivo and in vitro, estradiol increased the amount of imipramine binding at physiological concentrations; at high concentrations estradiol decreased imipramine binding. Ovariectomy (OVX) had no effect on imipramine binding, consonant with the biphasic dose-response relationship for estradiol. The effects of progesterone were dependent upon the concentration of estradiol. Effects of physiological concentrations of both estradiol and progesterone on imipramine binding in an isolated membrane preparation suggest that the hormones are affecting this aspect of serotonergic neuronal function by nongenomic mechanisms.


The Role of Gender in Cost-Related Medication Nonadherence Among Patients with Diabetes.
Under 50% of type 2 diabetic patients achieve the recommended glycemic control. One barrier to glycemic control is patients' cost-related nonadherence to medications. We hypothesize gender differences in medication nonadherence due to costs among diabetic patients. US National Health Interview Survey (2011 to 2014) data yielded 5260 males and 6188 females with diabetes for over a year. We applied 2 analytic methods (A and B below) across multiple outcome measures (1 to 4) of medication nonadherence due to cost. The key independent variable was participant's gender. Across methods and measure, females consistently report significantly higher rates of medication nonadherence due to costs. Pearson's χ2 showed that female patients were more likely to (1) skip medication (13.5%-10.2%; P < .001), take less than prescribed medication (13.9%-10.5%; P < .001), delay filling prescriptions (16.8%-12.5%; P < .001), and ask doctors to prescribe lower-cost alternative medications (31.8%-28.0%; P < .001). Controlling for covariates, logistic regression models found females more likely to skip medication (OR, 1.30; 95% CI, 1.09-1.55), take less than prescribed medication (OR, 1.26; 95%, CI, 1.06-1.50), delay filling prescriptions, (OR, 1.29; 95% CI, 1.11-1.50), and request lower-cost medication (OR, 1.17; 95% CI, 1.04-1.32). Our results report other factors that influence medication adherence, including socioeconomic and health status variables. A significant gender-based disparity exists on cost-related nonadherence of medication among diabetic patients. Health care providers and policy-makers should pay close attention to find ways to address cost-related nonadherence of medication among patients with chronic illness, especially among female patients.


Oligogalacturonides induce resistance in Arabidopsis thaliana by triggering salicylic acid and jasmonic acid pathways against Pst DC3000.
Oligogalacturonides (OGAs) are a biologically active carbohydrate derived from homogalacturonan, a major element of cell wall pectin. OGAs induced resistance and mechanism were assessed in Arabidopsis thaliana-Pseudomonas syringae pv. tomato DC3000 (Pst DC3000) interaction. The effective resistance was mainly observed at 25 mg/L OGAs with reduced disease index, bacterial multiplication, higher transcript level of salicylic acid (SA) pathway related genes (PR1, PR2, PR5) and jasmonic acid (JA) pathway related genes (PDF1.2, VSP2) as well as SA, JA content and production of reactive oxygen species (ROS), nitric oxide (NO). In SA (NahG, sid2) and JA (jar1) deficient mutants, disease severity indicated that both SA and JA pathways are necessary for Arabidopsis response to Pst DC3000. OGAs triggered less resistance to Pst DC3000 in JA-deficient mutant, and SA-deficient mutants signifying that SA and JA play redundant roles in OGAs induced resistance. Therefore, these evidences further reveal the signaling pathways of OGAs resistance, which is conducive to its application in agriculture to protect plants from diseases.


Lack of synergism of ampicillin and gentamicin in experimental listeriosis.
Strain SLCC 4013 of Listeria monocytogenes is susceptible in vitro to ampicillin (MIC 0.5 mg/l) as well as to gentamicin (MIC 0.5 mg/l). Whereas treatment of mice infected with this virulent strain with 0.5 mg ampicillin twice a day resulted in a marked decrease in bacterial counts per spleen, the administration of 2 mg gentamicin twice a day hardly reduced bacterial multiplication. The combination of both drugs was not much more effective than ampicillin alone. Thus, a synergistic effect of both these antibiotics on intracellularly growing bacteria could not be demonstrated.


EEG microstate analysis of emotion regulation reveals no sequential processing of valence and emotional arousal.
In electroencephalography (EEG), microstates are distributions of activity across the scalp that persist for several tens of milliseconds before changing into a different pattern. Microstate analysis is a way of utilizing EEG as both temporal and spatial imaging tool, but has rarely been applied to task-based data. This study aimed to conceptually replicate microstate findings of valence and emotional arousal processing and investigate the effects of emotion regulation on microstates, using data of an EEG paradigm with 107 healthy adults who actively viewed emotional pictures, cognitively detached from them, or suppressed facial reactions. Within the first 600 ms after stimulus onset only the comparison of viewing positive and negative pictures yielded significant results, caused by different electrodes depending on the microstate. Since the microstates associated with more and less emotionally arousing pictures did not differ, sequential processing could not be replicated. When extending the analysis to 2000 ms after stimulus onset, differences were exclusive to the comparison of viewing and detaching from negative pictures. Intriguingly, we observed the novel phenomenon of a microstate difference that could not be attributed to single electrodes. This suggests that microstate analysis can detect differences beyond those detected by event-related potential analysis.


Mesomorphic Behavior in Silver(I) N-(4-Pyridyl) Benzamide with Aromatic π⁻π Stacking Counterions.
Organic semiconductor materials composed of π⁻π stacking aromatic compounds have been under intense investigation for their potential uses in flexible electronics and other advanced technologies. Herein we report a new family of seven π⁻π stacking compounds of silver(I) bis-N-(4-pyridyl) benzamide with varying counterions, namely [Ag(NPBA)2]X, where NPBA is N-(4-pyridyl) benzamine, X = NO₃- (1), ClO₄- (2), CF₃SO₃- (3), PF₆- (4), BF₄- (5), CH₃PhSO₃- (6), and PhSO₃- (7), which form extended π-π stacking networks in one-dimensional (1D), 2D and 3D directions in the crystalline solid-state via the phenyl moiety, with average inter-ring distances of 3.823 Å. Interestingly, the counterions that contain π⁻π stacking-capable groups, such as in 6 and 7, can induce the formation of mesomorphic phases at 130 °C in dimethylformamide (DMF), and can generate highly branched networks at the mesoscale. Atomic force microscopy studies showed that 2D interconnected fibers form right after nucleation, and they extend from ~30 nm in diameter grow to reach the micron scale, which suggests that it may be possible to stop the process in order to obtain nanofibers. Differential scanning calorimetry studies showed no remarkable thermal behavior in the complexes in the solid state, which suggests that the mesomorphic phases originate from the mechanisms that occur in the DMF solution at high temperatures. An all-electron level simulation of the band gaps using NRLMOL (Naval Research Laboratory Molecular Research Library) on the crystals gave 3.25 eV for (1), 3.68 eV for (2), 1.48 eV for (3), 5.08 eV for (4), 1.53 eV for (5), and 3.55 eV for (6). Mesomorphic behavior in materials containing π⁻π stacking aromatic interactions that also exhibit low-band gap properties may pave the way to a new generation of highly branched organic semiconductors.


Optimization of an ultra low-phase noise sapphire--SiGe HBT oscillator using nonlinear CAD.
In this paper, the electrical and noise performances of a 0.8 microm silicon germanium (SiGe) transistor optimized for the design of low phase-noise circuits are described. A nonlinear model developed for the transistor and its use for the design of a low-phase noise C band sapphire resonator oscillator are also reported. The best measured phase noise (at ambient temperature) is -138 dBc/Hz at 1 kHz offset from a 4.85 GHz carrier frequency, with a loaded QL factor of 75,000.


Oncologic emergencies II. Hematologic and infectious complications of cancer and cancer treatment.
Proper supportive care of the child with cancer is necessary to maximize the child's quality and length of life. This article discusses the pathophysiology, diagnosis, and management of the common hematologic and infectious complications of childhood cancer that the primary care physician must face.


BHPF exposure impairs mouse and human decidualization.
Although BHPF has been widely used in plastic manufacturing as a substitute for BPA, current evidence suggests that BHPF also causes harmful effects on reproduction. However, effects of BHPF on mammalian early pregnancy are still poorly defined. This study aimed to explore the effects of BHPF on early pregnancy, especially decidualization and embryonic development in mice and human beings. The results showed that 50 and 100 mg/kg BHPF exposure reduced birth weight, and implantation site weight on the day 8 of pregnancy in mice. Because BHPF inhibits both embryo development and artificial decidualization in mice, suggesting that the detrimental effects of BHPF should be from its effects on embryo development and decidualization. Under in vitro decidualization, 10 μM BHPF inhibits decidualization and leads to disordered expression of Lamin B1 and collagen in mice. In addition, 10 μM BHPF also inhibits decidualization, and causes disordered expression of both collagen III and Lamin B1 under human in vitro decidualization. However, collagen III supplementation can rescue BHPF inhibition on decidualization. Further, our study demonstrates that BHPF impairs human decidualization through the HB-EGF/EGFR/STAT3/Collagen III pathway. Taken together these data suggest that exposure to BHPF impairs mouse and human decidualization during early pregnancy.


Pattern identification of biomedical images with time series: Contrasting THz pulse imaging with DCE-MRIs.
We provide a survey of recent advances in biomedical image analysis and classification from emergent imaging modalities such as terahertz (THz) pulse imaging (TPI) and dynamic contrast-enhanced magnetic resonance images (DCE-MRIs) and identification of their underlining commonalities. Both time and frequency domain signal pre-processing techniques are considered: noise removal, spectral analysis, principal component analysis (PCA) and wavelet transforms. Feature extraction and classification methods based on feature vectors using the above processing techniques are reviewed. A tensorial signal processing de-noising framework suitable for spatiotemporal association between features in MRI is also discussed. Examples where the proposed methodologies have been successful in classifying TPIs and DCE-MRIs are discussed. Identifying commonalities in the structure of such heterogeneous datasets potentially leads to a unified multi-channel signal processing framework for biomedical image analysis. The proposed complex valued classification methodology enables fusion of entire datasets from a sequence of spatial images taken at different time stamps; this is of interest from the viewpoint of inferring disease proliferation. The approach is also of interest for other emergent multi-channel biomedical imaging modalities and of relevance across the biomedical signal processing community.


Failure to detect norovirus in a large group of asymptomatic individuals.
Noroviruses are a major cause of both sporadic and epidemic gastroenteritis in humans, but the mechanisms by which norovirus circulates within the community are poorly understood. In this study, we examined the hypothesis that asymptomatic people act as a reservoir for norovirus. Faecal specimens from 399 asymptomatic individuals were tested for norovirus by reverse transcription polymerase chain reaction (RT-PCR) methodology, and no norovirus was detected. The failure to detect norovirus was not apparently due to the test sample being resistant to norovirus infection, nor to the presence of PCR inhibitors in the test sample. The findings suggest that, if norovirus is carried by asymptomatic people, the carriage rate is very low; the upper bound (95% confidence interval, binomial distribution) of the carriage rate was only 0.8%. Thus, it is unlikely that asymptomatic people are an important reservoir for norovirus.


Ligand dimerization programmed by hybridization to study multimeric ligand-receptor interactions.
Oligomerization of receptors induced or stabilized by polyvalent ligands is a fundamental mechanism in cellular recognition and signal transduction. Herein we report a general approach to encode complex peptide macrocycles with peptide nucleic acid (PNA) tags and program their oligomerization through hybridization as exemplified with a ligand binding to oligomeric DR5, a receptor of TRAIL cytokine.


The Sporomusa type Nfn is a novel type of electron-bifurcating transhydrogenase that links the redox pools in acetogenic bacteria.
Flavin-based electron bifurcation is a long hidden mechanism of energetic coupling present mainly in anaerobic bacteria and archaea that suffer from energy limitations in their environment. Electron bifurcation saves precious cellular ATP and enables lithotrophic life of acetate-forming (acetogenic) bacteria that grow on H2 + CO2 by the only pathway that combines CO2 fixation with ATP synthesis, the Wood-Ljungdahl pathway. The energy barrier for the endergonic reduction of NADP+, an electron carrier in the Wood-Ljungdahl pathway, with NADH as reductant is overcome by an electron-bifurcating, ferredoxin-dependent transhydrogenase (Nfn) but many acetogens lack nfn genes. We have purified a ferredoxin-dependent NADH:NADP+ oxidoreductase from Sporomusa ovata, characterized the enzyme biochemically and identified the encoding genes. These studies led to the identification of a novel, Sporomusa type Nfn (Stn), built from existing modules of enzymes such as the soluble [Fe-Fe] hydrogenase, that is widespread in acetogens and other anaerobic bacteria.


Photodynamic effect of haematoporphyrin throughout the cell cycle of the human cell line NHIK 3025 cultivated in vitro.
Cells from the established cell line NHIK 3025 were synchronized by repeated mitotic selections. Survival of the synchronized cells after treatment with haematoporphyrin and near-UV light was measured by testing the capacity of the cells to form macroscopic colonies. The sensitivity to photodynamic inactivation was small in early G1, late S and G2. The sensitivity increased throughout late G1 and early S to a maximum in mid S. More than a 100-fold variation is found in the survival after 20 min irradiation in the presence of 4 X 10(-4)M haematoporphyrin.


Raw milk preservation by hyperbaric storage: Effect on microbial counts, protein structure and technological functionality.
The possibility to apply hyperbaric storage (HS) at room temperature (20 °C) as a sustainable approach for preservation of raw skim milk was studied. Samples were stored at 200 and 150 MPa for up to 6 days. Optimal pressure for milk HS was found to be 150 MPa, since no clotting was detected for up to 6 days. 150 MPa-HS caused the irreversible inactivation of inoculated Escherichia coli (5.13 ± 0.33 logCFU mL-1) and Staphylococcus aureus (5.66 ± 0.93 logCFU mL-1) within 2 and 6 days, respectively. Inactivation of total and faecal coliforms (3.0 log reductions) below the detection limit was achieved after just 2 days, whereas lactic acid bacteria and coagulase-positive Staphylococci were inactivated after 6 days. Pressurized storage also caused an increase in proteose peptones and the release of submicelles from casein micelles. Micelles progressively aggregated with pressure-unfolded β-Lactoglobulin. These phenomena led to milk presenting up to 4-fold better foaming capacity, probably due to β-Lactoglobulin unfolding or higher proteose peptones content. This work demonstrated the capability of HS to guarantee milk preservation during storage, and brought attention on the opportunity to consider the technology for milk pasteurization and functionality improvement.


Ecological stoichiometry-based study of the influence of soil saline-alkali stress on nutrient homeostasis in L. chinensis.
Soil salinization is a major cause of land degradation and hinders the effective utilization of agricultural land resources. Leymus chinensis (L. chinensis), as a dominant species with wide ecological amplitude, plays an important role in improving saline-alkali grasslands and indicating the degree of salinization. In this study, a sand culture experiment (nitrogen and phosphorus addition accompanied by saline-alkali stress) was designed to investigate the impact of different saline-alkali environments on the ecological stoichiometric homeostasis of L. chinensis with the aim of elucidating the saline-alkali resistance mechanisms. The results showed that the homeostasis indexes of N, P and N:P in the aboveground part of L. chinensis were generally higher than those in the belowground part under different saline-alkali conditions. Furthermore, the homeostasis index of N (HN) was greater than that of P (HP) in the aboveground part, whereas HN was less than HP in the belowground part. This indicates that the growth aboveground of L. chinensis was mainly dependent on N, whereas the growth belowground was mainly affected by P. The homeostasis index of the aboveground organs was 4.45-12.93 under pH 7-9.8. In contrast, HN and HN:P(+N) in the belowground organs did not conform to a homeostasis model when pH > 9.1. Consequently, when L. chinensis is subjected to high saline-alkali stress, the homeostasis reaction of the roots is more sensitive than that of the aboveground organs.


Defective Ti2Nb10O27.1: an advanced anode material for lithium-ion batteries.
To explore anode materials with large capacities and high rate performances for the lithium-ion batteries of electric vehicles, defective Ti2Nb10O27.1 has been prepared through a facile solid-state reaction in argon. X-ray diffractions combined with Rietveld refinements indicate that Ti2Nb10O27.1 has the same crystal structure with stoichiometric Ti2Nb10O29 (Wadsley-Roth shear structure with A2/m space group) but larger lattice parameters and 6.6% O(2-) vacancies (vs. all O(2-) ions). The electronic conductivity and Li(+)ion diffusion coefficient of Ti2Nb10O27.1 are at least six orders of magnitude and ~2.5 times larger than those of Ti2Nb10O29, respectively. First-principles calculations reveal that the significantly enhanced electronic conductivity is attributed to the formation of impurity bands in Ti2Nb10O29-x and its conductor characteristic. As a result of the improvements in the electronic and ionic conductivities, Ti2Nb10O27.1 exhibits not only a large initial discharge capacity of 329 mAh g(-1) and charge capacity of 286 mAh g(-1) at 0.1 C but also an outstanding rate performance and cyclability. At 5 C, its charge capacity remains 180 mAh g(-1) with large capacity retention of 91.0% after 100 cycles, whereas those of Ti2Nb10O29 are only 90 mAh g(-1) and 74.7%.


Case-control study on symptoms and signs of "asymptomatic" primary hyperparathyroidism.
Symptoms, signs, and treatment of mild primary hyperparathyroidism (HPT) are controversial. One hundred two patients with HPT and matched controls were recruited from 5202 females attending population-based mammography screening at age 55 to 75 years. Patients' total serum calcium averaged 10.40 +/- 0.564 mg/dL and intact serum parathyroid hormone 58 +/- 33 ng/L. All patients lacked knowledge of their disease. Questions revealed traditional symptoms of HPT in 24% of cases and 43% of controls (P = .01). All individuals underwent the same biochemical analyses, bone mass determination, and questionnaires on symptoms, illnesses, medications, and background variables. Patients with HPT had more psychic complaints (P = .03 to .007) of lassitude, fatigue, irritability, and lack of sexual and emotional interests. They had lower bone density in total body, spine, and hip (P = .008 to .0004) and higher serum alkaline phosphatase, cholesterol (very-low-density lipoprotein), triglycerides (total, very-low-density lipoprotein), glucose, urate, and hemoglobin values (P = .02 to .0001). Patients visited physicians more often (P = .008) and had more antihypertensive therapy (P = .02). Mild, "asymptomatic" HPT in patients unaware of their disorder displays significant psychic symptoms, bone loss, and risk factors of cardiovascular disease.


Flavonol dioxygenase chemistry mediated by a synthetic nickel superoxide.
Nature exploits transition metal centers to enhance and tune the oxidizing power of natural oxidants such as O2 and H2O2. The design and interrogation of synthetic metallocomplexes with similar reactivity to metalloproteins provides one strategy for gaining insight into the mechanistic underpinnings of oxygen-activating enzymes such as oxidases, oxygenases, and dioxygenases like Ni-quercetinase (Ni-QueD). Ni-QueD catalyzes the oxidative ring opening of the polyphenol quercetin, a natural product with antioxidant properties. Herein, we report the synthesis and characterization of Ni(13-DOB), a Ni(II) species complexed by an N4-macrocycle that has been characterized by single crystal X-ray crystallography. Ni(13-DOB) forms a Ni-superoxide intermediate (Ni(13-DOB)O2•-) upon treatment with H2O2 and Et3N, as verified by resonance Raman spectroscopy. We demonstrate through UV/vis and LCMS that Ni(13-DOB)O2•- is capable of the 1-electron oxidation of flavonols, including both 3-hydroxyflavone (3-HF, the simplest flavonol) and quercetin itself. Incorporation of two O-atoms into the flavonol radical via superoxide from Ni(13-DOB)O2•- precedes oxidative cleavage of the flavonol scaffold in each case, consistent with quercetinase ring cleavage by Ni-QueD in Streptomyces sp. FLA. Conversion of 3-HF into 2-hydroxybenzoylbenzoic acid was accomplished with catalytic turnover of Ni(13-DOB) at ambient temperature, as confirmed by HPLC timecourses and GCMS analysis of isotopic labeling studies. The Ni(13-DOB)-mediated oxidative cleavage of quercetin to the corresponding biomimetic phenolic ester was also verified through 18O-isotopic labeling studies. Through the HPLC characterization of both on- and off-pathway products of flavonol dioxygenation by Ni(13-DOB)O2•-, the stringent reaction pathway control provided by enzyme active sites is highlighted.


Construction of a genetically engineered microorganism for CO2 fixation using a Rhodopseudomonas/Escherichia coli shuttle vector.
The CO2 fixation ability of Rhodopseudomonas palustris DH was enhanced by introducing the recombinant plasmid pMG-CBBM containing the form II ribulose-1,5-bisphosphate carboxylase/oxygenase (RubisCO) gene (cbbM) isolated from Rps. palustris NO. 7. Sequencing of a 3.0-kb PstI fragment containing the cbbM gene revealed an open reading frame encoding 461 amino acids, homologous to known cbbM genes, with a ribosome binding site upstream of cbbM and a terminator downstream of cbbM, without promoter. pMG-CBBM, a Rhodopseudomonas/Escherichia coli shuttle expression plasmid, was derived from the Rhodopseudomonas/E. coli shuttle cloning vector pMG105, by inserting the promoter of the pckA gene and the cbbM gene into its multiple cloning site. Plasmid pMG-CBBM was transformed into Rps. palustris DH by electroporation, and was stably maintained when transformants were grown either photoheterotrophically or photolithoautotrophically in the absence of antibiotics. This is the first report of an expression plasmid containing a Rps. palustris-specific promoter that allows stable expression of a foreign gene in the absence of antibiotic selection.


Mortality and morbidity from smoking-induced cardiovascular diseases: the necessity of the cardiologist's involvement and commitment.
This review deals with tobacco-associated cardiovascular effects and diseases. The importance of tabaccoism in primary care, its effects on cardiovascular, and immunology system and hemostasia, as well as, the role of smoking in atherosclerosis, coronary heart disease, acute myocardial infarct, diabetes, and other alterations are discussed. Finally we summarize the general tobacco control policies and the methods to achieve smoking cessation. Although it is well established the causal relationship between smoking and disease, and the general public is aware of this, the cardiologist's involvement and commitment is of utmost importance.


Oxygen toxicity: comparison of lung biochemical responses in neonatal and adult rats.
Neonatal rats (4--7 days old) and adult rats (approximately 80 days old) were continuously exposed to either 96--98% oxygen or air. Examination of the lungs of neonatal rats, who survived 5 days of oxygen exposure with no evidence of respiratory distress, showed significant increases in the pulmonary superoxide dismutase (SOD) activity (peak value: 144% of air-exposed controls), glutathione peroxidase (GP) activity (126%), glutathione reductase (GR) activity (122%), reduced glutathione (GSH) level (176%), and glucose-6-phosphate dehydrogenase activity (151%). Adult rats, most of whom succumbed within 3 days of oxygen exposure, did not show any significant increase in the activities of pulmonary SOD, GP, GR, and the level of GSH as compared to the air-exposed adult animals. Glucose-6-phosphate dehydrogenase was significantly elevated in the 72-hr oxygen-exposed adult rats. It is concluded that increases in the lung complement of SOD, GR, GP, and GSH in the neonatal rat during oxygen challenge may provide the mechanism(s) for their increased tolerance to hyperoxia-induced lung injury as compared to the adults.


Digital ethical reflection in long-term care: Leaders' expectations.
Healthcare leader support and facilitation for ethics work are of great importance for healthcare professionals' handling of ethical issues, moral distress, and quality care provision. A digital tool for ethical reflection in long-term care was developed in response to the demand for appropriate tools. This study aimed to explore healthcare leaders' expectations of using a digital tool for ethical reflection among their home nursing care staff. A qualitative research design with vignettes and focus group interviews was used. The data were analyzed using reflexive thematic analysis. The sample comprised ten healthcare leaders from municipal long-term care in Norway. Participation was voluntary and based on informed consent. The Norwegian Agency for Shared Services in Education and Research approved this study. The analysis resulted in the development of three themes representing leaders' expectations of the tool: (i) giving staff a voice, (ii) revealing ethics in practice, and (iii) keeping the pot boiling. Leaders must be informed about the ethical issues experienced to engage in supportive measures for their staff. Digital channels can increase the democratization, safety, and efficiency of communication between employees and leaders and increase awareness of ethical aspects in daily care work. The leaders had positive expectations of employees' activities and benefits from using the tool for ethical reflection. However, they admitted that realizing the tool's potential to ensure continuity in ethics work requires considerable organizational and leader involvement. This study shows that healthcare leaders are open to digital solutions for managing ethics work in home nursing care. Both opportunities and important prerequisites for successfully implementing the digital tool were identified.


Menstrual hygiene management among adolescent girls in India: a systematic review and meta-analysis.
To assess the status of menstrual hygiene management (MHM) among adolescent girls in India to determine unmet needs. Systematic review and meta-analysis. We searched PubMed, The Global Health Database, Google Scholar and references for studies published from 2000 to September 2015 on girls' MHM. India. Adolescent girls. Information on menarche awareness, type of absorbent used, disposal, hygiene, restrictions and school absenteeism was extracted from eligible materials; a quality score was applied. Meta-analysis was used to estimate pooled prevalence (PP), and meta-regression to examine the effect of setting, region and time. Data from 138 studies involving 193 subpopulations and 97,070 girls were extracted. In 88 studies, half of the girls reported being informed prior to menarche (PP 48%, 95% CI 43% to 53%, I(2) 98.6%). Commercial pad use was more common among urban (PP 67%, 57% to 76%, I(2) 99.3%, n=38) than rural girls (PP 32%, 25% to 38%, I(2) 98.6%, n=56, p<0.0001), with use increasing over time (p<0.0001). Inappropriate disposal was common (PP 23%, 16% to 31%, I(2) 99.0%, n=34). Menstruating girls experienced many restrictions, especially for religious activities (PP 0.77, 0.71 to 0.83, I(2) 99.1%, n=67). A quarter (PP 24%, 19% to 30%, I(2) 98.5%, n=64) reported missing school during periods. A lower prevalence of absenteeism was associated with higher commercial pad use in univariate (p=0.023) but not in multivariate analysis when adjusted for region (p=0.232, n=53). Approximately a third of girls changed their absorbents in school facilities (PP 37%, 29% to 46%, I(2) 97.8%, n=17). Half of the girls' homes had a toilet (PP 51%, 36% to 67%, I(2) 99.4%, n=21). The quality of studies imposed limitations on analyses and the interpretation of results (mean score 3 on a scale of 0-7). Strengthening of MHM programmes in India is needed. Education on awareness, access to hygienic absorbents and disposal of MHM items need to be addressed. CRD42015019197.


Microtropins Q-W, ent-Labdane Glucosides: Microtropiosides G-I, Ursane-Type Triterpene Diglucoside and Flavonol Glycoside from the Leaves of Microtropis japonica.
Microtropins Q-W, (2S,3R)-2-ethyl-2,3-dihydroxybutyrate of various glucosides and glucose, as well as three ent-labdane diterpenoid glucosides, named microtropiosides G, H and I, an ursane-type triterpene diglucoside and a flavonoid glycoside were isolated from the MeOH extract of the leaves of Microtropis japonica. The structure of microtropioside A, also isolated from the branches of M. japonica, was elucidated spectroscopically in a previous experiment and was found to possess a rare seven-membered oxyrane ring. Its structure was confirmed by X-ray crystallographic analysis of its pentaacetate.


Metastatic sweat gland carcinoma: response to 5-fluorouracil infusion.
A 78-year-old white male presented with metastatic sweat gland carcinoma involving regional lymph nodes, pleura, pericardium, and chest wall. A complete response of three months duration was achieved by using a 96-hour infusion of 5-fluorouracil. This is the first report of a complete response to systemic chemotherapy in metastatic sweat gland carcinoma.


Effect of indinavir used alone or in double or triple combination with AZT and ddC on human immune functions.
Indinavir (IDV) is a potent and selective human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) widely used in antiretroviral therapy, but its effects on the immune system are relatively unknown. In this study we have investigated the in vitro effect of IDV on normal human peripheral blood mononuclear cells (PBMC). We used the drug alone or in double and triple combination with AZT and ddC to assess whether IDV interferes with the previously observed immunomodulatory effects induced by AZT and ddC. We found that proliferative response, induction of immunoglobulins (Ig) production and cytokine production was not modulated by IDV. More importantly, IDV used in double or triple combination with AZT and ddC, does not further strenghten the inhibition of proliferative response induced by AZT and is able to abrogate the inhibitory effect induced by ddC on proliferative response. Similarly, IDV/AZT, IDV/ddC and IDV/AZT/ddC combinations does not strenghten the modulation of TNF-alpha, IFN-gamma and IL-4 induced by AZT, ddC and AZT/ddC. On the other hand, IDV neutralizes the up-regulating effects of AZT on IL-2 production while the up-regulating effects of ddC on IL-2 production is not affected. These data suggest that IDV used in combination with AZT and ddC did not add any further immunotoxicity.


TEL1, a gene involved in controlling telomere length in S. cerevisiae, is homologous to the human ataxia telangiectasia gene.
Yeast chromosomes terminate in tracts of simple repetitive DNA (poly[G1-3T]). Mutations in the gene TEL1 result in shortened telomeres. Sequence analysis of TEL1 indicates that it encodes a very large (322 kDa) protein with amino acid motifs found in phosphatidylinositol/protein kinases. The closest homolog to TEL1 is the human ataxia telangiectasia gene.


Identification and verification of FN1, P4HA1 and CREBBP as potential biomarkers in human atrial fibrillation.
Atrial fibrillation (AF) is a common arrhythmia that can lead to cardiac complications. The mechanisms involved in AF remain elusive. We aimed to explore the potential biomarkers and mechanisms underpinning AF. An independent dataset, GSE2240, was obtained from the Gene Expression Omnibus database. The R package, "limma", was used to screen for differentially expressed genes (DEGs) in individuals with AF and normal sinus rhythm (SR). Weighted gene co-expression network analysis (WGCNA) was applied to cluster DEGs into different modules based on functional disparities. Enrichment analyses were performed using the Database for Annotation, Visualization and Integrated Discovery. A protein-protein interaction network was constructed, and hub genes were identified using cytoHubba. Quantitative reverse-transcription PCR was used to validate mRNA expression in individuals with AF and SR. We identified 2, 589 DEGs clustered into 10 modules using WGCNA. Gene Ontology analysis showed specific clustered genes significantly enriched in pathways associated with the extracellular matrix and collagen organization. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the target genes were mainly enriched for proteoglycans in cancer, extracellular matrix-receptor interaction, focal adhesion, and the PI3K-Akt signaling pathway. Three hub genes, FN1, P4HA1 and CREBBP, were identified, which were highly correlated with AF endogenesis. mRNA expression of hub genes in patients with AF were higher than in individuals with normal SR, consistent with the results of bioinformatics analysis. FN1, P4HA1, and CREBBP may play critical roles in AF. Using bioinformatics, we found that expression of these genes was significantly elevated in patients with AF than in individuals with normal SR. Furthermore, these genes were elevated at core positions in the mRNA interaction network. These genes should be further explored as novel biomarkers and target candidates for AF therapy.


COVID-19 and Mortality, Depression, and Suicide in the Polish Population.
The study was aimed at assessing the mortality of the population, the occurrence of the phenomenon of depression and suicide before and during the COVID-19 pandemic. Data on total mortality in Poland in 2017-2021 came from the report of the Ministry of Health. Data on the number of sick leave due to mental disorders were taken from the report of the ZUS (Social Insurance Institution in Poland). Data on the number of suicides came from police statistics. Increase in the number of deaths in Poland in 2021 compared to the 2017-2019 average - 26.86%. In 2018-2020, the greatest number of fatal suicides was recorded in the age group - 60-64 years (in 2018 N = 565; 10.90%; in 2020 N = 524; 10.15%). In the years 2020-2021, an increase in mortality was observed in Poland compared to the previous years. Moreover, in 2020 there was an increase in sickness absence due to ICD-10 F.32 and an increase in the number of suicide attempts.


Non-invasive ways of administering insulin.
Insulin is crucial in the management of diabetes. However, requires injection which itself comes with some challenges. Alternative delivery routes have been investigated that are needle-free, with enhanced absorption and bioavailability. This review presents novel non-invasive insulin administration approaches that overcome some hurdles, as well as delineating their advantages and disadvantages. Information was primarily gathered by employing various PubMed scholarly articles for real-world examples in addition to data extraction from supplementary manuscripts. Articles were evaluated between 1958 and 2022. An introductive approach was used to identify matters related to the concept of different ways of administering insulin. Approaches aim to administer insulin in a safe, stable, and easy to use form, whether via oral, buccal, intranasal, oral inhalation, transdermal, ocular, rectal, or vaginal routes. Some have been shown to clinically improve blood glucose levels, while others are still in the investigational stage. Many approaches have been taken in an attempt to overcome physical barriers of insulin delivery. Some of these systems discussed may reach the market in the future and assist the millions of people who currently take subcutaneous injections of insulin.


Ischemic Heart Disease in Pregnancy.
The reported incidence of ischemic heart disease in pregnancy is 2.8 to 6.2 per 100,000 pregnancies. Although additional factors, such as maternal diabetes, obesity, and hypertension, are risk factors for ischemic heart disease, pregnancy itself more than doubles the risk for acute myocardial infarction. Given the increasing clinical importance of ischemic heart disease during pregnancy, this article addresses underlying pathophysiology, risk stratification, screening, and diagnosis of ischemic heart disease, as well as recommendations for management of acute myocardial infarction during pregnancy and the early postpartum period.


Comparison of the early production of extracellular matrix on dense hydroxyapatite and hydroxyapatite-coated titanium in cell and organ culture.
In order to investigate the earliest changes at the bone-hydroxyapatite (HA) interface, two materials, dense HA and HA-coated titanium alloy, were investigated for their ability to stimulate production of extracellular matrix both in cell and organ culture. Osteoblast-like cells were obtained from rabbit calvariae after preliminary culture for 3 d and seeded out onto the materials. When these cells were grown in culture on the dense HA no matrix production was seen with the scanning electron microscope after 4 d, but there did appear to be matrix produced on the rougher surface of the HA coating. In contrast, extracellular matrix production was greatly increased in organ culture where the material was placed on a section of bone, particularly on the HA coating, where it formed an organized layer of collagen within 4 d. These results showed that extracellular matrix production by both osteoblastic cells and in calvarial culture was greater on the HA coatings than dense HA. In addition, organ culture allows the investigation of the earliest changes in the bone-HA interface without having to undertake in vivo implantation studies of such short duration.


The influence of training on physical and functional growth before, during and after puberty.
In boys, the ages at which growth rates for body weight, height, VO2max, maximum O2 pulse and VImax reached their peaks were approximately the same (means and SD: 14.64 +/- 0.98, 14.67 +/- 0.99, 14.71 +/- 1.59, 14.38 +/- 1.36 and 14.64 +/- 1.42 years respectively). There was a positive relationship between the peak velocities of functional capacity indicators (VO2max 0.79 +/- 0.19 1.min-1.year-1, O2 pulse max 4.1 +/- 1.20 ml.year-1, VImax 27.3 +/- 7.15 l.min-1.year-1) and the peak growth velocity of weight and/or height (weight 9.1 +/- 1.92 kg.year-1, height 9.8 +/- 1.92 cm.year-1). A positive relationship between the age at peak velocity of VO2max and O2 pulse max with the age at peak velocity for body weight was also found (r = 0.524 and 0.400 respectively). No relationship was revealed between the age at peak velocity on the one hand and the peak velocities of body weight, height, VO2max, O2 pulse or VImax on the other. Moderate training did not influence acceleration in growth--the age at peak velocity and the peaks of the growth rate did not differ in groups with a different regime of exercise (higher - n = 8, medium - n = 9, lower - n = 12; the peak velocity of VO2max--means and SD--being 0.85 +/- 0.15, 0.76 +/- 0.22 and 0.78 +/- 0.17.min-1.year-1 respectively).


Properties and functions of KATP during mouse perinatal development.
Prevailing data suggest that ATP-sensitive potassium channels (K(ATP)) contribute to a surprising resistance to hypoxia in mammalian embryos, thus we aimed to characterize the developmental changes of K(ATP) channels in murine fetal ventricular cardiomyocytes. Patch clamp was applied to investigate the functions of K(ATP). RT-PCR, Western blot were used to further characterize the molecular properties of K(ATP) channels. Similar K(ATP) current density was detected in ventricular cardiomyocytes of late development stage (LDS) and early development stage (EDS). Molecular-biological study revealed the upregulation of Kir6.1/SUR2A in membrane and Kir6.2 remained constant during development. Kir6.1, Kir6.2, and SUR1 were detectable in the mitochondria without marked difference between EDS and LDS. Acute hypoxia-ischemia led to cessation of APs in 62.5% of tested EDS cells and no APs cessation was observed in LDS cells. SarcK(ATP) blocker glibenclamide rescued 47% of EDS cells but converted 42.8% of LDS cells to APs cessations under hypoxia-ischemic condition. MitoK(ATP) blocker 5-HD did not significantly influence the response to acute hypoxia-ischemia at either EDS or LDS. In summary, sarcK(ATP) played distinct functional roles under acute hypoxia-ischemic condition in EDS and LDS fetal ventricular cardiomyocytes, with developmental changes in sarcK(ATP) subunits. MitoK(ATP) were not significantly involved in the response of fetal cardiomyocytes to acute hypoxia-ischemia and no developmental changes of K(ATP) subunits were found in mitochondria.


Megakaryocyte colony stimulating activity in allogenic bone marrow recipients prepared with busulfan and cyclophosphamide.
Increased megakaryocyte colony stimulating activity (MK-CSA) has been reported after total body irradiation (TBI) for bone marrow transplant (BMT). We studied the effect of a busulfan (Bu) and cyclophosphamide (Cy) marrow transplant conditioning regimen, without radiation, on MK-CSA production. Initial screening of MK-CSA was done on previously collected and banked sera from 14 BMT patients. MK-CSA was expressed as the ability to stimulate growth of megakaryocyte progenitors (CFU-MK) in standard plasma clot cultures. In the initial samples, MK-CSA peaked at day 7. This preliminary data led to a prospective study of MK-CSA and clinical parameters in seven allogeneic recipients. MK-CSA activity increased from day -7 pre-transplant (2.9 +/- 1.7 CFU-MK/10(5) NATD, mean +/- SD) to day 0 (10.3 +/- 4.7 CFU-MK) and peaked by day 9 post-transplant (20.6 +/- 6.4 CFU-MK). MK-CSA activity decreased in all seven patients by day 21 at which time five of seven patients studied had recovery of platelet counts to greater than 100 x 10(9)/l. MK-CSA activity rose rapidly in both groups of sera after the initiation of this non-irradiation, BMT preparative regimen. High MK-CSA levels, early after transplant, may contribute to the rapid platelet recovery in some patients.


Enantioselective fungal biotransformation of risperidone in liquid culture medium by capillary electrophoresis and hollow fiber liquid-phase microextraction.
Knowing that microbial transformations of compounds play vital roles in the preparation of new derivatives with biological activities, risperidone and its chiral metabolites were determined by capillary electrophoresis and hollow fiber liquid-phase microextraction after a fungal biotransformation study in liquid culture medium. The analytes were extracted from 1 mL liquid culture medium into 1-octanol impregnated in the pores of the hollow fiber, and into an acid acceptor solution inside the polypropylene hollow fiber. The electrophoretic separations were carried out in 100 mmol/L sodium phosphate buffer pH 3.0 containing 2.0% w/v sulfated-α-CD and carboxymethyl-β-CD 0.5% w/v with a constant voltage of -10 kV. The method was linear over the concentration range of 100-5000 ng/mL for risperidone and 50-5000 ng/mL for each metabolite enantiomer. Within-day and between-day assay precisions and accuracies for all the analytes were studied at three concentration levels, and the values of relative standard deviation and relative error were lower than 15%. The developed method was applied in a pilot biotransformation study employing risperidone as the substrate and the filamentous fungus Mucor rouxii. This study showed that the filamentous fungus was able to metabolize risperidone enantioselectively into its chiral active metabolite, (-)-9-hydroxyrisperidone.


Reduced Verbal Fluency following Subthalamic Deep Brain Stimulation: A Frontal-Related Cognitive Deficit?
The decrease in verbal fluency in patients with Parkinson's disease (PD) undergoing subthalamic nucleus deep brain stimulation (STN-DBS) is usually assumed to reflect a frontal lobe-related cognitive dysfunction, although evidence for this is lacking. To explore its underlying mechanisms, we combined neuropsychological, psychiatric and motor assessments with an examination of brain metabolism using F-18 fluorodeoxyglucose positron emission tomography, in 26 patients with PD, 3 months before and after surgery. We divided these patients into two groups, depending on whether or not they exhibited a postoperative deterioration in either phonemic (10 patients) or semantic (8 patients) fluency. We then compared the STN-DBS groups with and without verbal deterioration on changes in clinical measures and brain metabolism. We did not find any neuropsychological change supporting the presence of an executive dysfunction in patients with a deficit in either phonemic or semantic fluency. Similarly, a comparison of patients with or without impaired fluency on brain metabolism failed to highlight any frontal areas involved in cognitive functions. However, greater changes in cognitive slowdown and apathy were observed in patients with a postoperative decrease in verbal fluency. These results suggest that frontal lobe-related cognitive dysfunction could play only a minor role in the postoperative impairment of phonemic or semantic fluency, and that cognitive slowdown and apathy could have a more decisive influence. Furthermore, the phonemic and semantic impairments appeared to result from the disturbance of distinct mechanisms.


Mediatophore regulates acetylcholine release from T cells.
Immunological stimulation of T cells by phytohemagglutinin (PHA) enhances the synthesis and release of acetylcholine (ACh), suggesting a role for the lymphocytic cholinergic system in the regulation of immune function. In the present study, we used two human leukemic T cell lines as models to investigate whether mediatophore, a homooligomer of a 16-kDa subunit homologous to the proteolipid subunit c of vacuolar H(+)-ATPase (V-ATPase), is involved in mediating ACh release from T cells. Immunohistochemical analysis revealed the presence of mediatophore in the cytoplasm and on the plasma membrane of both T cell lines. Mediatophore gene expression was up-regulated by immunological T cell activation by PHA. Transfection of anti-mediatophore small interference RNA down-regulated mediatophore gene expression and significantly reduced ACh release. These results suggest that T cells express mediatophore, which then plays a key role in mediating ACh release, and that mediatophore expression is regulated by immunological stimulation.