Egg white-derived peptides prevent cardiovascular disorders induced by mercury in rats: Role of angiotensin-converting enzyme (ACE) and NADPH oxidase.
The study aimed to investigate the effects of egg white hydrolysate (EWH) on vascular disorders induced by mercury (Hg). For this, male Wistar rats were treated for 60days: Untreated (saline, i.m.); Mercury (HgCl2, i.m., 1st dose 4.6μg/kg, subsequent doses 0.07μg/kg/day); Hydrolysate (EWH, gavage, 1g/kg/day); Hydrolysate-Mercury. Systolic (SBP) and diastolic (DBP) blood pressure measurement and vascular reactivity experiments in aorta were performed. We analyzed endothelial dependent and independent vasodilator responses and vasoconstrictor response to phenylephrine (Phe) in absence and presence of endothelium, a NOS inhibitor, a NADPH oxidase inhibitor, the superoxide dismutase, a non-selective COX inhibitor, a selective COX-2 inhibitor, an AT-1 receptors blocker. In situ superoxide anion production, SOD-1, NOX-4, p22phox, COX-2 and AT-1 mRNA levels and NOX-1 protein expression were performed in aorta while the determination of angiotensin converting enzyme (ACE) activity was measured in plasma. As results, EWH prevented the increase in SBP and Phe responses and the endothelial dysfunction elicited by Hg, which was related to decreased ACE activity and NOX activation by EWH and, subsequently, alleviated ROS production and improved NO bioavailability in aorta. In conclusion, EWH could be considered as alternative or complementary treatment tools for Hg-induced cardiovascular damage.


Development of the viscosity biosensor for the detection of DNase I based on the flow distance on the paper with DNA mucus.
Deoxyribonuclease I (DNase I) is a biomarker which has important applications in various biological processes. Thus, it is highly important to develop a user-friendly method for the detection of DNase I. Here, we present a paper-based distance sensor for the rapid detection of DNase I based on changes in the viscosity of DNA mucus. The viscosity of DNA mucus varies with different concentrations of DNase I, showing different water flow lengths on the pH test papers, this makes the quantification of DNase I possible. This method has a wide linear range (0.01-10 U/mL), excellent sensitivity, remarkable specificity and excellent reproducibility. The detection limit reaches 0.003 U/mL. Additionally, it can be well applied to detection of DNase I inhibitors, assay of DNase I in human serum and quality evaluation of nucleic acid scavengers. In general, this study offers a brief, convenient, label-free, and economical method to construct paper-based distance sensors using DNA mucus, which is very promising in the detection of DNase I in various applications.


Copper(II)-substituted horse liver alcohol dehydrogenase: structure of the minor species.
Oxygen treatment of horse liver alcohol dehydrogenase EE isozyme substituted with Cu(II) at the catalytic site leads to bleaching with concomitant reduction to Cu(I) of approximately 90% of total Cu(II). The Cu(II) of the remaining 'minor species' cannot be reduced nor does it interact with exogenous ligands, e.g. 2-mercaptoethanol, imidazole, pyrazole, or azide ions. The EPR spectrum is axial with a super-hyperfine splitting of 15.6 G indicating binding of one nitrogen atom to Cu(II). These data as well as the energies and intensities of the absorption and CD spectra suggest the Cu(II) ion of the minor species to be located in the catalytic site of HLADH in a position and geometry different from that of the major species.


Identifying the regional drivers of influenza-like illness in Nova Scotia, Canada, with dominance analysis.
The spread of viral pathogens is inherently a spatial process. While the temporal aspects of viral spread at the epidemiological level have been increasingly well characterized, the spatial aspects of viral spread are still understudied due to a striking absence of theoretical expectations of how spatial dynamics may impact the temporal dynamics of viral populations. Characterizing the spatial transmission and understanding the factors driving it are important for anticipating local timing of disease incidence and for guiding more informed control strategies. Using a unique data set from Nova Scotia, Canada, the objective of this study is to apply a new novel method that recovers a spatial network of the influenza-like viral spread where the regions in their dominance are identified and ranked. We, then, focus on identifying regional predictors of those dominant regions. Our analysis uncovers 18 key regional drivers among 112 regions, each distinguished by unique community-level vulnerability factors such as demographic and economic characteristics. These findings offer valuable insights for implementing targeted public health interventions and allocating resources effectively.


Synergistic Screening of Peptide-Based Biotechnological Drug Candidates for Neurodegenerative Diseases Using Yeast Display and Phage Display.
Peptide therapeutics are robust and promising molecules for treating diverse disease conditions. These molecules can be developed from naturally occurring or mimicking native peptides, through rational design and peptide libraries. We developed a new platform for the rapid screening of the peptide therapeutics for disease targets. In the course of the study, we aimed to employ our platform to screen a new generation of peptide therapeutic candidates against aggregation-prone protein targets. Two peptide drug candidates were screened for protein aggregation-prone diseases, namely, Parkinson's and Alzheimer's diseases. Currently, there are several therapeutic applications that are only effective in masking or slowing down symptom development. Nonetheless, different approaches are being developed for inhibiting amyloid aggregation in the secondary nucleation phase, which is critical for amyloid fibril formation. Instead of targeting secondary nucleated protein structures, we tried to inhibit the aggregation of monomeric amyloid units as a novel approach for halting the disease condition. To achieve this, we combined yeast surface display and phage display library platforms. We expressed α-synuclein, amyloid β40, and amyloid β42 on the yeast surface, and we selected peptides by using phage display library. After iterative biopanning cycles optimized for yeast cells, several peptides were selected for interaction studies. All of the peptides have been used for in vitro characterization methods, which are quartz crystal microbalance-dissipation (QCM-D) measurement, atomic force microscopy (AFM) imaging, dot-blotting, and ThT assay, and some of them have yielded promising results in blocking fibrillization. The rest of the peptides, although, interacted with amyloid units which made them usable as a sensor molecule candidate. Therefore, peptides selected by yeast surface display and phage display library combination are good choice for diverse disease-prone molecule inhibition, particularly those inhibiting fibrillization. Additionally, these selected peptides can be used as drugs and sensors to detect diseases quickly and halt disease progression.


Correlations of sialomucins and IgA in the maternal serum of primiparous and multiparous subjects at delivery.
Attention is drawn to correlations between placental coefficients and maternal serum levels of IgA at delivery in primiparae and multiparae. These correlations associate maternal serum IgA with gestational performance and appear to discriminate between groups which differ in that respect. Similar correlations exist between the placental coefficient and maternal serum seromucoid, with group discrimination preserved in primiparae, but not multiparae. Direct correlations between serum seromucoid and IgA in maternal serum can be attributed to their mutual dependence on the size and state of the feto-maternal interface, and may provide a means of detecting placental insufficiency in multigravidae.


Reconstitution of the lipid matrix of the outer membrane of gram-negative bacteria as asymmetric planar bilayer.
This paper is a report on the reconstitution of the lipid matrix of the outer membrane of Gram-negative bacteria as an asymmetric planar bilayer. This is the first time that a planar membrane is described, which consists on one side of a phospholipid (PL) mixture and on the other side of lipopolysaccharide (LPS). Therefore, strong emphasis is placed on a physical characterization of this membrane via its electrical properties. The membranes were prepared from spread monolayers or from vesicle-derived monolayers. Contrary to observations for symmetric phospholipid membranes, specific capacitances of (0.67 +/- 0.02) mu F.cm-2, breakdown voltages between 200 and 400 mV and specific conductances between 10(-8) and 2 x 10(-7) S.cm-2 were obtained independent of the preparation method. The LPS-containing membranes were stable up to 3 hr if they were formed and kept at temperatures above the hydrocarbon chain melting temperature of the LPS. For the specific capacitance, a dependence on the aperture radius was observed. This is explained by assuming a toroidal transition zone at the rim of the aperture. First results on the action of the pore-forming alpha-toxin from Staphylococcus aureus on bilayers of different composition demonstrate particular characteristics of this asymmetric bilayer system. The pore-formation rate is highest in symmetric phospholipid bilayers, considerably lower in asymmetric PL/LPS systems and fully inhibited in LPS/LPS systems.


MutS2 family protein from Pyrococcus furiosus.
MutS2 protein of Pyrococcus furiosus has been cloned and over-expressed. Initial characterization reveals that PfuMutS2 possesses a thermostable ATPase activity and a thermostable, nonspecific DNA binding activity. However, PfuMutS2 does not have any detectable mismatch-specific DNA binding activity. It is the first in vitro characterization of an MutS2 family protein.


Fibronectin promotes proplatelet formation in the human megakaryocytic cell line UT-7/TPO.
We investigated PPF (proplatelet formation) in the human megakaryocytic cell line UT-7/TPO in vitro and signal transduction pathways responsible for PPF. The megakaryocytic cell lines are useful for studying megakaryocyte biology, although PPF is induced only in the presence of phorbol ester. TPO (thrombopoietin) stimulates megakaryocyte proliferation and differentiation; however, no PPF occurred in the megakaryocytic cell lines, even after the addition of TPO. Therefore, factors other than TPO may play an important role in the process of PPF. As PPF occurs in the bone marrow in vivo, we noted extracellular matrix proteins and found that soluble FN (fibronectin) induced potent PPF in UT-7/TPO without phorbol ester. A Western blot analysis showed that the expression of integrins was not increased by FN treatment. Anti-β1 antibody and the RGD (arginine-glycine-aspartate) peptide inhibited FN-induced PPF. This result indicates that the signal originated from integrin β1, which is essential to inducing PPF in UT-7/TPO. Results of the experiments using several inhibitors suggest that activation of the MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase]-ERK and PI3K (phosphoinositide 3-kinase) pathways are necessary for PPF. The phosphorylation of ERK gradually increased for 2 h after the addition of soluble FN, which suggests that activation of ERK is essential for the initial induction of FN-induced PPF in UT-7/TPO. UT-7/TPO is a useful cell line that enables us to study the signals of PPF without effects of chemical compounds.


The novel trisubstituted pyran derivative D-142 has triple monoamine reuptake inhibitory activity and exerts potent antidepressant-like activity in rodents.
Major depression disorder is a significant health problem with 10-20% of all adults suffering from this disease. The underlying causes of depression are still unclear and 15% of depressed patients are resistant to all known therapies. Monoamine therapies have so far been the most successful approach for treating depression. Triple monoamine reuptake inhibitors have recently been implicated in generation of potent antidepressant activity while possibly exhibiting a low side-effect profile in addition to treating anhedonia. The additional, previously under-appreciated involvement of dopaminergic systems in depression prompted our efforts to develop novel asymmetric trisubstituted and disubstituted pyran derivatives as triple reuptake inhibitors. One of the lead compounds, D-142, exhibited uptake inhibition (K(i)) values of 29.3 nM, 14.7 nM and 59.3 ± 13.7 nM for norepinephrine, serotonin and dopamine transporters, respectively. Its affinity for serotonin transporter was comparable to fluoxetine, a well known SSRI. In the rat forced swimming test, compound D-142 exhibited potent antidepressant activity in the dose range tested (2.5, 5 and 10mg/kg) and was far more efficacious than the reference compound imipramine. In the mouse tail suspension test, compound D-142 reduced immobility in a dose (2.5, 5 and 10mg/kg) dependent manner, indicating a potent antidepressant effect. In locomotor activity tests, compound D-142 did not exhibit any stimulation in the same dose ranges. In the extended CNS receptors screening assay this molecule exhibited little or no non-specific interaction in the CNS, indicating high specificity for monoamine transporters. These results advance D-142 as a potential potent antidepressant.


Bone cadmium and lead in the ancient population from El Hierro, Canary Islands.
This study was performed to determine the levels of lead (Pb) and cadmium (Cd) in 63 bone samples of the prehispanic population of the island El Hierro, comparing them with the values obtained on 98 prehispanic samples from Tenerife, Fuerteventura, Gran Canaria, and La Palma, all of them in the Canary Islands, and with eight modern samples who served as controls. Prehispanic individuals from El Hierro showed the lowest bone Pb values of all the archipelago (0.72+/-1.01 mg/kg), significantly different (F=6.9, p<0.001) from the values obtained for the population of other islands such as Tenerife (4.87+/-5.36 mg/kg) or Fuerteventura (4.45+/-7.85 mg/kg) and also from those of the modern population (30.53+/-14.62 mg/kg). On the other hand, bone Cd, although slightly lower in the ancient population groups, was not significantly different when compared with the modern one. In addition, no differences were observed in bone Cd among the ancient population of the different islands. Bone lead but not cadmium kept an inverse significant relationship with the distance of the burial site both to south Spain (r=-0.31) and Atlantic Morocco (r=-0.28, p<0.001 in both cases).


The two Drosophila telomeric transposable elements have very different patterns of transcription.
The transposable elements HeT-A and TART constitute the telomeres of Drosophila chromosomes. Both are non-long terminal repeat (LTR) retrotransposons, sharing the remarkable property of transposing only to chromosome ends. In addition, strong sequence similarity of their gag proteins indicates that these coding regions share a common ancestor. These findings led to the assumption that HeT-A and TART are closely related. However, we now find that these elements produce quite different sets of transcripts. HeT-A produces only sense-strand transcripts of the full-length element, whereas TART produces both sense and antisense full-length RNAs, with antisense transcripts in more than 10-fold excess over sense RNA. In addition, features of TART sequence organization resemble those of a subclass of non-LTR elements characterized by unequal terminal repeats. Thus, the ancestral gag sequence appears to have become incorporated in two different types of elements, possibly with different functions in the telomere. HeT-A transcripts are found in both nuclear and cytoplasmic cell fractions, consistent with roles as both mRNA and transposition template. In contrast, both sense and antisense TART transcripts are almost entirely concentrated in nuclear fractions. Also, TART open reading frame 2 probes detect a cytoplasmic mRNA for reverse transcriptase (RT), with no similarity to TART sequence 5' or 3' of the RT coding region. This RNA could be a processed TART transcript or the product of a "free-standing" RT gene. Either origin would be novel. The distinctive transcription patterns of both HeT-A and TART are conserved in Drosophila yakuba, despite significant sequence divergence. The conservation argues that these sets of transcripts are important to the function(s) of HeT-A and TART.


Barriers for Nurses Providing Cancer Pain Management: A Qualitative Systematic Review.
Improperly managed pain can negatively affect physical and mental health, quality of life, and functional status of individuals with cancer. To address nurses' experiences with and barriers to providing cancer pain management, a systematic review was conducted. PubMed®, Embase®, Web of Science, CINAHL®, Cochrane Library, CNKI, VIP Chinese Science and Technology Periodicals Full-Text Database, Wanfang, and SINOMED databases were searched for articles published from database inception through August 2022. Two researchers independently evaluated the studies' quality, and meta-integration was performed using thematic synthesis. Eighteen qualitative studies, including 277 nurses from 11 different countries, were included in the review. The following three themes regarding nurses' barriers to providing cancer pain management were identified: (a) healthcare professional-related barriers, (b) patient-related barriers, and (c) organizational-related barriers. This systematic review provides an evidence-based reference for nurses to manage pain among individuals with cancer and develop appropriate interventions.


Anti-emetic principles of Magnolia obovata bark and Zingiber officinale rhizome.
Magnolol and honokiol, biphenyl compounds, were isolated as anti-emetic principles from the methanolic extract of Magnolia obovata bark. [6]-, [8]-, and [10]-shogaols and [6]-, [8]-, and [10]-gingerols were isolated from the methanolic extract of Zingiber officinale rhizome as anti-emetic principles. Some phenyl-propanoids with allyl side-chains were found to show the same activity. They inhibited the emetic action induced by the oral administration of copper sulfate pentahydrate to leopard and ranid frogs.


Vaccinia-rotavirus VP7 recombinants protect mice against rotavirus-induced diarrhoea.
Recombinant vaccinia viruses expressing wild type intracellular VP7 (VP7wt) from rotavirus SA11 or VP7sc, a cell surface-anchored variant, boosted antibody titres in SA11-immune mice. Pups born to these mice were protected from diarrhoea following challenge with SA11. In rotavirus-naive mice, two immunizations with recombinant vaccinia virus expressing VP7sc stimulated protective immunity that could be transferred to pups, whereas viruses expressing VP7wt did not stimulate protective immunity. Recombinant vaccinia viruses expressing intracellular or cell surface-anchored VP6, the rotavirus group-reactive antigen from the inner capsid, did not stimulate protective immunity. These experiments demonstrate that a live viral vector expressing cell surface anchored VP7 may represent a strategy for the development of safe, effective vaccines against rotavirus-induced diarrhoea.


Extracellular Vesicles: New Bullets to Fight Fungal Infections.
While behaving as a commensal yeast in healthy people, Candida albicans remains the deadliest fungal pathogen in immunocompromised patients. Halder et al. deciphered unprecedented immunomodulatory properties of monocyte extracellular vesicles in response to Candida infections, paving the way to consider therapeutic innovations for fungal infections but also inflammatory diseases.


Effects of septorhinoplasty on smell perception.
To assess whether significant changes in smell perception occur after septorhinoplasty, and evaluate whether septum deviation, allergic rhinitis, and surgical technique affect postoperative smell perception. Thirty-four patients (> 18 years old) awaiting septorhinoplasty were included, while those with previous severe hyposmia or anosmia were excluded. The participants self-assessed their smell perception using a 100-mm visual analogue scale (VAS), where 0 mm indicated the inability to smell and 100 mm indicated normal smell perception. The University of Pennsylvania Smell Identification Test (UPSIT) was applied before the procedure, and 4 and 12 weeks after surgery. The UPSIT score showed no significant changes at 4 (p = 0.59; 95% CI - 0.35 to + 2) or 12 weeks (p = 0.16; 95% CI - 1.13 to + 0.66). A comparison of the VAS scores before and 4 weeks after surgery (p = 0.62; 95% CI - 0.63 to + 0.39) yielded similar results. However, the average VAS scores improved 12 weeks after surgery (p = 0.007; 95% CI + 0.22 to + 1.30). Olfactory function, measured using the UPSIT, was not influenced by open or closed surgical techniques (p ≥ 0.10), the presence or absence of rhinitis (p ≥ 0.15), or obstructive septum deviation (p ≥ 0.38). Twelve weeks after surgery, self-evaluated smell perception was better in patients who underwent a closed procedure rather than an open procedure (p = 0.006; 95% CI: -1.39 to -0.37). A validated test demonstrates that septorhinoplasty does not compromise smell perception 4 and 12 weeks after surgery. However, it might improve smell perception by the self-report observation.


Protein engineering and electrochemical biosensors.
Protein engineered biosensors provide the next best step in the advancement of protein-based sensors that can specifically identify chemical substrates. The use of native proteins for this purpose cannot adequately embrace the limits of detection and level of stability required for a usable sensor, due to globular structure restraints. This review chapter attempts to give an accurate representation of the three main strategies employed in the engineering of more suitable biological components for use in biosensor construction. The three main strategies in protein engineering for electrochemical biosensor implementation are: rational protein design, directed evolution and de novo protein design. Each design strategy has limitations to its use in a biosensor format and has advantages and disadvantages with respect to each. The three design techniques are used to modify aspects of stability, sensitivity, selectivity, surface tethering, and signal transduction within the biological environment. Furthermore with the advent of new nanomaterials the implementation of these design strategies, with the attomolar promise of nanostructures, imparts important generational leaps in research for biosensor construction, based on highly specific, very robust, and electrically wired protein engineered biosensors.


The effect of sex hormones and tamoxifen on the growth of human gastric and colorectal cancer cell lines.
The authors studied the effect of serial concentrations of estradiol, 4-hydroxytamoxifen with estradiol, and 5-dihydrotestosterone on cell lines derived from human gastric and colorectal cancers. Significant stimulation of the gastric and 2 colorectal cell lines occurred at physiologic concentrations of estradiol. Addition of the active metabolite of the estrogen-receptor blocker/partial-agonist 4-hydroxytamoxifen had a stimulating effect on the growth rate of the gastric cell lines. The androgen, 5-dihydrotestosterone, had a modest inhibitory effect on the two gastric cell lines and two of the colorectal cell lines, and a stimulating effect on two further cell lines.


Patulin in grape must and new, still fermenting wine (Federweißer).
Extreme differences in temperature were anticipating a high mycotoxin contamination of the 2006 vintage. 96 samples of different grapes and must qualities of the producing region Mosel-Saar-Ruwer as well as Federweißer from retail sales were analyzed for patulin according to EN 14177, whereat the fermentation of the must was stopped by addition of sodium azide.


Clinical Utility of Circulating Tumor Cells in Patients With Esophageal Cancer.
As one of the most aggressive gastrointestinal tract cancers, esophageal carcinoma (EC) had the tenth morbidity and sixth mortality rate globally in 2020. This study was conducted to investigate whether circulating tumor cells (CTCs) could be used as diagnostic and prognostic tools for patients with EC. Peripheral blood samples were collected from 129 patients newly diagnosed with EC, 17 individuals with benign diseases, and 75 healthy donors for CTC analysis using the negative enrichment-fluorescence in situ hybridization (NE-FISH) approach. The relationship between CTCs (counts and karyotypes) and clinicopathological features was then investigated. Moreover, overall survival (OS) and progression-free survival (PFS) were analyzed to evaluate the predictive value of CTCs. The detection of CTCs using the NE-FISH approach helped in differentiating patients with EC from benign or healthy controls at a threshold of 2 per 3.2 ml peripheral blood with a sensitivity and specificity of 70.54% and 96.74%, respectively (area under the curve = 0.826, 95% CI 0.770-0.874, p < 0.001). The CTC count was associated with tumor depth (p = 0.012), but there was no correlation with other clinicopathological characteristics. Furthermore, the proportion of CTCs with chromosome 7 triploidy was linked to distant metastasis (p = 0.033) and TNM stage (p = 0.002). The OS was significantly shorter for patients with CTCs ≥ 3 than for those with CTCs < 3. Univariate analysis revealed that sex, vascular invasion, distant metastasis, tumor depth, lymph node metastasis, and TNM stage were the significant prognostic factors for patients with EC. Multivariate analysis demonstrated that distant metastasis (hazard ratio (HR) 3.262, 95% CI 1.671-6.369, p = 0.001 for PFS; HR 3.759, 95% CI 1.867-7.571, p < 0.001 for OS) was a significant prognostic factor for patients with EC. Detection of CTCs using NE-FISH could be helpful in the diagnosis of EC. The proportion of CTCs with chromosome 7 triploidy was related to distant metastasis and TNM stage. Patients with CTCs ≥ 3 had short OS, while distant metastasis was an independent factor indicating a poor prognosis for patients with EC.


Cardiac serum marker alterations after intraoperative radiotherapy with low-energy x-rays in early breast cancer as an indicator of possible cardiac toxicity.
To assess acute cardiac toxicity caused by intraoperative radiotherapy (IORT) with low-energy x‑rays for early breast cancer. We prospectively analyzed pre- and postoperative troponin I and NT-proBNP in 94 women who underwent breast-conserving surgery between 2013 and 2017 at the Department of Gynecology and Obstetrics of the University Medical Center Mannheim, Germany. Thirty-nine women received IORT using low-energy x‑rays during breast-conserving surgery while 55 patients without IORT formed the control group. Demographic and surgical parameters as well as cardiac markers were evaluated. There were no significant differences concerning age and side of breast cancer between the groups. Furthermore, no significant difference between the troponin I assays of the IORT and control groups could be found (preoperatively: 0.017 ± 0.006 ng/ml vs. 0.018 ± 0.008 ng/ml; p = 0.5105; postoperatively: 0.019 ± 0.012 ng/ml vs. 0.018 ± 0.010 ng/ml; p = 0.6225). N‑terminal fragment of B‑type natriuretic peptide (NT-proBNP) was significantly higher in the control group 24 h after surgery (preoperatively: 158.154 ± 169.427 pg/ml vs. 162.109 ± 147.343 pg/ml; p = 0.56; postoperatively: 168.846 ± 160.227 pg/ml vs. 232.527 ± 188.957 pg/ml; p = 0.0279). Troponin I levels as a marker of acute cardiac toxicity did not show any significant differences in patients who received IORT during breast-conserving surgery compared to those who did not.


Consumption of analgesics before a marathon and the incidence of cardiovascular, gastrointestinal and renal problems: a cohort study.
To prevent pain inhibiting their performance, many athletes ingest over-the-counter (OTC) analgesics before competing. We aimed at defining the use of analgesics and the relation between OTC analgesic use/dose and adverse events (AEs) during and after the race, a relation that has not been investigated to date. Prospective (non-interventional) cohort study, using an online questionnaire. The Bonn marathon 2010. 3913 of 7048 participants in the Bonn marathon 2010 returned their questionnaires. Intensity of analgesic consumption before sports; incidence of AEs in the cohort of analgesic users as compared to non-users. There was no significant difference between the premature race withdrawal rate in the analgesics cohort and the cohort who did not take analgesics ('controls'). However, race withdrawal because of gastrointestinal AEs was significantly more frequent in the analgesics cohort than in the control. Conversely, withdrawal because of muscle cramps was rare, but it was significantly more frequent in controls. The analgesics cohort had an almost 5 times higher incidence of AEs (overall risk difference of 13%). This incidence increased significantly with increasing analgesic dose. Nine respondents reported temporary hospital admittance: three for temporary kidney failure (post-ibuprofen ingestion), four with bleeds (post-aspirin ingestion) and two cardiac infarctions (post-aspirin ingestion). None of the control reported hospital admittance. The use of analgesics before participating in endurance sports may cause many potentially serious, unwanted AEs that increase with increasing analgesic dose. Analgesic use before endurance sports appears to pose an unrecognised medical problem as yet. If verifiable in other endurance sports, it requires the attention of physicians and regulatory authorities.


Inhibition by heparin of thrombin-catalyzed activation of the factor VIII-von Willebrand factor complex.
The activation of factor VIII (fVIII) by thrombin is associated with heavy chain cleavages at Arg372 and Arg740 and light chain cleavage at Arg1689. In a defined, plasma-free assay of fVIII activation and at physiological ionic strength and pH, heparin inhibited the rate of activation of either human or porcine fVIII by thrombin in either the presence or absence of von Willebrand factor (vWf). The inhibitory effect of heparin was associated with inhibition of all three thrombin-catalyzed bond cleavages. At plasma concentrations of fVIII (approximately 1 nM) and vWf (approximately 35 nM), the rate of fVIII activation was inhibited by 50% at approximately 0.1 unit/ml heparin, which is below the normal range of heparin concentrations in plasma during therapeutic anticoagulation (0.2-0.7 unit/ml). We propose that, in addition to catalyzing the inhibition of thrombin and other intrinsic pathway coagulation proteases by antithrombin, heparin functions as an anticoagulant by direct inhibition of the activation of the fVIII-vWf complex by thrombin.


Comparative evaluation of retreatment techniques by using different file systems from oval-shaped canals.
Endodontic failure resolves after complete removal of obturating material followed by disinfection, cleaning, shaping and three-dimensional obturation. Seventy single-rooted mandibular premolars, with single oval-shaped root canal were included. They were decoronated at a length of 16 mm from the apex. Shaping and cleaning were performed, and obturation was done using the warm lateral compaction technique. The teeth were divided into seven groups according to retreatment procedures (Hand files; ProTaper Universal retreatment files; MTwo® Retreatment system; R-Endo® Retreatment system; ProTaper Universal retreatment files with solvent and ultrasonics; MTwo® R with solvent, and ultrasonics and R-Endo® with solvent and ultrasonics). The data were obtained and subjected to the statistical analysis. All instrumentation techniques left obturating material with least in Group 6 and maximum Group 5. The mean time taken for complete retreatment procedure was minimum in Group 2 and maximum with Group 1. MTwo® R with solvent and ultrasonics, R-Endo®, and R-Endo® with solvent and ultrasonics were effective in gutta-percha removal from coronal third, middle third, and apical third, respectively. Significance: Nonsurgical endodontic retreatment using rotary files helps in gaining access to infected teeth. During retreatment procedure, this helps disinfectant to reach in critical areas of the root canal system, thereby decreasing the microbial load, leading to achieve healthy periradicular tissues.


Pioglitazone does not increase cerebral glucose utilisation in a murine model of Alzheimer's disease and decreases it in wild-type mice.
Clinical trials are in progress to test thiazolidinediones in neurodegenerative diseases such as Alzheimer's disease that involve deficiencies in brain glucose metabolism. While thiazolidinediones enhance glucose uptake in non-cerebral tissues, their impact on brain energy metabolism has not been investigated in vivo. We thus determined whether the thiazolidinedione pioglitazone reverses the decrease in cerebral glucose utilisation (CGU) in a model of brain metabolic deficiency related to Alzheimer's disease. Results are relevant to diabetes because millions of diabetic patients take pioglitazone as an insulin-sensitising drug, and diabetes increases the risk of developing Alzheimer's disease. The regional pattern of CGU was measured with the 2-deoxy [(14)C] glucose autoradiographic technique in adult awake mice overexpressing transforming growth factor beta1 (TGFbeta1), and in wild-type littermates. Mice were treated with pioglitazone for 2 months. Measurement of CGU in 27 brain regions confirmed that TGFbeta1 overexpression induced hypometabolism across the brain. Pioglitazone did not reverse the effect of TGFbeta1 overexpression and decreased regional CGU in control animals by up to 23%. The extent of the regional CGU decrease induced by pioglitazone, but not that induced by TGFbeta1, correlated strongly with basal CGU, suggesting that the higher the local metabolic rate the greater the reduction of CGU effected by pioglitazone. In contrast to its stimulatory effect in non-cerebral tissues, chronic treatment with pioglitazone decreases CGU in vivo. This evidence does not support the hypothesis that pioglitazone could act as a metabolic enhancer in Alzheimer's disease, and raises the question of how thiazolidinediones could be beneficial in neurodegenerative diseases.


Sphingomonas caeni sp. nov., a phenolic acid-degrading bacterium isolated from activated sludge.
A Gram-stain-negative, rod-shaped, polar flagellated or stalked and non-spore-forming bacterium, designated LB-2T, was isolated from activated sludge. Growth was observed at 20-30 °C (optimum 28 °C), pH 6.0-8.0 (optimum pH 7.0) and salinity of 0-0.5% (w/v; optimum 0.5%). Phylogenetic analysis based on the 16S rRNA gene indicated that strain LB-2T belongs to the genus Sphingomonas and showed the highest sequence similarity (96.7%) and less than 96.7% similarities to other type strains. The genome size of strain LB-2T was 4.10 Mb, with 66.8 mol% G + C content. The average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strains LB-2T and S. canadensis FWC47T were 77.8% and 21%, respectively. The predominant cellular fatty acids were summed feature 8 (C18:1ω7c and/or C18 : 1ω6c) and C16:0. The major polar lipids were aminolipid, glycolipid, sphingoglycolipid, phosphatidylcholine, phosphatidylglycerol, four unidentified lipids, glycophospholipid, phosphatidylethanolamine and diphosphatidylglycerol. The predominant respiratory quinone was Q-10 and the major polyamine was sym-homospermidine. On the basis of phenotypic, genotypic and phylogenetic evidences, strain LB-2T represents a novel species in the genus Sphingomonas, for which the name Sphingomonas caeni sp. nov. is proposed. The type strain is LB-2T (GDMCC 1.3630T = NBRC 115,102T).


Effect of dietary fatty acid composition on food intake, triglycerides, and hypothalamic peptides.
While a high-fat diet when compared to low-fat diet is known to produce overeating and health complications, less is known about the effects produced by fat-rich diets differing in their specific composition of fat. This study examined the effects of a high-fat diet containing relatively high levels of saturated compared to unsaturated fatty acids (HiSat) to a high-fat diet with higher levels of unsaturated fatty acids (USat). A HiSat compared to USat meal caused rats to consume more calories in a subsequent chow test meal. The HiSat meal also increased circulating levels of triglycerides (TG) and expression of the orexigenic peptides, galanin (GAL) in the hypothalamic paraventricular nucleus (PVN) and orexin (OX) in the perifornical lateral hypothalamus (PFLH). A similar increase in TG levels and PVN GAL and PFLH OX was also seen in rats given chronic access to the HiSat compared to USat diet, while neuropeptide Y (NPY) and agouti-related protein (AgRP) in the arcuate nucleus showed decreased expression. The importance of TG in producing these changes was supported by the finding that the TG-lowering medication gemfibrozil as compared to vehicle, when peripherally administered before consumption of a HiSat meal, significantly decreased the expression of OX, while increasing the expression of NPY and AgRP. These findings substantiate the importance of the fat composition in a diet, indicating that those rich in saturated compared to unsaturated fatty acids may promote overeating by increasing circulating lipids and specific hypothalamic peptides, GAL and OX, known to preferentially stimulate the consumption of a fat-rich diet.


Addition of sulphonylurea to metformin does not relevantly change body weight: a prospective observational cohort study (ZODIAC-39).
To investigate changes in body weight trajectories after the addition of individual sulphonylureas (SUs) to metformin in patients with type 2 diabetes. We conducted a retrospective observational cohort study, in a primary care setting in the Netherlands. Patients aged ≥18 years with type 2 diabetes who were included in the ZODIAC cohort between 1998 and 2012 and who received metformin monotherapy at inclusion (n = 29 195), and had used metformin as monotherapy for at least 1 year before receiving dual therapy through the addition of an SU for at least 1 year were eligible for inclusion. The primary outcome was within-drug yearly change in body weight after receiving add-on therapy with individual SUs during 5 years of follow-up. The secondary outcome was within-drug yearly change in glycated haemoglobin (HbA1c). Annual changes in weight and HbA1c were estimated with linear mixed models, adjusted for age, gender and diabetes duration. A total of 2958 patients were included. No significant weight changes were observed within and between any of the individual SUs after treatment intensification (p = 0.24). In addition, no significant difference in weight between the add-on therapy combinations was observed (p = 0.26). The average HbA1c the year before intensification was 7.2% (55 mmol/mol) and dropped below 7.0% (53 mmol/mol) the year after. In patients with type 2 diabetes treated in primary care, strict glycaemic control can be maintained with SUs used as add-on therapy to metformin, without the offset of relevant weight changes.


Preferential Mobilization of Colonic Hepatic Flexure Facilitates Pancreaticoduodenectomy Procedures.
Several studies recommend that colonic hepatic flexure (CHF) should be mobilized preliminarily in minimally invasive pancreaticoduodenectomy (PD). However, there are little data to support that preferential mobilization of the CHF can positively affect the perioperative events of PD. We aimed to assess the effect of preferential mobilization of the CHF in PD. A retrospective cohort study of patients who underwent PD was performed between 2016 and 2019. Clinical characteristics, operative data, and postoperative surgical complications were recorded. The study included 668 patients; 486 patients underwent open pancreaticoduodenectomy (OPD) and 182 patients underwent laparoscopic pancreaticoduodenectomy (LPD). Patients were divided into CHF-M (OPD, n=129; LPD, n=95) and conventional (OPD, n=357; LPD, n=87) groups according to preferential CHF mobilization. There were no differences between the groups regarding most demographics. Within patients who underwent OPD, decreased estimated blood loss (EBL) (251.2±146.4 vs. 307.3±173.5 mL, P<0.05) was observed in CHF-M group. Within patients who underwent LPD, operative time (328.7±66.3 vs. 406.5±85.5 min, P<0.001), EBL (166.8±96.4 vs. 271.8±130.7 mL, P<0.001), the incidence of clinically relevant pancreaticfistula (7.4% vs. 23.0%, P<0.05), and length of stay (12.3±5.1 vs. 16.0±7.4 d, P<0.05) were decreased in CHF-M group. Moreover, patients with high body mass index who underwent LPD showed more significant differences in operative time (336.0±67.7 vs. 431.9±79.1, P<0.001) and EBL (179.6±97.8 vs. 278.2±135.6, P<0.001) between groups. We first demonstrated that preferential mobilization of the CHF can facilitate PD. The patients who underwent minimally invasive surgery and the patients with high body mass index may benefit more from this technique.


Brief review of the recently described short QT syndrome and other cardiac channelopathies.
There are many diseases related to ion-channel disorders, so-called "channelopathies." Hereditary short QT syndrome is a clinical-electrocardiographic entity with autosomal-dominant mode of transmission and it is the most recently described channelopathy. The syndrome may affect infants, children, or young adults with strong positive family background of sudden cardiac death. Short QT syndrome is characterized by short QT and heart-rate-corrected QTc intervals. It is frequently associated with tall-, peaked-, and narrow-based T waves that are reminiscent of the typical "desert tent" T waves of hyperkalemia. There is a high tendency for paroxysmal atrial fibrillation due to the heterogeneous abbreviation of action potential duration and refractoriness of atrial myocytes. The arrhythmia can also be induced by programmed electrical stimulation. The safest treatment suggested is an implantable cardioverter defibrillator, though the possibilities of inappropriate shocks have caused some concern, especially in teenagers. The ability of quinidine to prolong the QT interval has the potential to be an effective therapy for patients with short QT syndrome. This is particularly important in developing countries, where the implantable cardioverter-defibrillator therapy is not always available. Since these patients are at risk of sudden cardiac death from birth, and implantable cardioverter-defibrillator implantation has a lot of limitations in very young children, the utility of quinidine has to be evaluated further. Clinicians need to be aware of this deadly electrocardiographic (ECG) pattern as it portends a high risk of sudden cardiac death in otherwise healthy subjects with structurally normal hearts.


Bioreduction performance of Cr(VI) by microbial extracellular polymeric substances (EPS) and the overlooked role of tryptophan.
Extracellular polymeric substances (EPS) have exhibited promising advantages in mitigating heavy metal contamination, e.g., single-valent silver (Ag(I)), trivalent gold (Au(III)), and hexavalent chromium (Cr(VI)). However, knowledge of the specific substrate in EPSs that supports Cr(VI) reduction has remained elusive. Here, we isolated a novel Cr(VI)-reducing strain with self-mediating properties in an aquatic environment with various pH values to investigate the mechanisms. After analysis by a batch assay coupled with X-ray photoelectron spectroscopy (XPS), electron paramagnetic resonance (EPR), and scanning electron microscopy-energy dispersive spectrometry (SEM-EDS) spectroscopic techniques, it was found that Cr(VI) was reduced by the strain and soluble-EPS (S-EPS), and then, organo-trivalent chromium (organo-Cr(III)) was successfully formed. In addition, compared with other components of the strain, the strain and S-EPS completely removed Cr(VI), and the S-EPS exhibited a positive effect on Cr(VI) reduction with a strong monotonic correlation (R2 = 0.999, p = 9.03 × 10-5), indicating that the reduction is an EPS-dependent process. Specifically, the Cr(VI) reduction efficiency was enhanced to 48.85% and 99.4% after EPS and EPS plus tryptophan were added; their respective efficiencies were 3.94 and 8.02 times higher than that of the control assay in which the reductant was depleted. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) analysis showed that the tryptophan concentration concomitantly decreased by 61.54%. These findings highlighted the importance of S-EPS and tryptophan and improved our understanding of EPS for Cr(VI) reduction, which might provide a novel strategy for decontaminating targeted heavy metals in future applications.


Beneficial compaction of spinal cord lesion by migrating astrocytes through glycogen synthase kinase-3 inhibition.
The migratory response of astrocytes is essential for restricting inflammation and preserving tissue function after spinal cord injury (SCI), but the mechanisms involved are poorly understood. Here, we observed stimulation of in vitro astrocyte migration by the new potent glycogen synthase kinase-3 (GSK-3) inhibitor Ro3303544 and investigated the effect of Ro3303544 administration for 5 days following SCI in mice. This treatment resulted in accelerated migration of reactive astrocytes to sequester inflammatory cells that spared myelinated fibres and significantly promoted functional recovery. Moreover, the decreased extent of chondroitin sulphate proteoglycans and collagen IV demonstrated that scarring was reduced in Ro3303544-treated mice. A variety of in vitro and in vivo experiments further suggested that GSK-3 inhibition stimulated astrocyte migration by decreasing adhesive activity via reduced surface expression of β1-integrin. Our results reveal a novel benefit of GSK-3 inhibition for SCI and suggest that the stimulation of astrocyte migration is a feasible therapeutic strategy for traumatic injury in the central nervous system.


A hypothesis for the etiology of interstitial cystitis based upon inhibition of bladder epithelial repair.
Interstitial cystitis (IC) is a chronic bladder disease characterized by distinct bladder mucosal abnormalities, for which the etiology is unknown. Although the epidemiology of this disorder is similar to that of bacterial cystitis, prospective studies using sensitive culture techniques and polymerase chain reaction assay for a variety of microorganisms have failed to identify a specific infectious etiology for IC. We have identified a low-molecular-weight peptide in the urine of IC patients that inhibits the proliferation of normal bladder epithelial cells in vitro. We therefore propose a model of IC, in which this peptide inhibits bladder epithelial regeneration following damage (such as that caused by bacterial cystitis). The chronically damaged epithelium is prone to colonization with various microorganisms, and the resulting exposure to these microorganisms, other urinary antigens, and/or damaged epithelial cells prompts the low-level inflammatory response commonly seen in this disorder.


Role of physical activity as a secondary intervention for healed myocardial infarction.
Five exercise clinical trials were conducted to determine the effectiveness of physical activity on selected outcomes, especially mortality and morbidity rates, in patients recovered from myocardial infarction. Although the design of every trial differed, each evaluated the effects of medically prescribed and supervised regular physical activity. In 3 studies there were substantially lower mortality rates in the exercise patients compared with control patients, but statistically significant differences occurred in only 1 of the 3 trials. No differences between treated and control patients were observed in another trial. In the fifth trial, a slight excess mortality rate was reported for the treatment group. However, both groups in this trial were assigned to an exercise regimen in which only the frequency of attendance and intensity of regimen differed. Although regular physical activity tended to reduce mortality rates in the first 3 trials, it is apparent that it did not affect recurrence rates of nonfatal myocardial infarction. In fact, this condition generally occurred more frequently in treated than in control patients. It is clear that more clinical investigations are required before a definitive statement confirming the effectiveness of regular physical activity as a secondary intervention for myocardial infarction can be made.


Ultrasensitive electrochemical sensor for p-nitrophenyl organophosphates based on ordered mesoporous carbons at low potential without deoxygenization.
p-Nitrophenyl organophosphates (OPs) including paraoxon, parathion and methyl parathion, etc, are highly poisonous OPs, for which sensitive and rapid detection method is most needed. In this work, an ultrasensitive electrochemical sensor for the determination of p-nitrophenyl OPs was developed based on ordered mesoporous carbons (OMCs) modified glassy carbon electrode (GCE) (OMCs/GCE). The electrochemical behavior and reaction mechanism of p-nitrophenyl OPs at OMCs/GCE was elaborated by taking paraoxon as an example. Experimental conditions such as buffer pH, preconcentration potential and time were optimized. By using differential pulse voltammetry, the current response of the sensor at -0.085 V was linear with concentration within 0.01-1.00 μM and 1.00-20 μM paraoxon. Similar linear ranges of 0.015-0.5 μM and 0.5-10 μM were found for parathion, and 0.01-0.5 μM and 0.5-10 μM for methyl parathion. The low limits of detection were evaluated to be 1.9nM for paraoxon, 3.4 nM for parathion and 2.1 nM for methyl parathion (S/N=3). Common interfering species had no interference to the detection of p-nitrophenyl OPs. The sensor can be applicable to real samples measurement. Therefore, a simple, sensitive, reproducible and cost-effective electrochemical sensor was proposed for the fast direct determination of trace p-nitrophenyl OPs at low potential without deoxygenization.


Nuclear magnetic resonance analysis of solution conformations in C4-V3 hybrid peptides derived from human immunodeficiency virus (HIV) type 1 gp120: relation to specificity of peptide-induced anti-HIV neutralizing antibodies.
Immunogenic peptides containing epitopes of the gp120 C4 and V3 regions from human immunodeficiency virus strains MN and EV91 have been studied by nuclear magnetic resonance and molecular modeling and used as immunogens in rhesus monkeys. The results, combined with those for other peptides, suggest a correlation between solution conformation and immunologic cross-reactivity.


Ambulatory blood pressure monitoring in pheochromocytoma - paraganglioma: A single center experience.
Pheochromocytoma and paraganglioma (PPGL) are rare tumors, and data on ambulatory blood pressure monitoring (ABPM) in these patients and the effect of blocking on ABPM parameters is limited. We aimed to describe ABPM parameters in a cohort of PPGL at our center in western India. Retrospective study of patients with PPGL whose ABPM data was available. Demographic details, secretory status, and ABPM data were retrieved. Coefficient of variability (CV) was calculated as standard deviation/mean in percentage. In the 39 included patients, mean age at presentation was 39.3 ± 14.2 yr; 20 (51.3%) were males, 25 (64.1%) hypertensive, and mean tumor diameter was 5.3 cm. In 18 patients whose baseline ABPM was done without medications, those with nocturnal blood pressure dipping (6/18, 33%) had higher serum metanephrines (median 313.2 vs. 34.7 pg/ml, P = 0.028). Despite normal office blood pressure (BP), 8.9% of systolic BP readings were >140 mmHg, and 1.2% were >160 mmHg. Among 29 patients with both pre and post-block ABPM, mean BP (systolic 121.6 vs. 132.5 mmHg, P = 0.014; diastolic 68.9 vs. 76.4 mmHg, P = 0.005) and percentage of BP readings above 140 mmHg (median 9.4% vs. 24.4%, P = 0.016) were significantly lowered after the preoperative blockade in hypertensive (n = 19) patients, whereas CV was similar. The post-blockade ABPM characteristics were similar in patients blocked with amlodipine or prazosin. ABPM provides additional information about BP characteristics in PPGL. The preoperative blocking decreases the magnitude of BP excursions but does not affect BP variability.


Concepts from paediatric extracorporeal membrane oxygenation for adult intensivists.
Over the last 5 years, there has been a dramatic increase in the use of extracorporeal membrane oxygenation (ECMO) in adult patients with severe respiratory or cardiac failure. This contrasts to the use of the technology in neonatal and paediatric intensive care units, where it has been regarded as a standard of care for a number of conditions for over 25 years. Many innovations in ECMO circuitry or clinical management evolve first in one particular discipline and it may be helpful for individual clinicians to keep abreast of developments in ECMO across the entire age range, from neonatology to older adults. This review addresses nine concepts in ECMO that are better studied or established in paediatric medicine and considers their application in adult patients.


Classification of pulmonary sounds through deep learning for the diagnosis of interstitial lung diseases secondary to connective tissue diseases.
Early diagnosis of interstitial lung diseases secondary to connective tissue diseases is critical for the treatment and survival of patients. The symptoms, like dry cough and dyspnea, appear late in the clinical history and are not specific, moreover, the current approach to confirm the diagnosis of interstitial lung disease is based on high resolution computer tomography. However, computer tomography involves x-ray exposure for patients and high costs for the Health System, therefore preventing its use for a massive screening campaign in elder people. In this work we investigate the use of deep learning techniques for the classification of pulmonary sounds acquired from patients affected by connective tissue diseases. The novelty of the work consists of a suitably developed pre-processing pipeline for de-noising and data augmentation. The proposed approach is combined with a clinical study where the ground truth is represented by high resolution computer tomography. Various convolutional neural networks have provided an overall accuracy as high as 91% in the classification of lung sounds and have led to an overwhelming diagnostic accuracy in the range 91%-93%. Modern high performance hardware for edge computing can easily support our algorithms. This solution paves the way for a vast screening campaign of interstitial lung diseases in elder people on the basis of a non-invasive and cheap thoracic auscultation.


Long-term Effectiveness of Adjuvant Treatment With Catechol-O-Methyltransferase or Monoamine Oxidase B Inhibitors Compared With Dopamine Agonists Among Patients With Parkinson Disease Uncontrolled by Levodopa Therapy: The PD MED Randomized Clinical Trial.
Many people with Parkinson disease (PD) develop motor complications that are uncontrolled by levodopa dose adjustment. Among these patients, it is uncertain which drug class is more effective as adjuvant therapy. To compare the long-term effects on patient-rated quality of life of adding a dopamine agonist vs a dopamine reuptake inhibitor (DRI), either a monoamine oxidase type B (MAO-B) inhibitor or a catechol-O-methyltransferase (COMT) inhibitor, to levodopa therapy for the treatment of patients with motor complications of PD. This pragmatic semifactorial (2 × 1) randomized clinical trial recruited from 64 neurology and geriatric clinics (62 in the United Kingdom, 1 in the Czech Republic, and 1 in Russia) between February 23, 2001, and December 15, 2009. A total of 500 patients with idiopathic PD who developed uncontrolled motor complications and did not have dementia were randomly assigned on a 1:1:1 basis using a computerized minimization program. Data were analyzed between 2017 and 2020. Open-label dopamine agonist, MAO-B inhibitor, or COMT inhibitor. Primary outcomes were scores on the 39-item Parkinson's Disease Questionnaire (PDQ-39) mobility domain and cost-effectiveness. Outcomes were assessed before study entry, at 6 and 12 months after randomization, and annually thereafter. Repeated-measures and log rank analyses were used in an intention-to-treat approach. Among 500 participants, the mean (SD) age was 73.0 (8.2) years; 314 participants (62.8%) were men. Over a median of 4.5 years (range, 0-13.3 years) of follow-up, the participants in the dopamine agonist group had a mean PDQ-39 mobility score that was 2.4 points (95% CI, -1.3 to 6.0 points) better than that of the combined MAO-B and COMT groups; however, this difference was not significant (P=.20). With regard to DRIs, participants in the MAO-B group had mean PDQ-39 mobility scores that were 4.2 points (95% CI, 0.4-7.9 points; P=.03) better than those of the COMT group and EuroQol 5-dimension 3-level (EQ-5D-3L) utility scores that were 0.05 points (95% CI, 0.003-0.09 points; P=.04) better than the COMT group. Nonsignificant improvements were found in the PDQ-39 summary index (mean difference, 2.2 points; 95% CI, -0.2 to 4.5 points; P=.07) along with nonsignificant reductions in dementia (rate ratio [RR], 0.70; 95% CI, 0.47-1.03; P = .07) and mortality (RR, 0.76; 95% CI, 0.56-1.03; P=.07). When dopamine agonists were compared with MAO-B inhibitors only, the outcomes were similar. In this study, patient-rated quality of life was inferior when COMT inhibitors were used as adjuvant treatment compared with MAO-B inhibitors or dopamine agonists among people with PD who experienced motor complications that were uncontrolled by levodopa therapy. The MAO-B inhibitors produced equivalent disease control, suggesting that these agents may be underused as adjuvant therapy. isrctn.org Identifier: ISRCTN69812316; EU Clinical Trials Register Identifier: 2005-001813-16.


Detection of Virus-Antibody Immune Complexes in Secondary Dengue Virus Infection.
It has been reported that virus-antibody immune complexes formed during secondary dengue virus infection are associated with increased disease severity. Here, we describe the details of a plaque titration method that uses FcγR -expressing BHK cells to detect and quantify infectious virus-immune complexes and a quantitative real-time PCR method for the quantification of virus genome in patients with secondary dengue infection. These methods detect both viruses in free-form and in immune complexes in patients with dengue infection, and are useful for determining viremia levels and patterns that better reflect in vivo conditions.


The use of gonadotropins for the induction of ovulation in women with polycystic ovarian disease.
Ten infertile patients with polycystic ovarian disease were treated with 18 cycles of "pure" human pituitary follicle-stimulating hormone (HP-FSH) and 10 cycles of human menopausal gonadotropin (HMG) consisting of FSH and luteinizing hormone (LH) in a 1:1 ratio. Human chorionic gonadotropin was used to trigger ovulation when optimal follicular development was achieved as judged by urinary estrogen determinations. Of the 18 cycles utilizing HP-FSH, 14 were presumptively ovulatory, 2 were conceptual, and in 5 cycles ovarian enlargement was noted. Of the 10 HMG cycles, none was ovulatory, no conceptions resulted, and 6 instances of hyperstimulation were noted. Pretreatment serum LH levels were significantly higher than normal follicular phase values. These observations suggest that endogenous LH levels in patients with polycystic ovaries are quite adequate for follicular development so that the administration of exogenous LH is unwarranted. Furthermore, the data suggest that HP-FSH or low-LH-containing HMG may prove to be an additional safe and effective nonsurgical treatment modality for patients who are anovulatory because of polycystic ovaries.


Metformin improves anxiety-like behaviors through AMPK-dependent regulation of autophagy following transient forebrain ischemia.
Stroke is one of the main threats to the public health worldwide. Metformin, an anti-diabetic drug, is an activator of AMP-activated protein kinase (AMPK). Metformin plays an important role on improving behavior in neurodegenerative diseases through diverse pathways. In the current study we aimed to investigate the probable effects of metformin on anxiety and autophagy pathway in global cerebral ischemia. Rats were divided into seven groups; Sham, ischemia (I/R), metformin (met), compound c (CC), CC+ischemia, met+ischemia, met+CC+ischemia. Metformin was pretreated for 2 weeks and CC administrated half an hour before global cerebral ischemia. Blood glucose, body weight, sensorimotor scores, elevated plus maze and open field test were evaluated after ischemia. Autophagy related factors were measured by Western blot and immunofluorescent assay in hippocampus of rats. Based on our results, pretreatment of rats by metformin improved sensory motor signs, anxiolytic behavior and locomotion in ischemic rats. CC injection in I/R rats attenuated the therapeutic effects of metformin. Autophagy factors such as light chain 3B, Atg7, Atg5-12 and beclin-1 decreased in ischemic rats compared to the sham group (P < 0.001 in all proteins). Level of autophagic factors increased in metformin pretreated rats compared to global cerebral ischemia (P < 0.001 in all proteins). These data indicated that the beneficial role of metformin in behavior and autophagy flux mediates via AMPK. Our results recommended that metformin therapy could improve psychological disorders and movement disability following I/R and profound understanding of AMPK-dependent autophagy would enhance its development as a promising target for intracellular pathway.


Fatal drug-induced heat stroke.
In the case reported, fatal hyperpyrexia resulted from massive doses of chlorpromazine combined with benztropine mesylate given to a paranoid schizophrenic admitted for increased psychotic symptoms. Phenothiazines disturb the thermoregulatory mechanism and also exert anticholinergic effects peripherally, including sweating. The goal of treatment of drug-induced hyperpyrexia is to reduce oxygen demand and core temperature. Ice water soaked towels, fanning, thermal blanket, or immersion in an ice bath can be used. Oxygenation will help combat further tissue anoxia. Severe acidosis may be present and must be corrected with sodium bicarbonate after arterial pH determination. Vasoconstrictors should be avoided if shock is present.


Roughness and wettability effect on histological and mechanical response of self-drilling orthodontic mini-implants.
Self-drilling orthodontic mini-implants can be used as temporary devices for orthodontic treatments. Our main goal was to evaluate surface characteristics, roughness and wettability, of surface modified mini-implants to increase their stability during orthodontic treatment without inducing bone fracture and tissue destruction during unscrewing. Modified mini-implants by acid etching, grit-blasting and its combination were implanted in 20 New Zealand rabbits during 10 weeks. After that, the bone-to-implant (BIC) parameter was determined and the torque during unscrewing was measured. The surface characteristics, roughness and wettability, were also measured, onto modified Ti c.p. discs. Acid-etched mini-implants (R a ≈ 1.7 μm, contact angle (CA) ≈ 66°) significantly improved the bone-to-implant parameter, 26 %, compared to as-machined mini-implants (R a ≈ 0.3 μm, CA ≈ 68°, BIC = 19 %) due to its roughness. Moreover, this surface treatment did not modify torque during unscrewing due to their statistically similar wettability (p > 0.05). Surface treatments with higher roughness and hydrophobicity (R a ≈ 4.5 μm, CA ≈ 74°) lead to a greater BIC and to a higher removal torque during unscrewing, causing bone fracture, compared to as-machined mini-implants. Based on these in vivo findings, we conclude that acid-etching surface treatment can support temporary anchoring of titanium mini-implants. This treatment represents a step forward in the direction of reducing the time prior to mini-implant loading by increasing their stability during orthodontic treatment, without inducing bone fracture and tissue destruction during unscrewing.


The second generation and asthma: Prevalence of asthma among Israeli born children of Ethiopian origin.
Immigrant populations moving from undeveloped countries with low asthma prevalence have shown increased asthma prevalence in their new Westernized environment. We compared the prevalence of asthma among Israeli born children of Ethiopian origin to that in non-Ethiopian children. Cross sectional study. Data was retrieved for children aged 6-18 years in four clinics with a large proportion of patients of Ethiopian origin. For each Israeli born child from Ethiopian origin we matched an Israeli born child of any other origin of the same age and gender, receiving primary care from the same physician at the same clinic. Asthma was defined as any visit to a primary care physician, emergency room or hospitalization related to asthma symptoms or subsequent purchasing of any asthma medication during 2008. 1217 children of Ethiopian origin and 1217 matched controls were studied. More Ethiopian children came from families with a low socioeconomic status (23.9% vs. 17%, p < 0.001), and with significantly lower parental smoking (5.1% vs. 40.1%, p < 0.001). The prevalence of asthma was 92/1217 (7.5%) among children of Ethiopian origin, compared to 122/1217 (10.0%) among the control group (OR = 0.74, 95% CI: 0.56-0.98, p = 0.032). When adjusted for tobacco exposure, the OR for risk of asthma in the Ethiopian children was 0.80 (95% CI: 0.59-1.09, p = 0.16). Asthma prevalence in the second generation of Israeli born children of Ethiopian origin does not seem to differ from other children in their community. This observation supports the theory that environmental exposures, rather than genetic factors, dictated the increase in asthma in this immigrant population.


In Search of HIV Entry Inhibitors Using Molecular Docking, ADME, and Toxicity Studies of Some Thiazolidinone-Pyrazine Derivatives Against CXCR4 Co-receptor.
Entry inhibitors prevent the binding of human immunodeficiency virus protein to the chemokine receptor CXCR4 and are used along with conventional anti-HIV therapy. They aid in restoring immunity and can prevent the development of HIV-TB co-infection. In the present study, various thiazolidinone-pyrazine derivatives earlier studied for NNRT inhibition activity were gauged for their entry inhibitor potential. The objective of the study is to perform molecular docking, ADME, toxicity studies of some thiazolidinone-pyrazine derivatives as entry inhibitors targeting CXCR4 co-receptors. In-silico docking studies were performed using AutoDock Vina software and compounds were further studied for ADME and toxicity using SwissADME and pkCSM software, respectively. Taking into consideration the docking results, pharmacokinetic behaviour and toxicity profile, four molecules (compounds 1, 9, 11, and 16) have shown potential as entry inhibitors. These compounds have shown potential as both NNRTI and entry inhibitors and hence can be used in management of immune compromised diseases like TB-HIV coinfection.


The premarket assessment of the cost-effectiveness of a predictive technology "Straticyte™" for the early detection of oral cancer: a decision analytic model.
Approximately half of oral cancers are detected in advanced stages. The current gold standard is histopathological assessment of biopsied tissue, which is subjective and dependent on expertise. Straticyte™, a novel prognostic tool at the pre-market stage, that more accurately identifies patients at high risk for oral cancer than histopathology alone. This study conducts an early cost-effectiveness analysis (CEA) of Straticyte™ and histopathology versus histopathology alone for oral cancer diagnosis in adult patients. A decision-analytic model was constructed after narrowing the scope of Straticyte™, and defining application paths. Data was gathered using the belief elicitation method, and systematic review and meta-analysis. The early CEA was conducted from private-payer and patient perspectives, capturing both direct and indirect costs over a five-year time horizon. One-way and probabilistic sensitivity analyses were conducted to investigate uncertainty. Compared to histopathology alone, histopathology with Straticyte™ was the dominant strategy, resulting in fewer cancer cases (31 versus 36 per 100 patients) and lower total costs per cancer case avoided (3,360 versus 3,553). This remained robust when Straticyte™ was applied to moderate and mild cases, but became slightly more expensive but still more effective than histopathology alone when Straticyte™ was applied to only mild cases. The probabilistic and one-way sensitivity analyses demonstrated that incorporating Straticyte™ to the current algorithm would be cost-effective over a wide range of parameters and willingness-to-pay values. This study demonstrates high probability that Straticyte™ and histopathology will be cost-effective, which encourages continued investment in the product. The analysis is informed by limited clinical data on Straticyte™, however as more data becomes available, more precise estimates will be generated.


Effect of Frequency of Platelet Apheresis on Coagulation Function in Donors: A Prospective Cohort Study.
The maximum number of plateletpheresis donation was permitted up to 24 times every year for each donor in China. This study was investigated the effect of donation frequency on coagulation function of the plateletpheresis donors. A total of 96 plateletpheresis regular donors (splitted into A, B, C groups with 32 donors each group. A was 6-11 times donations, B with 12-17 times and C with 18-24 times) and 32 first time plateletpheresis donors (D group) were analyzed. The coagulation reaction time (R), blood clot formation time (K), α-Angle, normal maximum amplitude (MA) were tested using thromboelastography instrument. Platelet (PLT) count was measured using a hematology analyzer. The ratio of the male to female were 23:9, 24:8, 27:5 and 24:8, the mean age were 40.7 ± 7.6, 39.8 ± 8.3, 40.2 ± 7.9 and 37.0 ± 9.3, and the platelet collection amount were 1.55 ± 0.37 U, 1.58 ± 0.38 U, 1.61 ± 0.33 U and 1.46 ± 0.31 U in the A, B, C, D groups respectively. There were significant difference in the values of the R, K, α-Angle, MA and PLT count between before and after plateletpheresis donation in each group (p < 0.05). However, the values of R, K, α-Angle, MA and PLT count in the before donation were not difference among the A, B, C, D groups (p > 0.05). Similar results were found in the after plateletpheresis donation. The number of the PLT was significantly correlated with the values of the R, K, α-Angle and MA (p < 0.05). However, the frequency of plateletpheresis were not significantly correlated with R, k, α and MA parameters (p > 0.05) using Spearman correlation analysis. The regular donation of apheresis platelets and the frequency of annual blood donation had no adverse effect upon coagulation function of the donors in China.


Alterations in Preterm Brain Development: Relation to Developmental Assessment and Prediction.
Infants born extremely preterm are at risk for compromised cognitive and motor outcome. There are various possibilities as to why this occurs. The "two-hit" hypothesis consists of interrelated developmental disruptions and insults. Both specifically affect the transient subplate neuronal layer (SNL) and the early development of brain circuitry. The SNL, analogous to a switchboard, is critical in connecting cortical and lower brain centers and is highly susceptible to disruptions and insults, producing dysfunctional neural networks. Damage to the SNL provides the putative link between atypical early brain development and later cognitive and academic function that require complex neural circuitry. This, in turn, has major ramifications for developmental assessment and prediction. KEY POINTS: · Preterm brains are highly susceptible to disruptions and insults, this being the two-hit hypothesis.. · There is a variation in which low-grade stressors "sensitize" the infant increasing susceptibility to a second stressor-causing brain damage.. · Subplate neuronal layer damage compromises outcome by interfering with thalamocortical connections.. · Combining neuroimaging and developmental testing is the best way to gain insight into these processes.. · Atypical early brain development may not be evident until the network is mature and challenged..


Angiographic outcomes following stenting or coronary artery bypass surgery of the left main coronary artery: fifteen-month outcomes from the synergy between PCI with TAXUS express and cardiac surgery left main angiographic substudy (SYNTAX-LE MANS).
The SYNTAX-LE MANS substudy prospectively evaluated 15-month angiographic and clinical outcomes in patients with treated left main (LM) disease. In the SYNTAX trial, 1,800 patients with three-vessel and/or LM disease were randomised to either CABG or PCI; of these, 271 LM patients were prospectively assigned to receive a 15-month angiogram. The primary endpoint for the CABG arm was the ratio of ≥50% to <100% obstructed/occluded grafts bypassing LM lesions to the number placed. The primary endpoint for the PCI arm was the proportion of patients with ≤50% diameter stenosis ('patent' stents) of treated LM lesions. Per protocol, no formal comparison between CABG and PCI arms was intended based on the differing primary endpoints. Available 15-month angiograms were analysed for 114 CABG and 149 PCI patients. At 15 months, 9.9% (26/263) of CABG grafts were 100% occluded and an additional 5.7% (15/263) were ≥50% to <100% occluded. Overall, 27.2% (31/114) of patients had ≥1 obstructed/occluded graft. The 15-month CABG MACCE rate was 8.8% (10/114) and MACCE at 15 months was not significantly associated with graft obstruction/occlusion (p=0.85). In the PCI arm, 92.4% (134/145) of patients had ≤50% diameter LM stenosis at 15 months (89.7% [87/97] distal LM lesions and 97.9% [47/48] non-distal LM lesions). The 15-month PCI MACCE rate was 12.8% (20/156) and this was significantly associated with lack of stent patency at 15 months (p<0.001), mainly due to repeat revascularisation. At 15 months, 15.6% (41/263) of grafts were at least 50% obstructed but this was not significantly associated with MACCE; 92.4% (134/145) of patients had stents that remained patent at 15 months, and stent restenosis was significantly associated with MACCE, predominantly due to revascularisation.


Methods for detecting disulfiram in biologic fluids: application in studies of compliance and effect of divalent cations on bioavailability.
Studies regarding the efficacy of disulfiram in the treatment of alcoholism have not included a method of evaluating compliance to the prescribed regimen. This article outlines current methods used to detect disulfiram in blood, breath, and urine.


Evaluation of the osteogenic potential of Hancornia speciosa latex in rat calvaria and its phytochemical profile.
Hancornia speciosa Gomes, commonly known as Mangabeira, is a Brazilian native fruit tree belonging to the Apocynaceae family. In folk medicine, the latex obtained from Mangabeira's trunk has been used as an adjunct therapy for bone fractures. Few pharmacological studies on the Hancornia speciosa latex have been developed and despite its popular use for bone healing there is no data about its biological effect on bone. The present study aimed to investigate the osteogenic potential of Hancornia speciosa latex in rat calvaria, as well as its phytochemical profile. A neutral gel composition containing 5% latex was topical applied to a critical size bone defect and over intact calvaria of rats. Areas of newly formed bone on the borders of the defect and of calvaria periosteum were quantified, as well as the percentage of BrdU-positive cells and total cells in the periosteum at different periods of time after latex application. The cytotoxicity of the latex aqueous phase was evaluated in rat calvarial cells in vitro by MTT assay and its phytochemical profile was investigated by ESI-MS/MS. The area of newly formed bone on the borders of the calvaria defect was larger in rats that received latex at 15 and 30 days of healing. After 3 days of latex application over the intact calvaria, the periosteum area was increased and newly formed bone was observed after 5 and 11 days. There was also an increase in periosteum cell proliferation and population followed latex application on calvaria (p<0.05). The latex aqueous phase limited rat calvarial cell viability in vitro in concentrations larger than 0.6mg/mL. Chlorogenic acid and naringenin-7-O-glucoside were identified in the latex aqueous phase, along with catechin and procyanidin compounds. There was a stimulus for periosteum cell proliferation and bone formation when Hancornia speciosa latex was topically applied on rat calvaria. In addition, chlorogenic acid and naringenin-7-O-glucoside present in Hancornia speciosa latex may contribute to its effects on bone formation.


Binding mode dependent signaling for the detection of Cu2+: An experimental and theoretical approach with practical applications.
Two amido-schiff bases (3-Hydroxy-naphthalene-2-carboxylic acid pyren-1-ylmethylene-hydrazide and Naphthalene-2-carboxylic acid pyren-1-ylmethylene-hydrazide) have been synthesized having a common structural unit and only differs by a -OH group in the naphthalene ring. Both of them can detect Cu2+ ion selectively in semi-aqueous medium in distinctly different output modes (one detects Cu2+ by naked-eye color change where as the other detects Cu2+ by fluorescence enhancement). The difference in the binding of Cu 2+ with the compounds is the reason for this observation. The detection limit is found to be micromolar region for compound which contains -OH group whereas the compound without -OH group detects copper in nano-molar region. DFT calculations have been performed in order to demonstrate the structure of the compounds and their copper complexes. Practical utility has been explored by successful paper strip response of both the compounds. The biological applications have been evaluated in RAW 264.7.


The effects of levofloxacin on rabbit anterior cruciate ligament cells in vitro.
Articular cartilage, epiphyseal growth plate and tendons have been recognized as targets of fluoroquinolone-induced connective tissue toxicity. The effects of fluoroquinolones on ligament tissues are still unknown. The aim of this study was to investigate the effects of levofloxacin, a typical fluoroquinolone antibiotic drug, on rabbit anterior cruciate ligament (ACL) cells in vitro. Rabbit ACL cells were treated with levofloxacin at different concentrations (0, 14, 28, 56, 112 and 224 μM) and were assessed to determine the possible cytotoxic effects of levofloxacin on ACL cells. Levofloxacin, with concentrations ranging from 28 to 224 μM, induced dose-dependent ACL cell apoptosis. Characteristic markers of programmed cell death and degenerative changes were identified by electron microscopy in the ACL cells treated with 28 μM of levofloxacin. Moreover, levofloxacin significantly increased the mRNA expression of matrix metalloproteinase 3 (MMP-3) and MMP-13 and decreased the expression of tissue inhibitors of metalloproteinase 1 (TIMP-1) in a concentration-dependent manner; TIMP-3 and collagen type I alpha 1 (Col1A1) mRNA expression was not affected. Immunocytochemical analysis indicated that levofloxacin markedly increased the expression of active caspase-3 within a concentration range of 28 to 224 μM, whereas a clear-cut decrease in Col1A1 expression was found with levofloxacin treatment concentrations of 112 and 224 μM, compared to controls. Our data suggest that levofloxacin has cytotoxic effects on ACL cells characterized by enhanced apoptosis and decreased extracellular matrix, which suggest a potential adverse effect of fluoroquinolones.


Prognostic significance of intestinal claudins in high-risk synchronous and metachronous multiple gastric epithelial neoplasias after initial endoscopic submucosal dissection.
Endoscopic submucosal dissection (ESD) is useful in en bloc curative resection and enables patients with early gastric carcinoma (GC) to have a better quality of life. But metachronous recurrence of GC at other sites in the stomach has become a major issue after initial ESD. The purpose of the present paper was to examine gastric (claudin-18) and intestinal claudin (claudin-3 and claudin-4) expression in early GC on immunohistochemistry to clarify the association with clinicopathology, mucin phenotypes, microsatellite instability (MSI) status and the incidence of synchronous and metachronous gastric epithelial neoplasias after initial ESD. According to intestinal claudin expression, a total of 73 early GC were divided into two groups: intestinal claudin-positive (I-CLDN(+)) phenotype (n = 52; 71%); and intestinal claudin-negative (I-CLDN(-)) phenotype (n = 21; 29%). Although no significant association was found with clinicopathology and the MSI status, the I-CLDN(+) early GC correlated with the mucin phenotypes and had a significantly higher incidence of synchronous and metachronous multiple GC and gastric adenomas (P = 0.049). These results indicate that early GC demonstrating I-CLDN(+) phenotype have a high risk of synchronous and metachronous secondary gastric epithelial neoplasias.


Life-threatening vascular complications after central venous catheter placement.
The purpose of this retrospective study was to report 11 cases of severe vascular complications after central venous catheter misplacement. For each patient, data collection included body mass index, the diagnosis at admission, the site of the procedure, the type of catheter, coagulation parameters, the imaging modalities performed and the applied treatment. Eight patients had a lesion of the subclavian artery. Brachiocephalic vein perforations were assessed in three more patients. All patients had a chest roentgenogram after the procedure, six a CT examination, and four an angiographic procedure. Seven patients had a body mass index above 30, and 5 patients had coagulation disorders prior to the procedure. Seven patients were conservatively managed, 2 patients died despite resuscitation, 1 patient was treated with a stent graft, and one by superselective embolization. Subclavian or jugular vein temporary catheter positioning is a practical approach. Identification of any iatrogenic perforation of the subclavian artery or central veins urges obtaining a chest roentgenogram and, when required, a chest CT, selective angiograms or venograms. Body mass index superior to 30, previous unsuccessful catheterization attempts, and coagulation factor depletion seemed to account for risk factors. Recognition of clinical and radiological complications is mandatory.


Sequential chemotherapy by CHOP and DHAP regimens followed by high-dose therapy with stem cell transplantation induces a high rate of complete response and improves event-free survival in mantle cell lymphoma: a prospective study.
Mantle cell lymphoma (MCL) is a distinct clinico-pathological entity with a poor prognosis. We have conducted a prospective study in patients with MCL to evaluate a therapeutic strategy in which CHOP polychemotherapy was followed by DHAP if CHOP failed to induce complete remission. Responding patients then proceeded to an intensification therapy with autologous peripheral blood stem cell transplantation (APBSCT). Twenty-eight consecutive patients with newly diagnosed aggressive MCL were included. After four cycles of CHOP regimen, two complete responses (CR) were obtained (7%) and 14 (50%), five (18%) and seven (25%) patients achieved partial (PR), minor (MR) and no response, respectively (one patient died from septic complications during CHOP induction). The two patients in CR after CHOP underwent intensification with TBI, high-dose cyclophosphamide-etoposide and APBSCT. The other twenty-five patients received DHAP and in this group a response rate of 92% (21 CR (84%), two PR (8%)) was observed. Two patients had progressive disease. The twenty-three responding patients received high-dose therapy (TAM8 regimen: TBI-cytarabine-melphalan) followed by APBSCT. One of the two partial responding patients achieved CR after TAM8. After a median follow-up of 47.6 months (range, 14-70), seven patients have relapsed. Our data confirm that: (1) CHOP regimen induces a low CR rate in MCL; (2) CHOP plus DHAP appears to be much more efficient and allows a large proportion of patients to proceed to high-dose therapy in CR; (3) consolidation therapy including TBI and high-dose Arac-C followed by APBSCT may improve event-free survival.


Nothing makes sense in drug resistance except in the light of evolution.
Our ability to fight infectious diseases is being increasingly compromised due to the emergence and spread of pathogens that become resistant to one or several drugs. This phenomenon is ubiquitous among pathogens and has parallels in cancer treatment. Given the urgency of the problem, there is a need for a paradigm shift in drug therapy toward one in which the objective to prevent the evolution of drug resistance is considered alongside the main objective of eliminating the infection or tumor. Here, I stress the importance of considering an evolutionary perspective to achieve this goal, and review recent advances in this direction, including therapies that exploit the fitness trade-offs of resistance.


Mothers' Experiences of Childbirth and Perspectives on Korean Medicine-Based Postpartum Care in Korea: A Qualitative Study.
This study aimed to record the experiences of childbirth and postpartum care of postpartum women and gain an in-depth understanding of their experiences of Korean medicine-based postpartum healthcare. The investigator conducted a 60-90-min interview with the 8 participants (mean age 34 years), and the comments were analyzed using the thematic analysis method. The two major themes emerging from the participants' comments were: "experience and awareness of childbirth and postpartum care" and "experiences of the Korean medicine-based postpartum program". The first theme was analyzed in four primary categories: (1) experiences of breakdown of the body and mind; (2) impossibility of postpartum care without help; (3) experiences of relentless effort for recovery; and (4) experiences of body and mind recovery. The second theme was analyzed in four primary categories: (1) participation with vague expectations; (2) experiences of the effects of managing postpartum symptoms; (3) the need for a comprehensive Korean medicine management for postpartum women; and (4) suggested improvements for the Korean medicine-based postpartum program. Mothers recognized the importance of Korean medicine treatment during the postpartum period for the management of Sanhupung symptoms and postpartum care and reported the benefits of body warming, Sanhupung prevention, pain reduction, and sense of psychological stability.


Digital histopathological images of biopsy predict response to neoadjuvant chemotherapy for locally advanced gastric cancer.
Neoadjuvant chemotherapy (NAC) has been recognized as an effective therapeutic option for locally advanced gastric cancer as it is expected to reduce tumor size, increase the resection rate, and improve overall survival. However, for patients who are not responsive to NAC, the best operation timing may be missed together with suffering from side effects. Therefore, it is paramount to differentiate potential respondents from non-respondents. Histopathological images contain rich and complex data that can be exploited to study cancers. We assessed the ability of a novel deep learning (DL)-based biomarker to predict pathological responses from images of hematoxylin and eosin (H&E)-stained tissue. In this multicentre observational study, H&E-stained biopsy sections of patients with gastric cancer were collected from four hospitals. All patients underwent NAC followed by gastrectomy. The Becker tumor regression grading (TRG) system was used to evaluate the pathologic chemotherapy response. Based on H&E-stained slides of biopsies, DL methods (Inception-V3, Xception, EfficientNet-B5, and ensemble CRSNet models) were employed to predict the pathological response by scoring the tumor tissue to obtain a histopathological biomarker, the chemotherapy response score (CRS). The predictive performance of the CRSNet was evaluated. 69,564 patches from 230 whole-slide images of 213 patients with gastric cancer were obtained in this study. Based on the F1 score and area under the curve (AUC), an optimal model was finally chosen, named the CRSNet model. Using the ensemble CRSNet model, the response score derived from H&E staining images reached an AUC of 0.936 in the internal test cohort and 0.923 in the external validation cohort for predicting pathological response. The CRS of major responders was significantly higher than that of minor responders in both internal and external test cohorts (both p < 0.001). In this study, the proposed DL-based biomarker (CRSNet model) derived from histopathological images of the biopsy showed potential as a clinical aid for predicting the response to NAC in patients with locally advanced GC. Therefore, the CRSNet model provides a novel tool for the individualized management of locally advanced gastric cancer.


High risk association of IL-1 receptor antagonist (IL-1RN) VNTR polymorphism with asthma in a North Indian population: a pilot study.
A pilot case-control study was conducted to evaluate the role of IL-1 receptor antagonist (IL-1RN) VNTR penta-allelic polymorphism in asthma that has been associated with various inflammatory diseases worldwide. This is the first case-control study conducted in India, investigating the role of IL-1RN VNTR polymorphism in asthma pathogenesis. A case-control study was performed with a total of 824 adult subjects, inducting 410 asthma patients and 414 healthy controls from North India. The genotypes were identified by polymerase chain reaction. Statistical analysis for the IL-1RN VNTR polymorphism revealed that the IL-1RN(*)2 allele was significantly associated with asthma with OR=1.45, 95% CI (1.15-1.85) and p=0.001. The IL-1RN(*)2/2 genotype posed a risk towards asthma with OR=1.66, 95% CI (0.97-2.86) and p=0.048. Most of the phenotypic traits were significantly associated with the disease. IL-1RN(*)2 allele is a high risk factor for asthma in the studied North Indian population.


A cuticle protein gene in the honeybee: expression during development and in relation to the ecdysteroid titer.
A cDNA encoding a cuticle protein containing the R&R Consensus was characterized in the honeybee integument. AmelCPR14 developmental expression is distinguished by an on-off-on pattern, the transition from a low to a high level of transcripts occurring as the ecdysteroid titer is declining after the peak that triggers the onset of pharate (pupal and adult) development. The transcript is abundant during cuticle tanning and sclerotization, and persists even in the adult integument, suggesting that the corresponding protein is required for differentiation and maintenance of the adult cuticle. Such developmental pattern suggested that AmelCPR14 gene might be regulated by the titer of ecdysteroids. We confirmed this hypothesis using different experimental strategies. By tying a ligature in early pupae to prevent exposure of abdominal integument to a high ecdysteroid titer, we delayed the accumulation of AmelCPR14 transcripts in the abdominal integument. This is consistent with ecdysteroid priming being required in pupae for the increase in AmelCPR14 expression in pharate adults. By injecting 20-hydroxyecdysone (20E) in early pupae we demonstrated that hormone titer decay after the peak is critical for AmelCPR14 expression induction. Exposure of pupal integument in vitro to a 20E concentration mimicking the pupal ecdysteroid peak repressed AmelCPR14 expression, which was recovered by hormone removal. Taken together, these data are consistent with an ecdysteroid pulse (increase in hormone titer followed by its decline) being critical for a high AmelCPR14 gene expression in pharate adults.


Design and evaluation of an IPE module at the beginning of professional training in medicine, nursing, and physiotherapy.
Interprofessional education (IPE) is a central feature of modern education in the health care professions. Despite this, empirically founded and systematically structured IPE courses are absent from many curricula. To answer the WHO's call for improved interprofessional collaboration in the health care system, a seminar was designed, implemented and evaluated. The target group consisted of students beginning nursing and medical studies (first and second semesters) and physiotherapy students (first year of training). The aim was to develop a basic IPE module focusing not only on the demands placed by academia and politics, but also the interests of the target group. This module was evaluated on the basis of the modified four-level Kirkpatrick approach. Based on focus group interviews analyzed qualitatively using Mayring's content analysis, it was possible to define five learning objectives and develop four practice-oriented modules. The seminar was then implemented and evaluated using written pre- and post-seminar evaluations and group discussions. Analysis confirmed the success of the IPE concept in that the seminar was positively rated by attendees not only in terms of their immediate reactions, but also attitude, knowledge and skills according to Kirkpatrick. In the future, it is intended to offer the IPE module on a permanent basis and assess the competencies acquired in the seminar using observation. Courses to ensure sustained learning outcomes would also be desirable.


Interpretation of blood cultures yielding Staphylococcus aureus.
Forty-eight patients with blood cultures positive for Staphylococcus aureus were classified according to clinical criteria in three groups: "definite", "possible", and "doubtful" septicemia. Using traditional blood culture sets with two bottles (thioglycollate and tryptic soy broths), we found that patients with "definite" septicemia always showed more than one positive bottle per day if more than one set was drawn, that the mean detection time was 1.7 days, and that 95% of the first positive bottles and 92% of all positive bottles grew within two days of incubation. Patients with "doubtful" septicemia were more often (88%) positive in one bottle only, the mean detection time for all bottles was 3.7 days, and only 35% of the first positive bottles and 33% of all positive bottles yielded growth within two days. "Possible" cases took a position between these two extremes but tended more towards the "doubtful" cases. The implications of these findings for the interpretation of blood cultures with S. aureus are discussed.


The presence of corpus luteum may have a negative impact on in vitro developmental competency of bovine oocytes.
The aim of the current study was to investigate the effects of the presence or absence of corpus luteum (CL) on in vitro developmental competence of bovine oocytes. In experiment 1, cumulus oocyte complexes (COCs) were collected from slaughterhouse ovaries and divided according to the presence (CL(+) oocytes) or absence (CL(-) oocytes) of a CL in the ovary. Control oocytes (C group) were obtained from ovaries which were not selected toward the presence or absence of CL. All oocytes were submitted to in vitro maturation, fertilization and culture. In experiment 2, the oocytes from the CL(+) and CL(-) ovaries were divided into grown (BCB(+)) and growing (BCB(-)) categories by means of the brilliant cresyl blue (BCB) test. The oocytes from all groups (CL(+)/BCB(+), CL(-)/BCB(+), CL(+)/BCB(-), CL(-)/BCB(-) and control oocytes) were subjected to in vitro embryo production. In experiment 1, the cleavage and blastocyst rates of CL(-) oocytes were higher than those of CL(+) oocytes (83.9% and 43% vs. 69.3% and 22.5%, respectively). In experiment 2, there was less BCB(+) oocytes (more competent oocytes) in the group of CL(+) oocytes than in the group of CL(-) oocytes. Furthermore, developmental competence of all CL(+) oocytes (CL(+)/BCB(+) and CL(+)/BCB(-)) was lower than that of all CL(-) oocytes (CL(-)/BCB(+) and CL(-)/BCB(-)). Thus, the presence of a corpus luteum in the ovary may have negative effects on developmental competence of ipsilateral oocytes.


Commitment to community mental health aftercare services: staffing and structural implications.
This study examines the views of community mental health practitioners toward aftercare services and deinstitutionalized patients. A survey of 361 practitioners in Allegheny County, Pennsylvania, finds that these views are related to practitioner experience in psychotherapeutic practice, professional affiliation, educational level, and amount of specialization in aftercare. Implications are drawn for staffing and structuring community mental health aftercare services in ways that are likely to enhance practitioner committment to aftercare.


[Structural characteristics of the cuticule of the phytonematode, Aporcelaimellus obtusicaudatus in mechanical injury].
The fine structure of the cuticle of A. obtusicaudatus (Dorylaimidae) during the turgor unbalance was studied. Mechanical injury causes the delamination of the cuticle and reveals the tonofibrillary interrelations between its structures. The cortex and basal layer were found to possess the highest tensile strength. The peculiarities of the structures destruction dynamics depending on the removal from the perforation place were recognized.