Evaluation of 18F-labeled targeted perfluorocarbon-filled albumin microbubbles as a probe for microUS and microPET in tumor-bearing mice.
In this study, albumin-shelled, targeted MBs (tMBs) were first demonstrated with the expectation of visualization of biodistribution of albumin-shelled tMBs. The actual biodistribution of albumin-shelled tMBs is of vital importance either for molecular imaging or for drug delivery. Recently, albumin microbubbles (MBs) have been studied for drug and gene delivery in vitro and in vivo through cavitation. Targeted lipid-shelled MBs have been applied for ultrasound molecular imaging and conjugated with radiolabeled antibodies for whole-body biodistribution evaluations. The novelty of the work is that, in addition to the lipid tMBs, the albumin tMBs was also applied in biodistribution detection. Multimodality albumin-shelled, (18)F-SFB-labeled VEGFR2 tMBs were synthesized, and their characteristics in mice bearing MDA-MB-231 human breast cancer were investigated with micro-positron-emission tomography (microPET) and high-frequency ultrasound (microUS). Albumin-shelled MBs can be labeled with (18)F-SFB directly and conjugated with antibodies for dual molecular imaging. The albumin-shelled tMBs show a lifetime in 30min in the blood pool and a highly specific adherence to tumor vessels in mice bearing human breast cancer. From the evaluations of whole-body biodistribution, the potential of the dual molecular imaging probe for drug or gene delivery in animal experiments with albumin shelled MBs has been investigated.


The Therapeutic Potential of Naringenin: A Review of Clinical Trials.
Naringenin is a flavonoid belonging to flavanones subclass. It is widely distributed in several Citrus fruits, bergamot, tomatoes and other fruits, being also found in its glycosides form (mainly naringin). Several biological activities have been ascribed to this phytochemical, among them antioxidant, antitumor, antiviral, antibacterial, anti-inflammatory, antiadipogenic and cardioprotective effects. Nonetheless, most of the data reported have been obtained from in vitro or in vivo studies. Although some clinical studies have also been performed, the main focus is on naringenin bioavailability and cardioprotective action. In addition, these studies were done in compromised patients (i.e., hypercholesterolemic and overweight), with a dosage ranging between 600 and 800 μM/day, whereas the effect on healthy volunteers is still debatable. In fact, naringenin ability to improve endothelial function has been well-established. Indeed, the currently available data are very promising, but further research on pharmacokinetic and pharmacodynamic aspects is encouraged to improve both available production and delivery methods and to achieve feasible naringenin-based clinical formulations.


The clinical spectrum of malignant nasal tumors.
Unlike other head and neck cancer, which is almost exclusively squamous cell carcinoma, nasal malignancies present a wide and varied spectrum of tumor types. Classification of these tumors is not standardized and treatment tends to be individualized. In a review of 35 patients with primary nasal malignancies, only 33% had squamous cell carcinoma. Glandular, neurogenic, and hemopoietic tumors accounted for the other major subgroups. Despite the diverse histopathological tumor types, the diagnosis, treatment, and clinical problems seem related more to the nasal location than to the actual type of tumor. Selected cases are presented to illustrate the clinical behavior and problems that occur with nasal tumors.


Under the microscope: focus on Chlamydia pneumoniae infection and multiple sclerosis.
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the Central Nervous System (CNS) of supposed autoimmune origin whose etiology still remains unknown. Epidemiological studies suggest that MS pathogenesis could be related to an infection superimposed on a predisposing genetic background. However, at present, no direct evidence for an infectious implication in MS autoimmunity exists. Recently, the potential role of Chlamydia pneumoniae as a causative agent of MS has received increasing attention. After the initial high rates reported for molecular and culture demonstration of C. pneumoniae in cerebrospinal fluid (CSF) of MS patients, the association between C. pneumoniae and MS was intensively investigated with controversial results. Seroepidemiological reports did not show any strong association between C. pneumoniae infection and the risk of MS. Isolation techniques failed to detect C. pneumoniae in CSF and brain tissue of MS patients. Polymerase chain reaction (PCR) evidence of C. pneumoniae in CSF and intrathecal synthesis of anti-C. pneumoniae IgG have been undetectable in MS patients or, if present, were not selectively associated with MS, but were shared by several inflammatory neurological conditions. Nevertheless, in a subgroup of MS patients, an association between PCR positivity for C. pneumoniae in CSF and disease activity was found. Intrathecal production of anti-C. pneumoniae high-affinity IgG predominated in MS progressive forms and metabolically active C. pneumoniae was identified in CSF. C. pneumoniae was recognized in CSF and brain tissue at immunohistochemical, molecular and ultrastructural levels. C. pneumoniae was also able to induce the animal model of MS. This growing body of data does not support a central role for C. pneumoniae as a candidate in MS pathogenesis, but suggests that, in a subset of MS patients, C. pneumoniae could induce a chronic persistent brain infection acting as a cofactor in the development of the disease. Thus, the actual involvement of C. pneumoniae in MS still remains to be elucidated.


Temperature-sensitive fitness cost of insecticide resistance in Chinese populations of the diamondback moth Plutella xylostella.
Alleles conferring a higher adaptive value in one environment may have a detrimental impact on fitness in another environment. Alleles conferring resistance to pesticides and drugs provide textbook examples of this trade-off as, in addition to conferring resistance to these molecules, they frequently decrease fitness in pesticide/drug-free environments. We show here that resistance to chlorpyrifos, an organophosphate (OP), in Chinese populations of the diamondback moth, Plutella xylostella, is conferred by two mutations of ace1 - the gene encoding the acetylcholinesterase enzyme targeted by OPs - affecting the amino acid sequence of the corresponding protein. These mutations were always linked, consistent with the segregation of a single resistance allele, ace1R, carrying both mutations, in the populations studied. We monitored the frequency of ace1R (by genotyping more than 20 000 adults) and the level of resistance (through bioassays on more than 50 000 individuals) over several generations. We found that the ace1R resistance allele was costly in the absence of insecticide and that this cost was likely recessive. This fitness costs involved a decrease in fecundity: females from resistant strains laid 20% fewer eggs, on average, than females from susceptible strains. Finally, we found that the fitness costs associated with the ace1R allele were greater at high temperatures. At least two life history traits were involved: longevity and fecundity. The relative longevity of resistant individuals was affected only at high temperatures and the relative fecundity of resistant females - which was already affected at temperatures optimal for development - decreased further at high temperatures. The implications of these findings for resistance management are discussed.


Continuing medical education case study series. An innovative programme for general practitioners on malignant melanoma.
Increasing interest in continuing medical education is reflected in greater demand for educational programmes. Content and educational strategies should be appropriate to the needs of the target audience. Proper matching of content and strategies to target needs of users requires the instructional design to be carefully planned and based on a needs-assessment study. We illustrate the influence of educational needs on content and learning strategies through an educational programme for general practitioners on the subject of malignant melanoma. Its design includes: i. a trigger leaflet; ii. a core text; iii. a set of interactive case studies; iv. a job-aid card; v. a follow-up leaflet; and vi. recorded messages available by telephone. It addressed, in particular, the key decision to be taken by the general practitioner: 'When should I refer a patient with a suspected early melanoma: when should I merely reassure the patient?' Doctors were invited, in the programme, to make decisions about referral of patients. They received immediate feedback on their decisions. Various strategies reinforced this feedback.


Extended field of view soft x-ray Fourier transform holography: toward imaging ultrafast evolution in a single shot.
Panoramic full-field imaging is demonstrated by applying spatial multiplexing to Fourier transform holography. Multiple object and reference waves extend the effective field of view for lensless imaging without compromising the spatial resolution. In this way, local regions of interest distributed throughout a sample can be simultaneously imaged with high spatial resolution. A method is proposed for capturing multiple ultrafast images of a sample with a single x-ray pulse.


Effects of salt concentration and H1 histone removal on the differential scanning calorimetry of nuclei.
The effects of increasing NaCl concentrations on the melting profiles of chromatin in isolated nuclei contradicted published claims that structural transitions near 76 degrees C (Tn-7), near 89 degrees C (Tn-8), and near 105 degrees C (Tn-10) were respectively the melting of linker DNA, the melting of extended nucleosomal strands, and the collapse of nucleosomes in the 300-A fiber. Contrary to expectations of such an interpretation, decreases in salt concentration stabilized Tn-7 and failed to eliminate Tn-10. Moreover, nuclei depleted of H1 histone, which is known to be essential for the formation of the 300-A fiber, gave the same melting profile as intact nuclei with regard to the relative magnitudes of Tn-8 and Tn-10. The effect of salt concentration on the melting profiles and the insensitivity of Tn-8 and Tn-10 to H1 histone removal supports the notion that Tn-7 is the collapse of the nucleosome while Tn-8 and Tn-10 are respectively the unstacking of nucleotide bases in relaxed chromatin and supercoiled chromatin. The identification of Tn-8 as the unstacking of bases in relaxed DNA, and Tn-10 as unstacking in supercoiled DNA, shows that scanning calorimetry can be used to measure the state of repair of DNA in the nucleus. The gain in Tn-8 at the expense of Tn-10 that is seen as the mitotic index drops and differentiation occurs suggests that nicks accumulate in the DNA, perhaps because the gross aggregation of the inactive majority of the chromatin makes it inaccessible to repair enzymes.


Impact of war on American adolescents.
The impact of the Persian Gulf war on adolescents in Columbia, Charleston, and Sumter, SC. Four semiannual surveys measured adolescents' exposure to and evaluations of the Persian Gulf war, and the relationship between this exposure and mental distress. Of the sample, 814 (65.9%) reported being distressed by the war and 849 (69%) reported feeling better after the war ended. More than half the sample had a friend or relative sent to the war (n = 725, 58.8%), and of these, 458 were African American. Nine percent (n = 111) of the sample had a mother, father, or both a mother and a father in the war. There was a positive correlation between adolescents' ratings on the Negative Impact of War Scores and Mental Distress Scores despite the easy victory and public support for the war in the United States. Females and African Americans viewed the war more negatively than did Caucasian males.


Structural, kinetic and computational investigation of Vitis vinifera DHDPS reveals new insight into the mechanism of lysine-mediated allosteric inhibition.
Lysine is one of the most limiting amino acids in plants and its biosynthesis is carefully regulated through inhibition of the first committed step in the pathway catalyzed by dihydrodipicolinate synthase (DHDPS). This is mediated via a feedback mechanism involving the binding of lysine to the allosteric cleft of DHDPS. However, the precise allosteric mechanism is yet to be defined. We present a thorough enzyme kinetic and thermodynamic analysis of lysine inhibition of DHDPS from the common grapevine, Vitis vinifera (Vv). Our studies demonstrate that lysine binding is both tight (relative to bacterial DHDPS orthologs) and cooperative. The crystal structure of the enzyme bound to lysine (2.4 Å) identifies the allosteric binding site and clearly shows a conformational change of several residues within the allosteric and active sites. Molecular dynamics simulations comparing the lysine-bound (PDB ID 4HNN) and lysine free (PDB ID 3TUU) structures show that Tyr132, a key catalytic site residue, undergoes significant rotational motion upon lysine binding. This suggests proton relay through the catalytic triad is attenuated in the presence of lysine. Our study reveals for the first time the structural mechanism for allosteric inhibition of DHDPS from the common grapevine.


Understanding countertransference reactions in working with adolescent perpetrators of sexual abuse.
Recognizing countertransference reactions in working with adolescent perpetrators of sexual abuse is essential in order to provide optimal treatment. The author examines the broad societal reaction to these patients' acts as well as individual therapists' personal reactions to the material and transferences presented by the teenagers. Therapists' awareness of their reactions can help them understand the internal world of the patient and avoid destructive acting out of countertransference reactions.


Studies on the endoplasmic reticulum. I. Its identification in cells in situ.
A series of representative cell types including avian fibroblasts, and macrophages; rabbit mesothelia, endothelia, and nephron epithelia; and rat glandular epithelia (parotid) were studied comparatively in vitro and in situ with the electron microscope. Cells in vitro were examined in whole mounts and in sections whereas cells in situ were observed exclusively in sections. It was found that an endoplasmic reticulum similar to that previously described in cultured material is present in situ in all cell types examined. Modifications in its appearance introduced by the sectioning technique were discussed and explained. The observations showed in addition that the endoplasmic reticulum is a network of cavities which may enlarge into relatively vast, flattened vesicles here described as cisternae.


Prokaryotic assemblages in suspended and subglacial sediments within a glacierized catchment on Qeqertarsuaq (Disko Island), west Greenland.
Microbes transported by glacial meltwater streams are thought to be a product of passive dispersal from both supra- and subglacial sources, though studies investigating the origins of these assemblages are scarce. Here, we conducted a survey within a large catchment containing multiple glaciers on Qeqertarsuaq (Disko Island), west Greenland, to investigate whether meltwater-exported microbial assemblages in suspended sediments differ between glacial meltwater streams, and if they reflect corresponding bulk subglacial and extraglacial sediment communities. Using 16S rRNA gene amplicon sequencing, we found proglacial stream assemblages substantially differ from one another, despite their close spatial proximity. Furthermore, proglacial stream assemblages were composed of greater proportions of Cyanobacteria compared to bulk subglacial sediment communities, dominated by Betaproteobacteria, demonstrating large contributions of meltwater and microbial cells from supraglacial habitats. Corresponding physico-chemical characteristics of meltwater suggest that streams draining smaller glaciers had more equal contributions of both supra- and subglacial inputs compared with the main catchment outlet, aligning with observed changes in assemblage structure, such as the decreased proportion of Cyanobacteria. These results suggest that glacier size and hydrological drainage systems may influence the structure of exported microbial assemblages, and collectively provide insights into their formation and fate in thiscurrent age of deglaciation.


Safrana l Prevents Prostate Cancer Recurrence by Blocking the Re-activation of Quiescent Cancer Cells via Downregulation of S-Phase Kinase-Associated Protein 2.
The re-proliferation of quiescent cancer cells is considered to be the primary contributor to prostate cancer (Pca) recurrence and progression. In this study, we investigated the inhibitory effect of safranal, a monoterpene aldehyde isolated from Crocus sativus (saffron), on the re-proliferation of quiescent Pca cells in vitro and in vivo. The results showed that safranal efficiently blocked the re-activation of quiescent Pca cells by downregulating the G0/G1 cell cycle regulatory proteins CDK2, CDK4, CDK6, and phospho-Rb at Ser807/811 and elevating the levels of cyclin-dependent kinase inhibitors, p21 and p27. Further investigation on the underlying mechanisms revealed that safranal suppressed the mRNA and protein expression levels of Skp2, possibly through the deregulation of the transcriptional activity of two major transcriptional factors, E2F1 and NF-κB subunits. Moreover, safranal inhibited AKT phosphorylation at Ser473 and deregulated both canonical and non-canonical NF-κB signaling pathways. Safranal suppressed the tumor growth of quiescent Pca cell xenografts in vivo. Furthermore, safranal-treated tumor tissues exhibited a reduction in Skp2, E2F1, NF-κB p65, p-IκBα (Ser32), c-MYC, p-Rb (Ser807), CDK4, CDK6, and CDK2 and an elevation of p27 and p21 protein levels. Therefore, our findings demonstrate that safranal suppresses cell cycle re-entry of quiescent Pca cells in vitro and in vivo plausibly by repressing the transcriptional activity of two major transcriptional activators of Skp2, namely, E2F1 and NF-κB, through the downregulation of AKT phosphorylation and NF-κB signaling pathways, respectively.


The Impact of Domestic Cooking Methods on Myrosinase Stability, Glucosinolates and Their Hydrolysis Products in Different Cabbage (Brassica oleracea) Accessions.
Glucosinolate hydrolysis products are responsible for the health-promoting properties of Brassica vegetables. The impact of domestic cooking on the myrosinase stability, glucosinolates and hydrolysis products in 18 cabbage accession was investigated. Cabbages were steamed, microwaved, and stir-fried before analysis. Cooking significantly affected myrosinase stability and glucosinolate concentrations within and between cabbage morphotypes. Myrosinase was most stable after stir-frying, with up to 65% residual activity. Steaming and microwaving resulted in over 90% loss of myrosinase activity in some accessions. Stir-frying resulted in the greatest decrease in glucosinolate concentration, resulting in up to 70% loss. Steamed cabbages retained the highest glucosinolates after cooking (up to 97%). The profile and abundance of glucosinolate hydrolysis products detected varied across all cooking methods studied. Cooking reduced the amounts of nitriles and epithionitriles formed compared to raw samples. Steaming led to a significant increase in the concentration of beneficial isothiocyanates present in the cabbage and a significantly lower level of nitriles compared to other samples. Microwaving led to a reduction in the concentrations of both nitriles and isothiocyanates when compared to other cooking methods and raw cabbage. The results obtained help provide information on the optimal cooking methods for cabbage, suggesting that steaming may be the best approach to maximising beneficial isothiocyanate production.


The North Carolina evidence-based transition-to-practice initiative.
Successful transition of newly licensed nurses into practice is essential for safe nursing practice. North Carolina has begun an initiative to implement an evidence-based formal transition-to-practice requirement for all newly licensed entry-level nurses in the state by 2015. Phase I of this collaborative project uses a longitudinal design to study new nurse-preceptor dyads. Resulting data will describe competence and confidence development in newly licensed North Carolina RNs practicing in acute care hospitals. Longitudinal data about practice errors and risk for practice breakdown in the first 6 months of the newly licensed nurse's employment will also be collected. The study will provide data to determine the essential components of this evidence-based transition requirement and will contribute to the evidence base for best practices related to transition experiences for newly licensed RNs.


Acute macular neuroretinopathy: pathogenetic insights from optical coherence tomography angiography.
To describe the optical coherence tomography angiography (OCT-A) features of patients affected by acute macular neuroretinopathy (AMN). This is a prospective, observational, cross-sectional study. Multimodal imaging, including spectral domain OCT (Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany) and 6×6 mm swept source OCT-A (ZEISS PLEX Elite 9000; ZEISS, Dublin, California), was performed on all patients. The primary outcome measure was assessment of the vascular alterations of the superficial (SCP) and deep (DCP) capillary plexuses and choriocapillaris (CC). A segmentation of the AMN lesions using enface OCT images of photoreceptors-retinal pigment epithelium complex was used to discriminate intralesional and extralesional regions on the OCT-A enface slabs of the DCP and CC reconstructions. Each OCT-A slab was imported into ImageJ V.1.50 and digitally binarised for quantitative analyses. Overall, seven patients (mean age 19.4±3.2 years, six women) affected by AMN were included. The mean best-corrected visual acuity was 0.00±0.00 logarithm of the minimum angle of resolution. Twelve healthy age-matched subjects (mean age 22±3.4 years, 10 women) represented the control group. The quantitative analysis of global vessel densities showed that the CC vessel density was significantly lower in patients with AMN (0.495±0.03) compared with the age-matched controls (0.545±0.02) (corrected p=0.0003). The intralesional vessel density of the DCP was 0.349±0.04 in AMN and vs 0.497±0.02 in the controls (corrected p=0.0002). Our study confirmed inner choroidal vascular flow void as a possible pathogenetic mechanism of AMN. We also found a focal impairment of the DCP within the AMN lesions. Future studies are needed to clarify which is the primary location of the vascular insult in this condition.


Tracheal intubation with a flexible intubation scope versus other intubation techniques for obese patients requiring general anaesthesia.
The prevalence of obesity (body mass index (BMI) > 30 kg/m(2)) is increasing in both developed and developing countries, leading to a rise in the numbers of obese patients requiring general anaesthesia. Obese patients are at increased risk of anaesthetic complications, and tracheal intubation can be more difficult. Flexible intubation scopes (FISs) are recommended as an alternative method of intubation in these patients. Intubation with an FIS is considered an advanced method, requiring training and experience; therefore it may be underused in clinical practice. Patient outcomes following intubation with these scopes compared with other devices have not been systematically reviewed. We wished to compare the safety and effectiveness of a flexible intubation scope (FIS) used for tracheal intubation in obese patients (BMI > 30 kg/m(2)) with other methods of intubation, including conventional direct laryngoscopy, non-standard laryngoscopy and the use of intubating supraglottic airway devices. We aimed to compare the frequency of complications, as well as process indicators, such as time taken for intubation and the proportion of first attempts that were successful, between groups using the different methods of intubation. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and two trial registers on 18 January 2013, and performed reference checking and citation searching and contacted study authors to identify additional studies. We included randomized controlled trials (RCTs) of participants aged 16 years and older with a BMI > 30 kg/m(2) that had compared the use of an FIS for tracheal intubation with any one of three comparison groups: direct laryngoscopy; non-standard laryngoscopy (including indirect laryngoscopy using a videolaryngoscope (VLS) or a rigid or semi-rigid stylet); or intubation of supraglottic airway devices (SADs). We used standard methodological approaches expected by The Cochrane Collaboration, including independent review of titles, data extraction and risk of bias assessment by two investigators. Three eligible studies were identified, all comparing the use of an FIS with a VLS. All studies were small, with only 131 participants in total across all trials. It was impossible for the intubators to be unaware of the device used, so all studies were at high risk of performance and detection bias for outcomes related to intubation. Because of substantial differences in design between the studies, we did not combine their results in meta-analyses. The results for all outcomes were inconclusive, with no differences noted between FIS and VLS. Two studies with experienced intubators reported first attempt success rates greater than 70% in both groups and less than 5% of participants requiring a change of intubation device. No evidence was found of any difference in difficulty or time taken between FIS and VLS intubation. No serious complications or airway trauma was reported, so we were unable to address these outcomes. Bleeding was uncommon, occurring in less than 5% of participants, and we found no evidence that it was more likely in the FIS group. One small study with a novice intubator reported no successful intubations using an FIS and compared with the use of an intubating SAD and stylet, as well as with a VLS. With only five participants in each group, no conclusions can be drawn from these additional comparisons. The evidence base is sparse, and the existing literature does not address the clinical questions of patient safety posed by this review. We are therefore unable to draw any conclusions on safety or effectiveness. More primary research is needed to investigate optimal intubation techniques in obese patients, and new studies should be powered to detect differences in complications and in success rates rather than process measures such as speed, which are of limited clinical importance.


Postoperative Outcomes in Vedolizumab-Treated Patients Undergoing Abdominal Operations for Inflammatory Bowel Disease.
Vedolizumab was recently approved by the Food and Drug Administration for the treatment of moderate to severe ulcerative colitis [UC] and Crohn's disease [CD]. No study to date has examined the rate of postoperative infectious complications among patients who received vedolizumab in the perioperative period. We sought to determine the 30-day postoperative infectious complication rate among inflammatory bowel disease [IBD] patients who received vedolizumab within 12 weeks of an abdominal operation as compared to patients who received tumour necrosis factor α [TNFα] inhibitors or no biological therapy. A retrospective chart review between May 1, 2014 and December 31, 2015 of adult IBD patients who underwent an abdominal operation was performed. The study cohort comprised patients who received vedolizumab within 12 weeks of their abdominal operation and the control cohorts were patients who received TNFα inhibitors or no biological therapy. In total, 94 patients received vedolizumab within 12 weeks of an abdominal operation. Fifty experienced postoperative complications [53%], 35 of which were surgical site infections [SSIs] [36%]. The vedolizumab group experienced significantly higher rates of any postoperative infection [53% vs 33% anti-TNF and 28% non-biologics; p<0.001] and SSI [37% vs 10% and 13%; p<0.001]. On univariate and multivariate analysis, exposure to vedolizumab remained a significant predictor of postoperative SSI [p<0.001]. Thirty-seven per cent of IBD patients who received vedolizumab within 30 days of a major abdominal operation experienced a 30-day postoperative SSI, significantly higher than patients receiving TNFα inhibitors or no biological therapy. Vedolizumab within 12 weeks of surgery remained the only predictor of 30-day postoperative SSI on multivariate analysis.


Greater Obstetric Barriers for Female Urologists Compared to Peer-Physicians.
To determine the prevalence of pregnancy complications, infertility, and maternal support for female urologists in comparison to the general population and other female physicians. An anonymous, voluntary survey was distributed to female physicians via private physician social media groups from June to August 2021. The survey queried pregnancy demographics and complications, infertility diagnosis and treatment, workplace environment, and prior education on these topics. Results were compared between urologists and the general population and other female physicians with Fisher exact test, chi-square with Yates's correction, or Student's t tests as indicated. Four thousand six hundred twelve female physicians completed the survey including 241 (5%) urologists. Compared with the general population, urologists were more likely to have a miscarriage or preterm birth, have children later in life, and undergo infertility evaluation or infertility treatment (all P < .0001). 42% of urologists reported experiencing a pregnancy complication and only 9% of those surveyed received education on the risks of delaying pregnancy. Despite being educated more often regarding the risks of delaying pregnancy compared to other physicians, urologists were less likely to have children, had fewer children, and were more likely to be discouraged from starting a family during training and practice (all P < .0001). Additionally, urologists reported shorter parental leave, worked more hours per week while pregnant, and were less likely to receive lactation accommodations compared to other female physicians (all P < .001). Education for trainees on family planning and fostering a culture of support are deficits identified in overcoming obstetric barriers in urologists.


Association of Socioeconomic Disparities With Nasopharyngeal Carcinoma Survival in an Endemic Area, China.
This retrospective cohort study investigated the association of socioeconomic status with survival outcomes among patients with nasopharyngeal carcinoma in an endemic area of China. The primary endpoint was overall survival. Survival outcomes were estimated by the Kaplan-Meier method and compared by the log-rank test, and the multivariate Cox proportional hazards model was used to estimate hazard ratios, 95% CIs, and independent prognostic factors. A total of 11 069 adult patients with NPC were enrolled and included in the analysis. Kaplan-Meier survival analysis revealed that overall survival was significantly different among socioeconomic status. Compared with high socioeconomic status patients, low socioeconomic status patients (HR, 1.190; 95% CI, 1.063-1.333) and medium socioeconomic status patients (HR, 1.111; 95% CI, 1.006-1.226) were associated with increased hazard ratio (HR) of overall survival. This analysis highlights patients with nasopharyngeal carcinoma who had high socioeconomic status had better overall survival compared with those who had low and medium socioeconomic status.


Intramolecular donor-acceptor cyclopropane ring-opening cyclizations.
Cyclization reactions of donor-acceptor (D-A) cyclopropanes are recognized as versatile methods for construction of carbocyclic and heterocyclic scaffolds. In the literature, many examples of these polarized cyclopropanes' reactivity with nucleophiles, electrophiles, and radicals are prevalent. Although intermolecular reactivity of donor-acceptor cyclopropanes is widely reported, reviews that center on their intramolecular chemistry are rare. Thereupon, this tutorial review focalizes on new intramolecular transformations of donor-acceptor cyclopropanes for cycloisomerizations, formal cycloadditions, umpolung reactions, rearrangements and ring-opening lactonizations/lactamizations from 2009 to 2013. Furthermore, the role of D-A acceptor cyclopropanes as reactive subunits in natural product synthesis is underscored.


The tumor vasculature an attractive CAR T cell target in solid tumors.
T cells armed with a chimeric antigen receptor, CAR T cells, have shown extraordinary activity against certain B lymphocyte malignancies, when targeted towards the CD19 B cell surface marker. These results have led to the regulatory approval of two CAR T cell approaches. Translation of this result to the solid tumor setting has been problematic until now. A number of differences between liquid and solid tumors are likely to cause this discrepancy. The main ones of these are undoubtedly the uncomplicated availability of the target cell within the blood compartment and the abundant expression of the target molecule on the cancerous cells in the case of hematological malignancies. Targets expressed by solid tumor cells are hard to engage due to the non-adhesive and abnormal vasculature, while conditions in the tumor microenvironment can be extremely immunosuppressive. Targets in the tumor vasculature are readily reachable by CAR T cells and reside outside the immunosuppressive tumor microenvironment. It is therefore hypothesized that targeting CAR T cells towards the tumor vasculature of solid tumors may share the excellent effects of CAR T cell therapy with that against hematological malignancies. A few reports have shown promising results. Suggestions are provided for further improvement.


Using a handheld UV device for disinfection in the patient care environment: A descriptive qualitative study.
Frontline nurses play a critical role in the prevention of healthcare-acquired infections (HAIs) through daily practices of hand hygiene and decontamination of surfaces. Despite these practices, environmental contamination and HAIs persist. Emerging use of UV light at wavelengths safe for human exposure provides additional strategies for disinfecting the patient care environment. The purpose of this qualitative study is to explore frontline nursing feedback regarding a novel handheld UV device prototype. A convenience sample of nurses were invited to participate in facilitated individual or small group discussions led by one member of the research team. Thematic analysis of discussion transcripts was completed by two members of the research team. Sixteen registered nurses participated. Four themes found in the study were time considerations, complexity, safety (patient and nurse), and characteristics of technology to improve patient care. Findings suggest that while nursing staff are willing to use technology, it must be considered valuable to patient care and should not hinder the provision of care. Inclusion of inputs from nursing staff for development of technology identifies potential barriers to acceptance and use in the practice environment.


An investigation of the neurophysiologic effect of tone-reducing AFOs on reflex excitability in subjects with spasticity following stroke while standing.
Tone-reducing ankle-foot orthoses (TRAFOs) are said to improve the control and functioning of spastic lower limbs by their biomechanic and neurophysiologic effects. Unfortunately, there is limited evidence in literature to support the theory that TRAFOs can effectively decrease spasticity in the foot and ankle neurophysiologically. The primary purpose of this investigation was to determine the neurophysiologic effect of TRAFOs on soleus muscle reflex excitability in subjects with spasticity following stroke while standing. A repeated-measures intervention study was conducted on 15 adult subjects with stroke who were recruited from the community. Custom-made articulated ankle-foot orthoses (AFOs) and TRAFOs with orthokinetic compression garments (OCGs) were fabricated for each subject. Five conditions were tested: (1) Shoes only, (2) AFO, (3) TRAFO, (4) TRAFO with OCG, (5) shoes only, to determine if the TRAFOs were most effective in decreasing spasticity as assessed by the ratio of maximum Hoffmann reflex amplitude to maximum muscle response amplitude (Hmax:Mmax ratio) of the soleus. The results found that there were no significant treatment effects for the interventions (F = 0.992, df = 2.167, p = 0.388), however, when analysed subject-by-subject, four subjects displayed significant increases in their Hmax:Mmax ratios to at least one treatment condition. Overall, the results demonstrated that the tone-reducing devices had no significant neurophysiologic effect on soleus reflex excitability in subjects with spasticity, however individual responses showed that the TRAFOs increased spasticity in some individuals.


Diagnostic accuracy of the Depression subscale of the Hospital Anxiety and Depression Scale (HADS-D) for detecting major depression: protocol for a systematic review and individual patient data meta-analyses.
The Depression subscale of the Hospital Anxiety and Depression Scale (HADS-D) has been recommended for depression screening in medically ill patients. Many existing HADS-D studies have used exploratory methods to select optimal cut-offs. Often, these studies report results from a small range of cut-off thresholds; cut-offs with more favourable accuracy results are more likely to be reported than others with worse accuracy estimates. When published data are combined in meta-analyses, selective reporting may generate biased summary estimates. Individual patient data (IPD) meta-analyses can address this problem by estimating accuracy with data from all studies for all relevant cut-off scores. In addition, a predictive algorithm can be generated to estimate the probability that a patient has depression based on a HADS-D score and clinical characteristics rather than dichotomous screening classification alone. The primary objectives of our IPD meta-analyses are to determine the diagnostic accuracy of the HADS-D to detect major depression among adults across all potentially relevant cut-off scores and to generate a predictive algorithm for individual patients. We are already aware of over 100 eligible studies, and more may be identified with our comprehensive search. Data sources will include MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, PsycINFO and Web of Science. Eligible studies will have datasets where patients are assessed for major depression based on a validated structured or semistructured clinical interview and complete the HADS-D within 2 weeks (before or after). Risk of bias will be assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Bivariate random-effects meta-analysis will be conducted for the full range of plausible cut-off values, and a predictive algorithm for individual patients will be generated. The findings of this study will be of interest to stakeholders involved in research, clinical practice and policy.


New method for the isolation and identification of methanogenic bacteria.
A new technique is reported for the rapid growth and detection of methanogenic bacteria by using petri plates. The method employs an anaerobic glove box containing an inner chamber with separate gas-flushing facilities. The numbers of methanogenic bacteria recovered from domestic sewage sludge are comparable to those recovered by other methods. The methanogenic organisms isolated from sludge include Methanosarcina, Methanospirillum, Methanobacterium strain M.o.H., and Methanobacterium formicicum. Identification of colonies containing methanogenic bacteria is facilitated by taking advantage of the unique fluorescence properties of these organisms. Colonies as small as 0.5 mm can be detected by exposing them to long-wave ultraviolet light.


The mechanism of the mutagenic action of hydroxylamine XII. Phenotypic suppression of amber mutants of phage T7 by hydroxylamine and O-methylhydroxylamine.
The reproduction of phage T7 in the presence of hydroxylamine (HA) (mutagenesis in vivo) results in the phenotypic suppression of some amber mutants. The presence of O-methylhydroxylamine (OMHA) results in a similar effect, indicating a similar mechanism for the action of the two compounds. Since the rate of reaction of mutagen with nucleoside residues under these conditions in negligibly low, one of the most plausible explanations of this effect is the enzymic formation of modified precursors and their incorporation into bacterial tRNAs or phage-induced RNA.


Digital Tomosynthesis: A Viable Alternative to Noncontrast Computed Tomography for the Follow-Up of Nephrolithiasis?
Digital tomosynthesis (DT) is a new X-ray-based imaging technique that allows image enhancement with minimal increase in radiation exposure. The purpose of this study was to compare DT with noncontrast computed tomography (NCCT) and to evaluate its potential role for the follow-up of patients with nephrolithiasis in a nonemergent setting. A retrospective review of patients with nephrolithiasis at our institution that underwent NCCT and DT from July 2012 to September 2013 was performed. Renal units (RUs) that did not undergo treatment or stone passage were randomly assigned to two blinded readers, who recorded stone count, size area (mm(2)), maximum stone length (mm), and location, for both DT and NCCT. Mean differences per RU were compared. Potential variables affecting stone detection rate, including stone size and body mass index (BMI), were evaluated. Interobserver agreement was determined using the intraclass correlation coefficient to measure the consistency of measurements made by the readers. DT and NCCT demonstrated similar stone detection rates in terms of stone counts and stone area mm(2). Of the 79 RUs assessed, 41 RUs showed exact stone counts on DT and NCCT. The mean difference in stone area was 16.5 mm(2) (-4.6 to 38.5), p = 0.121. The mean size of the largest stone on NCCT and DT was 9.27 and 8.87 mm, respectively. Stone size and BMI did not cause a significant difference in stone detection rates. Interobserver agreement showed a strong correlation between readers and adequate reproducibility. We found DT to be a comparable imaging modality to NCCT for the detection of intrarenal stones, without a significant effect from stone size and BMI and adequate reproducibility between multiple readers. DT appears to be an ideal alternative for following patients with nephrolithiasis due to its acceptable stone detection rates, low radiation exposure, and decreased cost compared to NCCT.


Clinical and pathologic effects of oral administration of transmissible gastroenteritis vaccine to gnotobiotic pigs.
Pigs from 3 litters kept under gnotobiotic conditions were inoculated orally with virulent transmissible gastroenteritis (TGE) virus, a TGE vaccine, or Hank's balanced salt solution at 2 days of age and then euthanatized at intervals ranging from 1 to 7 days after inoculation. Pigs exposed to the vaccine had clinical evidence of diarrhea and weakness. Lesions resembling those of TGE were revealed grossly, microscopically, and by scanning electron microscopy. Viral antigen was seen in intestinal epithelial cells by the direct fluorescent antibody technique. The disease induced by the vaccine virus had a longer incubation period and lesions were less severe than that induced by the virulent virus.


Retrospective record review of pregnant women treated for rifampicin-resistant tuberculosis in South Africa.
Tuberculosis (TB) is amongst the top five causes of death in women of childbearing age (15-≤44 years). Little is known about treatment of pregnant women with drug-resistant TB (DR-TB). Treatment for pregnant women remains challenging and more complex in DR-TB/HIV co-infection, where an evidence-based guide to clinical practice is limited. The study reviewed treatment and pregnancy outcomes and birth outcomes of their new-born in a cohort of pregnant women with DR-TB from three MDR-TB hospitals during 2010 and 2018. Data were extracted from: TB register and patient clinic notes using a standardized case record form. Information on DR-TB treatment, pregnancy and Adverse Drug Events (ADEs) of twenty-six pregnant women treated with individualized second-line TB medications were captured. The frequency of favourable and adverse outcomes regarding disease and pregnancy were evaluated. The mean age was 29 years (SD ±5.1), with the minimum and maximum age of 21 and 40 years, respectively. Eleven (42.3%) were previously treated with first-line TB drugs, 11 (42.3%) never treated before and 4 (15.4%) were previously treated for DR-TB. Of the 26 women, 15 (57.7%) had at least one ADE, but most had more than one ADE. Seventeen women were successfully treated, and 22 live births recorded. Live birth outcome was significantly associated with trimester of initiation of DR-TB treatment (p = 0.036). The proportion of live births for the pregnancy trimester when DR-TB treatment was initiated, were 60.0%, 90.9% and 100.0%, for first, second and third trimester, respectively. DR-TB treatment should be delayed until after the first trimester. Routine pharmacovigilance surveillance integrated antenatal and delivery services with an integrated record of DR-TB treatment during pregnancy is recommended. Prospective studies using standardised case record forms for DR-TB treatment for pregnant women could provide more insight on the effect of DR-TB treatment on the birth outcome.


Epitope mapping of epidermal growth factor receptor (EGFR) monoclonal antibody and induction of growth-inhibitory polyclonal antibodies by vaccination with EGFR mimotope.
One of the proposed approaches in cancer therapy is to induce and direct the patient's own immune system against cancer cells. In this study, we determined the epitope mapping of the rat anti-human epidermal growth factor receptor (EGFR) monoclonal antibody ICR-62 using a phage display of random peptide library and identified a 12 amino acids peptide, which was recognized as a mimotope. The peptide was synthesized and conjugated to bovine serum albumin (BSA) as carrier protein (P-BSA). We have shown that ICR-62 can react specifically with P-BSA as well as native EGFR. Two rabbits were immunized either by BSA or P-BSA and the rabbits IgGs were purified and examined for binding to the antigens, mimotope and the EGFR protein purified from the EGFR overexpressing A431 cell line. We showed that the rabbit IgG generated against the mimotope is capable of inhibiting the growth of A431 cells by 15%, but does not have any effect on the growth of EGFR-negative MDA-MB-453 cell line in vitro. Our results support the need for further investigations on the potential of vaccination with either mimotope of the EGFR or epitope displayed on the surface of phage particles for use in active immunotherapy of cancer.


Agreement between information recorded during antenatal care and in the MINA-Brazil study.
This article aims to examine agreement of pre-pregnancy weight, pregnancy weight, height and systolic (SBP) and diastolic (DBP) blood pressure measurements recorded on antenatal record cards with the same information obtained in the MINA-Brazil longitudinal study. 428 pregnant women who participated in the MINA-Brazil study and had an antenatal card at time of childbirth were selected. Concordance analysis of the data used Lin's correlation coefficient and Bland-Altman analysis. There was moderate agreement on self-reported pre-pregnancy weight (0.935) and height (0.913) information, and substantial agreement on the pregnant women's weight in the second (0.993) and third (0.988) trimesters of pregnancy. Little agreement was found on SBP and DBP measured in the second (SBP = 0.447; DBP = 0.409) and third (SBP = 0.436; DBP = 0.332) trimesters of pregnancy. Anthropometric measurements showed strong agreement. There was weak agreement between blood pressure measurements, which may relate both to the variability and the standardisation of these measurements, suggesting the need for continued training of antenatal teams in primary health care.


A nucleotide substitution in the tRNA(Lys) primer binding site dramatically increases replication of recombinant simian immunodeficiency virus containing a human immunodeficiency virus type 1 reverse transcriptase.
A recombinant simian immunodeficiency virus (SIV) derived from strain 239 (SIVmac239) with reverse transcriptase (RT) sequences from human immunodeficiency virus type 1 (HIV-1) strain HXB2 was severely impaired for replication. Detectable p27(Gag) levels were not observed until day 65 and peak p27(Gag) levels were not reached until day 75 after transfection of CEMx174 cells with the recombinant DNA. Sequences from the latter time point did not contain amino acid substitutions in HIV-1 RT; however, a single nucleotide substitution (thymine to cytosine) was found at position eight of the SIV primer binding site. We engineered an RT/SHIV genome with the thymine-to-cytosine substitution, called RT/SHIV/TC, and observed dramatically faster replication kinetics than were observed with the parental RT/SHIV from which this variant was derived. RT/SHIV/TC provides an improved system for study of the impact of drug resistance mutations in HIV-1 RT in a relevant animal model.


Oral lesions in leprosy.
Leprotic oral lesions are more common in the lepromatous form of leprosy, indicate a late manifestation, and have a great epidemiological importance as a source of infection. Patients with leprosy were examined searching for oral lesions. Biopsies of the left buccal mucosa in all patients, and of oral lesions, were performed and were stained with H & E and Wade. Oral lesions were found in 26 patients, 11 lepromatous leprosy, 14 borderline leprosy, and one tuberculoid leprosy. Clinically 5 patients had enanthem of the anterior pillars, 3 of the uvula and 3 of the palate. Two had palatal infiltration. Viable bacilli were found in two lepromatous patients. Biopsies of the buccal mucosa showed no change or a nonspecific inflammatory infiltrate. Oral clinical alterations were present in 69% of the patients; of these 50% showed histopathological features in an area without any lesion. Our clinical and histopathological findings corroborate earlier reports that there is a reduced incidence of oral changes, which is probably due to early treatment. The maintenance of oral infection in this area can also lead to and maintain lepra reactions, while they may also act as possible infection sources. Attention should be given to oral disease in leprosy because detection and treatment of oral lesions can prevent the spread of the disease.


Age-related impairment of conducted dilation in human coronary arterioles.
Conducted vasodilation is essential to coordinate vascular resistance along distances to ensure adequate tissue perfusion. We hypothesized that conducted vasodilation of coronary resistance arteries declines with age. Coronary arterioles were dissected from right atrial appendage of patients (n = 27) undergoing cardiac surgery. Arterioles (~100 μm) were cannulated and pressurized (80 mmHg), and developed spontaneous myogenic tone. Conducted vasodilation was initiated by locally administering the endothelium-dependent agonist bradykinin (BK; 100 μM) ejected from a glass micropipette (~3 μm tip opening, positioned in close proximity to the vessel wall). Diameter changes were measured at local and upstream sites (500 and 1,000 μm from the stimulus) with videomicroscopy. Local administration of BK elicited vasodilation, the magnitude of which increased with the duration of stimulus (69 ± 6, 81 ± 6, 90 ± 2%, after 1, 3, and 5 × 100 ms, respectively). BK-induced dilation remained substantial at upstream sites (500 μm: 53 ± 7%; 1,000 μm: 46 ± 9%). The gap junction uncoupler carbenoxolone or 18-α-glycyrrhetinic acid did not affect local responses, but diminished conducted vasodilation. Inhibitors of small/intermediate conductance calcium-activated potassium channels (SKCa/IKCa), apamin and TRAM34, reduced dilations both at local and remote sites. We found that conducted dilation, but not the local response, was significantly reduced in older (≥64 yr) patients. The nitric oxide (NO) synthesis inhibitor N(ω)-nitro-l-arginine methyl ester did not affect local responses, but markedly reduced conducted dilation in younger (<64 yr) individuals. Collectively, we show that human coronary arterioles exhibit SKCa/IKCa-mediated hyperpolarization spread through gap junctions, which contributes to conducted vasodilation initiated by focal application of BK. We demonstrate that conducted dilation declines with age, likely due to reduced NO availability, which plays a permissive role in propagating longitudinal vasomotor signaling.


Ethanol production in immobilized-cell bioreactors from mixed sugar syrups and enzymatic hydrolysates of steam-exploded biomass.
We investigated ethanol production from mixed sugar syrups. Hydrolysates were prepared from enzymatic saccharification of steam-pretreated aspen chips. Syrups containing 45 g/L of glucose and 12 g/L of xylose were detoxified through two ion-exchange resins and then fermented with Pichia stipitis and Saccharomyces cerevisiae immobilized in Ca-alginate gel beads. Combinations of different gel fractions in the fermentation volume, amount of yeast cells, and ratios of P. stipitis vs S. cerevisiae within each bead were compared. In the best conditions, by using a total beads volume corresponding to 25% of the working volume, we obtained a yield of 0.39 g(ethanol)/g(initial sugars). This amount of gel entrapped an initial cell concentration of 6 x 1012cells/L with ratio of S. cerevisiae/P. stipitis of 0.25 g/g. Modified stirred-tank reactors were obtained either by adding marbles or by inserting a perforated metal cylinder, which reduced considerably the rupture of beads while visibly improving oxygenation of the medium.


Pathophysiology and treatment of obesity hypertension.
Excess weight gain accounts for as much as 65-75% of the risk for essential hypertension and also greatly increases the risk for end stage renal disease (ESRD). Obesity raises blood pressure by increasing renal tubular reabsorption, impairing pressure natriuresis, and causing volume expansion due to activation of the sympathetic nervous system (SNS) and renin-angiotensin aldosterone system (RAAS), and by physical compression of the kidneys, especially when visceral obesity is present. The mechanisms of SNS activation in obesity are still unclear but may be due, in part, to hyperleptinemia that stimulates the hypothalamic pro-opiomelanocortin (POMC) pathway. With prolonged obesity, there may be a gradual loss of kidney function that worsens with time, exacerbates hypertension, and makes blood pressure more difficult to control. Lifestyle modifications, including weight reduction and increased physical activity, are essential first steps in the management of obesity hypertension and renal disease. Anti-obesity drugs offer potential pharmacotherapy for obesity hypertension, but current drugs are very limited and additional long-term studies are needed to test their safety and efficacy. Clinical trials are also needed to determine the most effective antihypertensive drugs for obese hypertensive patients. Special considerations for the obese patient, in addition to adequately controlling the blood pressure, include correcting the metabolic abnormalities and protecting the kidneys from further injury.


Parenthood and opioid dependence.
Many patients in maintenance treatment programs for opioid dependence are parents to underage children. The aim of this study was to explore how parents who are regular patients in maintenance treatment perceive their parenthood. The study used a qualitative approach. The informants were recruited by staff at a substance abuse clinic in Sweden. Criteria for inclusion were participation in the local maintenance treatment program, having a child or children younger than 18 years, and being in contact with the child or children. Data were collected in 2012-2013 by in-depth interviews of seven fathers and five mothers and analyzed using concepts and procedures of qualitative content analysis. The central findings of the study were: 1) the parents' concerns about possible future discrimination against their children, ie, stigma by association; and 2) the patients' own parents' role as the most important support in parenthood. The issue of anticipated discrimination against the children of parents undergoing maintenance treatment might be an aspect to consider in the development of interventions and support. Considering the role of the patients' own parents also seems important.


Effectiveness and feasibility of convalescent blood transfusion to reduce COVID-19 fatality ratio.
Background: As of December 2020, COVID-19 has spread all over the world with more than 81 million cases and more than 1.8 million deaths. The rapidly increasing number of patients mandates the consideration of potential treatments for patients under severe and critical conditions. Convalescent plasma (CP) treatment refers to the approach of infusing patients with plasma from recently recovered patients. CP appears to be a possible therapeutic option to manage patients suffering from severe or even lethal infectious disorders, in which 'traditional therapies' have failed to obtain any result. Methods: In the present study, we develop a mathematical model on the treatment-donation-stockpile dynamics for an optimal implementation of CP therapy to examine potential benefits and complications in the logistic realization of this therapy in a large-scale population. We parametrize the model with COVID-19 epidemics in Italy, and conduct scenario analyses to estimate outcomes of population-wide CP therapy and to examine the maximum number of CP donation processions per day. Results: Under the assumption that the efficacy of CP is 90%, we show that by the end of year 2020, initiating the population-wide CP therapy from April 2020 can save as many as 19 215 lives (ranging from 5000 to 28 000 depending on donor availability), while the demand for apheresis use is manageable in all scenarios: the maximum daily demand is 156 (ranging from 27 to 519 depending on donor availability) for the first outbreak wave and 1434 (ranging from 224 to 4817 depending on donor availability) for the second wave. Given that Italy has 61 centres with apheresis this maximum demand level corresponds to a daily average of 2.5 and 23.5 processions of CP donation being performed by each centre with respect to each outbreak wave. Conclusions: Our analyses show that population-wide CP therapy can contribute to curbing COVID-19-related deaths, and the logistic implementation is feasible for developed countries. The reduction of deaths can be very significant if the CP therapy is started earlier in the outbreak, and remains significant even if it is implemented during the outbreak peak time.


A synergistic increase of apoptosis utilizing Fas antigen expression induced by low doses of anticancer drug.
Anticancer drugs have been known to enhance both Fas receptor and Fas ligand expression on tumor cells. Recently, low doses of cytosine arabinoside (ara-C) were reported to enhance Fas antigen expression in the human myeloid leukemia cell line HL60. Here, we showed that low doses of ara-C (LD-ara-C) and etoposide (LD-VP-16) but not vincristine (LD-VCR) induce Fas expression in the human monocytic leukemia cell line U937. We determined the concentrations of ara-C, VP-16 and VCR as 10, 100 and 1 ng/ml, respectively. The ratios for Fas antigen expression induced in non-treated U937 by 24 h incubations with ara-C, VP-16 or VCR were 1.90, 1.36 and 1.00, respectively. Utilizing the Fas antigen expression induced by low doses of anticancer drugs, we examined whether anti-Fas IgM monoclonal antibody (CH-11) combined with LD-ara-C, LD-VP-16 or LD-VCR enhances apoptosis. When CH-11 and LD-anticancer drug were added simultaneously, the ratios of annexin V positive cells were 67.8 +/- 2.4% with ara-C, 70.0 +/- 1.6% with VP-16 and 54.2 +/- 1.3% with VCR. Thus, the ratios of annexin V positive cells significantly increased when CH-11 was simultaneously added to the cells with ara-C (p < 0.0001) and VP-16 (p < 0.0001), but not with VCP (p = 0.5559), compared with the sums of annexin V positive ratios of CH-11 and LD-anticancer drug added separately. We examined whether a broad-range caspase inhibitor (C.I.) can inhibit the Fas expression enhanced by LD-anticancer drugs. However, the Fas expression enhanced by LD-ara-C or LD-VP-16 was not inhibited by a broad-range caspase inhibitor. We demonstrated that apoptosis induced by LD-ara-C or LD-VP-16 is synergistically increased by the addition of CH-11 in U937.


Oversight of human participants research: identifying problems to evaluate reform proposals.
The oversight of research involving human participants is widely believed to be inadequate. The U.S. Congress, national commissions, the Department of Health and Human Services, the Institute of Medicine, numerous professional societies, and others are proposing remedies based on the assumption that the main problems are researchers' conflict of interest, lack of institutional review board (IRB) resources, and the volume and complexity of clinical research. Developing appropriate reform proposals requires carefully delineating the problems of the current system to know what reforms are needed. To stimulate a more informed and meaningful debate, we delineate 15 current problems into 3 broad categories. First, structural problems encompass 8 specific problems related to the way the research oversight system is organized. Second, procedural problems constitute 5 specific problems related to the operations of IRB review. Finally, performance assessment problems include 2 problems related to absence of systematic assessment of the outcomes of the oversight system. We critically assess proposed reforms, such as accreditation and central IRBs, according to how well they address these 15 problems. None of the reforms addresses all 15 problems. Indeed, most focus on the procedural problems, failing to address either the structure or the performance assessment problems. Finally, on the basis of the delineation of problems, we outline components of a more effective reform proposal, including bringing all research under federal oversight, a permanent advisory committee to address recurrent ethical issues in clinical research, mandatory single-time review for multicenter research protocols, additional financial support for IRB functions, and a standardized system for collecting and disseminating data on both adverse events and the performance assessment of IRBs.


[Dual-source computed tomography: effect on regional and global left ventricular function assessment compared to magnetic resonance imaging].
To determine regional and global left ventricular (LV) functional parameters and to perform segmental wall thickness (SWT) and motion (WM) analysis of dual-source CT (DSCT) with optimized temporal resolution versus MRI. 30 patients with known or suspected CAD, non-obstructive HCM, DCM, ARVCM, Fallot Tetralogy, cardiac sarcoidosis and cardiac metastasis underwent DSCT and MRI. The DSCT and MR images were evaluated: end-systolic (ESV), end-diastolic LV (EDV) volumes, stroke volume (SV), ejection fraction (EF), and myocardial mass (MM) as well as LV wall thickening and segmental WM applying the AHA model were obtained and statistically analyzed. The mean LV-EDV (r = 0.96) and ESV (r = 0.98) as well as LV-EF (r = 0.97), SV (r = 0.83), and MM (r = 0.95) correlated well. Bland Altman analysis revealed little systematic underestimation of LV-EF (-1.1 +/- 7.8 %), EDV (-0.3 +/- 18.2 ml), SV (-1.3 +/- 16.7 ml) and little overestimation of ESV (1.1 +/- 7.8 ml) and MM (12.8 +/- 14.4 g) determined by DSCT. Systolic reconstruction time points correlated well (DSCT 32.2 +/- 6.7 vs. MRI 35.6 +/- 4.4 % RR-interval). The LV wall thickness obtained by DSCT and MRI showed close correlation in all segments (Ø diff 0.42 +/- 1 mm). In 413 segments (89 %) WM abnormalities were equally rated, whereas DSCT tended to underestimate the degree of wall motion impairment. DSCT with optimized temporal resolution enables regional and global LV function analysis as well as segmental WM analysis in good correlation with MRI. However, the degree of WM impairment is slightly underestimated by DSCT.


Sexual practices in a broad cross-sectional sample of Sydney gay men.
The aim of this study was to provide current data on the sexual practices in a broad cross-sectional sample of gay and homosexually active men in Sydney. Anonymous, short questionnaires were completed by 1611 gay men recruited at the 1996 Gay and Lesbian Mardi Gras Fair Day or at one of six venues (including two sexual health centres) across the metropolitan area during the following week. The sample was diverse, but the men tended to be of Anglo-Australian background, well educated, professionally employed, attached to gay community and gay identified. They mainly had sex with other men rather than with men and women. Most (86.0 per cent) had been tested for human immunodeficiency virus. Excluding 241 men recruited in sexual health centres, 11.2 per cent were HIV-positive and 73.4 per cent were negative. Where it occurred in regular relationships, unprotected anal intercourse was usually between seroconcordant partners (78.5 per cent). Unprotected anal intercourse between discordant or nonconcordant regular partners was much less common, and in about half the cases involved withdrawal prior to ejaculation exclusively rather than ejaculation inside. Almost 12 per cent of the men had at least 'occasionally' engaged in unprotected anal intercourse with a casual partner in the previous six months, with approximately half of these men having adopted a withdrawal strategy on every occasion. We conclude that short surveys can provide valuable and timely data on sexual practices in a broad cross-sectional sample of gay and homosexually active men. Key messages for those involved in gay men's education are the high rates of unprotected anal intercourse between casual partners and the extensive practice of withdrawal.


[Cloning of amplicon of chromosomal SCO1206 sequences of Streptomyces coelicolor A 3(2)].
With the help of polymerase cycle reaction a fragment of chromosome Streptomyces coelicolor A 3(2) was amplified which contains gene SCO1206 coding subunit proteins of polyketide synthase III. Cloning of amplified DNA in the structure of shuttle vectors pAX5a and pWHM4 in Escherichia coli XL1 Blue was done. Plasmids of some selected ampicillin-resistent clones were transformed into protoplasts of plasmidless variant of Streptomyces globisporus 1912. Restrictional analysis of plasmid DNA of all investigated transformants both Escherichia coli and Streptomyces globisporus 1912 showed that 1.1 kb fragments of DNA were cloned in them. Research of the complex of metabolites, synthesized by transformants of Streptomyces globisporus 1912 revealed the presence of new substances which were not synthesized by the recipient.


Image/patient registration from (partial) projection data by the Fourier phase matching method.
A technique for 2D or 3D image/patient registration, PFPM (projection based Fourier phase matching method), is proposed. This technique provides image/patient registration directly from sequential tomographic projection data. The method can also deal with image files by generating 2D Radon transforms slice by slice. The registration in projection space is done by calculating a Fourier invariant (FI) descriptor for each one-dimensional projection datum, and then registering the FI descriptor by the Fourier phase matching (FPM) method. The algorithm has been tested on both synthetic and experimental data. When dealing with translated, rotated and uniformly scaled 2D image registration, the performance of the PFPM method is comparable to that of the IFPM (image based Fourier phase matching) method in robustness, efficiency, insensitivity to the offset between images, and registration time. The advantages of the former are that subpixel resolution is feasible, and it is more insensitive to image noise due to the averaging effect of the projection acquisition. Furthermore, the PFPM method offers the ability to generalize to 3D image/patient registration and to register partial projection data. By applying patient registration directly from tomographic projection data, image reconstruction is not needed in the therapy set-up verification, thus reducing computational time and artefacts. In addition, real time registration is feasible. Registration from partial projection data meets the geometry and dose requirements in many application cases and makes dynamic set-up verification possible in tomotherapy.


Effect of cold plasma on polyphenol oxidase inactivation in cloudy apple juice and on the quality parameters of the juice during storage.
Direct cold plasma treatment has been investigated as an alternative non-thermal technology as a means of maintaining and improving quality of fresh cloudy apple juice. Process variables studied included type of plasma discharge, input voltage and treatment time on polyphenol oxidase (PPO) inactivation. Spark discharge plasma at 10.5 kV for 5 min was the best treatment, with near total inactivation of PPO achieved, although good PPO inactivation was also recorded using shorter treatment times. Residual activity (RA) of PPO was 16 and 27.6% after 5 and 4 min of treatment respectively. This PPO inactivation was maintained throughout the storage trials, but decreased with samples treated for a shorter time. Plasma treatment improved key quality parameters of Golden delicious cloudy apple juice, with retention of critical quality parameters during extended storage trials. Color was the most noticeable change, which was enhanced with retention of a greener color. An increase of 69 and 64% was obtained in the total phenolic content after 4 and 5 min of treatment, respectively. Therefore, cold plasma was demonstrated to be a good alternative to traditional heat treatments for enhanced quality retention of fresh cloudy apple juice and over its storage.


The efficacy of an association of palmitoylethanolamide and alpha-lipoic acid in patients with chronic prostatitis/chronic pelvic pain syndrome: A randomized clinical trial.
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a complex condition, characterized by uncertain etiology and by limited response to therapy. The definition of CP/CPPS includes genitourinary pain with or without voiding symptoms in the absence of uropathogenic bacteria, as detected by standard microbiological methods, or another identifiable cause such as malignancy. The efficacy of various medical therapies, has been evaluated in clinical studies, but evidence is lacking or conflicting. We compared Serenoa Repens in monotherapy versus Palmitoylethanolamide (PEA) in combination with Alpha-lipoic acid (ALA) and evaluated the efficacy of these treatments in patients with CP/CPPS. We conducted a randomized, single-blind trial. 44 patients diagnosed with CP/CPPS (mean age 41.32 ± 1.686 years) were randomly assigned to treatment with Palmitoylethanolamide 300 mg plus Alpha-lipoic acid 300 mg (Peanase®), or Serenoa Repens at 320 mg. Three questionnaires (NIH-CPSI, IPSS and IIEF5) were administered at baseline and after 12 weeks of treatment in each group. 12 week treatment with Peanase significantly improved the IPSS score compared to the same period of treatment with Serenoa Repens, and significantly reduced NIH-CPSI score. Similar results were observed in the different NIH-CPSI subscores break down. However, the same treatment did not result in significant improvement of the IIEF5 score. Both treatments did not produce undesired effects. The present results document the efficacy of an association of Palmitoylethanolamide (PEA) and Alpha-lipoic acid (ALA) administered for 12 weeks for treating patients with CP/CPPS, compared with Serenoa Repens monotherapy.


Wave optics simulation approach for partial spatially coherent beams.
A numerical wave optics approach for simulating a partial spatially coherent beam is presented. The approach involves the application of a sequence of random phase screens to an initial beam field and the summation of the intensity results after propagation. The relationship between the screen parameters and the spatial coherence function for the beam is developed and the approach is verified by comparing results with analytic formulations for a Gaussian Schell-model beam. The approach can be used for modeling applications such as free space optical laser links that utilize partially coherent beams.


Linking Decision Theory and Quantitative Microbial Risk Assessment: Tradeoffs Between Compliance and Efficacy for Waterborne Disease Interventions.
Achieving health gains from the U.N. Sustainable Development Goals of universal coverage for water and sanitation will require interventions that can be widely adopted and maintained. Effectiveness-how an intervention performs based on actual use-as opposed to efficacy will therefore be central to evaluations of new and existing interventions. Incomplete compliance-when people do not always use the intervention and are therefore exposed to contamination-is thought to be responsible for the lower-than-expected risk reductions observed from water, sanitation, and hygiene interventions based on their efficacy at removing pathogens. We explicitly incorporated decision theory into a quantitative microbial risk assessment model. Specifically, we assume that the usability of household water treatment (HWT) devices (filters and chlorine) decreases as they become more efficacious due to issues such as taste or flow rates. Simulations were run to examine the tradeoff between device efficacy and usability. For most situations, HWT interventions that trade lower efficacy (i.e., remove less pathogens) for higher compliance (i.e., better usability) contribute substantial reductions in diarrheal disease risk compared to devices meeting current World Health Organization efficacy guidelines. Recommendations that take into account both the behavioral and microbiological properties of treatment devices are likely to be more effective at reducing the burden of diarrheal disease than current standards that only consider efficacy.


Computer-assisted diagnosis of acute Crohn's diseases.
A study comparing the symptoms and signs of patients with acute Crohn's disease and those with acute appendicitis and intestinal obstruction is reported and a preliminary evaluation of computer-assisted diagnosis in this problem is given. There are significant differences between the three conditions. However, the accuracy of computer-assisted diagnosis in Crohn's disease is reduced by the high false positive rate of diagnosis in both appendicitis and intestinal obstruction. Computer accuracy in Crohn's disease may increase when further information is available to extend the data base.


Anxiety symptoms and children's eye gaze during fear learning.
The eye region of the face is particularly relevant for decoding threat-related signals, such as fear. However, it is unclear if gaze patterns to the eyes can be influenced by fear learning. Previous studies examining gaze patterns in adults find an association between anxiety and eye gaze avoidance, although no studies to date examine how associations between anxiety symptoms and eye-viewing patterns manifest in children. The current study examined the effects of learning and trait anxiety on eye gaze using a face-based fear conditioning task developed for use in children. Participants were 82 youth from a general population sample of twins (aged 9-13 years), exhibiting a range of anxiety symptoms. Participants underwent a fear conditioning paradigm where the conditioned stimuli (CS+) were two neutral faces, one of which was randomly selected to be paired with an aversive scream. Eye tracking, physiological, and subjective data were acquired. Children and parents reported their child's anxiety using the Screen for Child Anxiety Related Emotional Disorders. Conditioning influenced eye gaze patterns in that children looked longer and more frequently to the eye region of the CS+ than CS- face; this effect was present only during fear acquisition, not at baseline or extinction. Furthermore, consistent with past work in adults, anxiety symptoms were associated with eye gaze avoidance. Finally, gaze duration to the eye region mediated the effect of anxious traits on self-reported fear during acquisition. Anxiety symptoms in children relate to face-viewing strategies deployed in the context of a fear learning experiment. This relationship may inform attempts to understand the relationship between pediatric anxiety symptoms and learning.


Genetic Test for the Channelopaties: Useful or Less Than Useful for Patients? (Part II).
The advanced knowledge about genetic diseases and their mutations has widened the possibility to have a more precise and definitive diagnosis in many patients, but the use of genetic testing is still controversial. Actually, many cardiomyopathies show the availability of genetic testing. The clinical utility of this testing has been widely debated, but it is evident that the use of genetics must be put in a more organic diagnostic pathway that includes the evaluation of risks and benefits for the patient and his relatives, as well as the costs of the procedure. This review aims to clarify the role of genetic in clinics regarding Channelopaties, less frequent but equally important than other Cardiomyopathies because patients can often be asymptomatic until the first fatal manifestation.


Potential renal sequelae in survivors of hantavirus cardiopulmonary syndrome.
Although other hantaviruses are associated with renal manifestations, hantavirus cardiopulmonary syndrome (HCPS) has not been associated with such sequelae. The HCPS survivors were prospectively evaluated for renal complications. Subjects underwent yearly evaluation, laboratory studies, and 24-hour urine collection. Thirty subjects were evaluated after recovery from HCPS with the first follow-up at a median of 7.4 months after discharge. Subjects were a wide age range (18-51) but had an equal gender composition. Eighteen of 30 (60%) returned for > 1 evaluation. Half (15/30) had a 24-hour urine collection with > 150 mg of total protein and 6 had > 300 mg. Seven had a Cockcroft-Gault creatinine clearance (CrClCG) < 90 mL/min/1.73 m2 and 2 were < 60. Fifty-three percent met the definition of chronic kidney disease. Those treated with extracorporeal membrane oxygenation had less renal sequelae (P = 0.035). Our data suggest that renal sequelae may occur in HCPS. Further study of renal complications of New World hantavirus infections are needed.


Prevalence of imaginary companions in Japanese children.
Having an imaginary companion (IC) is an example of children's pretend play. However, most research regarding children's ICs is from Western cultures. In this study, the prevalence of ICs was assessed among Japanese children (2- to 9-year-old children, N = 800). The developmental (age), biological (sex), and environmental (birth order) effects on Japanese children's ICs were also assessed. Moreover, whether IC status can be an indicator of fantasy orientation in Japanese children was examined. The results revealed that the prevalence of the invisible friend was relatively rare, but the personified object was prevalent in Japanese children. Age and sex, but not birth order, significantly affected the prevalence of ICs in Japan. Moreover, IC status significantly indicated children's fantasy orientation. The results suggest that the characteristics of Japanese children's ICs are partly different from those in Western children. Social-cultural contexts can affect this difference.


Identification of novel biomarkers in obstructive sleep apnea via integrated bioinformatics analysis and experimental validation.
Obstructive sleep apnea (OSA) is a complex and multi-gene inherited disease caused by both genetic and environmental factors. However, due to the high cost of diagnosis and complex operation, its clinical application is limited. This study aims to explore potential target genes associated with OSA and establish a corresponding diagnostic model. This study used microarray datasets from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) related to OSA and perform functional annotation and pathway analysis. The study employed multi-scale embedded gene co-expression network analysis (MEGENA) combined with least absolute shrinkage and selection operator (LASSO) regression analysis to select hub genes and construct a diagnostic model for OSA. In addition, the study conducted correlation analysis between hub genes and OSA-related genes, immunoinfiltration, gene set enrichment analysis (GSEA), miRNA network analysis, and identified potential transcription factors (TFs) and targeted drugs for hub genes. Finally, the study used chronic intermittent hypoxia (CIH) mouse model to simulate OSA hypoxic conditions and verify the expression of hub genes in CIH mice. In this study, a total of 401 upregulated genes and 275 downregulated genes were identified, and enrichment analysis revealed that these differentially expressed genes may be associated with pathways such as vasculature development, cellular response to cytokine stimulus, and negative regulation of cell population proliferation. Through MEGENA combined with LASSO regression, seven OSA hub genes were identified, including C12orf54, FOS, GPR1, OR9A4, MYO5B, RAB39B, and KLHL4. The diagnostic model constructed based on these genes showed strong stability. The expression levels of hub genes were significantly correlated with the expression levels of OSA-related genes and mainly acted on pathways such as the JAK/STAT signaling pathway and the cytosolic DNA-sensing pathway. Drug-target predictions for hub genes were made using the Connectivity Map (CMap) database and the Drug-Gene Interaction database (Dgidb), which identified targeted therapeutic drugs for the hub genes. In vivo experiments showed that the hub genes were all decreasing in the OSA mouse model. This study identified novel biomarkers for OSA and established a reliable diagnostic model. The transcriptional changes identified may help to reveal the pathogenesis, mechanisms, and sequelae of OSA.


Endocyclic oxygen in 3-fluorodihydro-2H-pyran-4(3H)-one that does not induce the gauche effect.
2-Fluorocyclohexanone undergoes chair inversion, giving rise to axial and equatorial conformers, with the equatorial form being highly preferred in solution, for example, 87% in chloroform and 93% in methylene chloride. Modifications in the conformational preferences can modify macroscopic properties of 2-fluoro ketones. The introduction of an endocyclic oxygen in 2-fluorocyclohexanone to give 3-fluorodihydro-2H-pyran-4(3H)-one would be expected to create a gauche effect in the axial conformer along with the O-C-C-F moiety, inducing an increase of its population. However, small changes were verified in the conformational populations both in the gas phase and solution because the carbonyl group plays an important role for the hyperconjugation in the equatorial conformer, despite experiencing strong dipolar repulsion with the fluorine atom. These data were obtained theoretically and by NMR spectroscopy, while the nature of the interactions governing these conformational shifts were investigated on the basis of natural bond orbital analysis.


[VA-MENGOC-BC vaccine: its impact on meningococcal disease in children 1-4 years old].
VA-MENGOC-BC vaccine has been administered to Cuban infants since 1991 through the National Immunization Program (NIP) so it was necessary to evaluate its effects on 1-4 years-old children included in the highest risk group. To this end, a descriptive study of the morbidity and mortality from meningococal disease was carried out taking the vaccine histories of 145 cases occurred from 1991 to 1996 into account. The decreasing trend of the incidence density (ID) of meningococcal disease in all the age groups in the studied period was among the most important results, the highest decline was observed in one-year old infants with an ID of. 10.8 per 100,000 children/years at the end of the period. The percent distribution of occurrence showed a predominance of one-year old group at the beginning of the program. Implementation, and a change to 3-4 years old group at the end of the period. A high of percent of vaccinated sick children had been immunized against MD over one year ago (697.5 days as average). 35 children died during the period and the highest mortality density decline (1 per 100,000 children a year) was observed as of 1993; 2 years-old children were at highest risk of death. Seventy three percent (73.1%) of those vaccinated had been immunized for over once year. The general lethality was 24.1%, the lowest was 14.3% in one year old children. The changes occurred in meningococcal disease behaviour within this high risk group, which are attributed to the administration of vaccine as part of the NIP fully justifies the continuation of the application of this vaccine.


[Can cardiovascular events be prevented by raising HDL cholesterol?].
Low HDL cholesterol is a risk factor for development of atherosclerotic disease. The possibility of increasing HDL cholesterol levels to prevent cardiovascular disease is an issue of great interest. Literature was retrieved from Pubmed and Embase and relevant literature and reference lists were reviewed. Physical exercise, smoking cessation, weight control and moderate alcohol intake has been shown to increase HDL cholesterol levels. Of today's available drugs, Niacin has the greatest HDL cholesterol-enhancing effect, but clinical effects have not been adequately documented. Fibrates increase HDL cholesterol, but it has not been documented that this results in clinical benefit. Statins increase HDL cholesterol moderately, but it is not clear whether such increase has been crucial for the reduction of cardiovascular events in the large statin trials. Combinations of various lipid-lowering agents can increase HDL cholesterol additively, but clinical benefit has not been proven. Inhibition of cholesterol ester transfer protein with torcetrapib raised HDL cholesterol markedly, but increased the risk of death and cardiovascular events. Infusion of a apolipoprotein A-I Milano/phospholipid complex was associated with regression of coronary atherosclerosis. New HDL-modifying therapies are under investigation. HDL cholesterol can be used for assessment of cardiovascular risk, but it has not been documented that drug-induced enhancement of HDL cholesterol can reduce the occurrence of cardiovascular events.


Tracking Lithium Ions via Widefield Fluorescence Microscopy for Battery Diagnostics.
Direct tracking of lithium ions with time and spatial resolution can provide an important diagnostic tool for understanding mechanisms in lithium ion batteries. A fluorescent indicator of lithium ions, 2-(2-hydroxyphenyl)naphthoxazole, was synthesized and used for real-time tracking of lithium ions via widefield fluorescence microscopy. The fluorophore can be excited with visible light and was shown to enable quantitative determination of the lithium ion diffusion constant in a microfluidic model system for a plasticized polymer electrolyte lithium battery. The use of widefield fluorescence microscopy for in situ tracking of lithium ions in batteries is discussed.


Dynamic responses of renal oxygenation at the onset of cardiopulmonary bypass in sheep and man.
The renal medulla is susceptible to hypoxia during cardiopulmonary bypass (CPB), which may contribute to the development of acute kidney injury. But the speed of onset of renal medullary hypoxia remains unknown. We continuously measured renal medullary oxygen tension (MPO2) in 24 sheep, and urinary PO2 (UPO2) as an index of MPO2 in 92 patients, before and after induction of CPB. In laterally recumbent sheep with a right thoracotomy (n = 20), even before CPB commenced MPO2 fell from (mean ± SEM) 52 ± 4 to 41 ±5 mmHg simultaneously with reduced arterial pressure (from 108 ± 5 to 88 ± 5 mmHg). In dorsally recumbent sheep with a medial sternotomy (n = 4), MPO2 was even more severely reduced (to 12 ± 12 mmHg) before CPB. In laterally recumbent sheep in which a crystalloid prime was used (n = 7), after commencing CPB, MPO2 fell abruptly to 24 ±6 mmHg within 20-30 minutes. MPO2 during CPB was not improved by adding donor blood to the prime (n = 13). In patients undergoing cardiac surgery, UPO2 fell by 4 ± 1 mmHg and mean arterial pressure fell by 7 ± 1 mmHg during the 30 minutes before CPB. UPO2 then fell by a further 12 ± 2 mmHg during the first 30 minutes of CPB but remained relatively stable for the remaining 24 minutes of observation. Renal medullary hypoxia is an early event during CPB. It starts to develop even before CPB, presumably due to a pressure-dependent decrease in renal blood flow. Medullary hypoxia during CPB appears to be promoted by hypotension and is not ameliorated by increasing blood hemoglobin concentration.


Modulation of P-glycoprotein at the blood-brain barrier: opportunities to improve central nervous system pharmacotherapy.
Pharmacotherapy of central nervous system (CNS) disorders (e.g., neurodegenerative diseases, epilepsy, brain cancer, and neuro-AIDS) is limited by the blood-brain barrier. P-glycoprotein, an ATP-driven, drug efflux transporter, is a critical element of that barrier. High level of expression, luminal membrane location, multispecificity, and high transport potency make P-glycoprotein a selective gatekeeper of the blood-brain barrier and thus a primary obstacle to drug delivery into the brain. As such, P-glycoprotein limits entry into the CNS for a large number of prescribed drugs, contributes to the poor success rate of CNS drug candidates, and probably contributes to patient-to-patient variability in response to CNS pharmacotherapy. Modulating P-glycoprotein could therefore improve drug delivery into the brain. Here we review the current understanding of signaling mechanisms responsible for the modulation of P-glycoprotein activity/expression at the blood-brain barrier with an emphasis on recent studies from our laboratories. Using intact brain capillaries from rats and mice, we have identified multiple extracellular and intracellular signals that regulate this transporter; several signaling pathways have been mapped. Three pathways are triggered by elements of the brain's innate immune response, one by glutamate, one by xenobiotic-nuclear receptor (pregnane X receptor) interactions, and one by elevated beta-amyloid levels. Signaling is complex, with several pathways sharing common signaling elements [tumor necrosis factor (TNF) receptor 1, endothelin (ET) B receptor, protein kinase C, and nitric-oxide synthase), suggesting a regulatory network. Several pathways include autocrine/paracrine elements, involving release of the proinflammatory cytokine, TNF-alpha, and the polypeptide hormone, ET-1. Finally, several steps in signaling are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the clinic.


The better substitute for tricuspid valve replacement in patients with severe isolated tricuspid regurgitation.
The ideal alternative for tricuspid valve replacement (TVR) in patients with severe isolated tricuspid regurgitation remains unclear. The aim of the present study was to retrospectively investigate the outcomes of using bioprosthetic and mechanical valves at the tricuspid position. A total of 98 consecutive patients without left-side cardiac disease or history of heart surgery who underwent first-time TVR between January 2010 and March 2017 at the West China Hospital, China were included in the study. Patient data, including all-cause death and need for tricuspid valve reoperation as the main end points, were retrospectively evaluated. A total of 76 patients were enrolled into the study. The mean follow-up period was 43.3±21.9 (10-87) months. The mean age of the patients was 45.7±13.4 years. The study comprised 32.9% of male patients. During the follow-up period, 4, 3, 12, and 3 cases of death, reoperation, prosthesis dysfunctions, and prosthesis-related thrombosis were noted, respectively. Biological and mechanical valves were used in 56.6% and 43.4% of the patients, respectively. However, there was no significant difference between mechanical and biological valves with respect to echocardiographic date and survival, reoperation, prosthetic valve dysfunction, and thromboembolism rate. TVR is not a very high-risk procedure in patients with isolated tricuspid regurgitation, and the decision for prosthesis implantation in TVR should be made on an individual basis according to suitable clinical judgment.


Homologous desensitization of substance-P-induced inositol polyphosphate formation in rat parotid acinar cells.
Maximal concentrations of substance P and methacholine induced a rapid increase in [3H]inositol trisphosphate ([3H]IP3) formation. After about 1 min, the [3H]IP3 in the substance-P-treated cells ceased to increase further, whereas in the methacholine-treated cells [3H]IP3 continued to increase. Addition of methacholine to the substance-P-treated cells caused a rapid increase in [3H]IP3, whereas a second addition of a 10-fold excess of substance P had no effect. Pretreatment of cells with substance P, followed by removal of the substance P by washing, resulted in a decreased response to a second application of substance P. A similar protocol involving pretreatment with methacholine had no effect on subsequent responsiveness to substance P. Analysis of [3H]substance P binding to substance-P-treated cells indicated that the number of receptors for substance P was decreased, but the affinity of the receptors for substance P was unaffected. After substance P pretreatment, a prolonged incubation (2 h) restored responsiveness of the cells to substance P, measured as [3H]IP3 formation, and restored the number of binding sites to control values. These findings indicate that, in the rat parotid gland, substance P induces a homologous desensitization of its receptor, which involves a slowly reversible down-regulation or sequestration of substance-P-binding sites.


Dietary intake of magnesium may modulate depression.
Depressive symptoms are frequent in students and may lead to countless problems. Several hypotheses associate magnesium with depression because of the presence of this mineral in several enzymes, hormones, and neurotransmitters, which may play a key role in the pathological pathways of depression. The aim of this study was to assess whether magnesium intake could modulate depressive symptoms. A cross-sectional study was conducted on a convenience sample of 402 Iranian postgraduate students studying in Malaysia to assess the relationship between magnesium intake and depressive symptoms. The mean age of the participants was 32.54 ± 6.22 years. The results of the study demonstrated an inverse relationship between magnesium intake and depressive symptoms, which persisted even after adjustments for sex, age, body mass index, monthly expenses, close friends, living on campus, smoking (current and former), education, physical activity, and marital status.


Do humans integrate routes into a cognitive map? Map- versus landmark-based navigation of novel shortcuts.
Do humans integrate experience on specific routes into metric survey knowledge of the environment, or do they depend on a simpler strategy of landmark navigation? The authors tested this question using a novel shortcut paradigm during walking in a virtual environment. The authors find that participants could not take successful shortcuts in a desert world but could do so with dispersed landmarks in a forest. On catch trials, participants were drawn toward the displaced landmarks whether the landmarks were clustered near the target location or along the shortcut route. However, when landmarks appeared unreliable, participants fell back on coarse survey knowledge. Like honeybees (F. C. Dyer, 1991), humans do not appear to derive accurate cognitive maps from path integration to guide navigation but, instead, depend on landmarks when they are available.


Intraframework migration of tetrahedral atoms in a zeolite.
The transformation from a disordered into an ordered version of the zeolite natrolite occurs on prolonged heating of this material in the crystallizing medium, but not if the mother liquor is replaced by water or an alkaline solution. This process occurs for both aluminosilicate and gallosilicate analogues of natrolite. In cross experiments, the disordered Al-containing (or Ga-containing) analogue is heated while in contact with the mother liquor of the opposite analogue, that is, the Ga-containing (or Al-containing) liquor. Therefore, strong evidence for the mechanism of the ordering process was obtained, which was thus proposed to proceed by intraframework migration of tetrahedral atoms without diffusion along the pores. Migration is first triggered, then fuelled by surface rearrangement through reactions with the mother liquor, and stops when an almost fully ordered state is attained. Classical dissolution-recrystallization and Ostwald ripening processes do not appear to be relevant for this phase transformation.