Effects of corticotropin releasing factor on locomotor activity in hypophysectomized rats.
Corticotropin releasing factor (CRF) injected intracerebroventricularly to hypophysectomized and sham hypophysectomized rats produced a dose dependent increase in locomotor activity, but in untreated hypophysectomized rats 10X more CRF was needed to produce a significant increase in activity. Concomitant daily supplements of rat growth hormone, thyroxine, and corticosterone to the hypophysectomized rats eliminated locomotor activity differences between the two groups. There was no statistically significant difference in locomotor response to either saline, 0.1 micrograms CRF, 1.0 micrograms CRF or 10.0 micrograms CRF in the group of animals receiving hormonal supplements. These results demonstrate that CRF can produce behavioral activation in rats independently of its effects on releasing hormones from the pituitary gland.


Minimally invasive ablative therapies for invasive breast carcinomas: an overview of current literature.
Minimally invasive treatment may be an alternative to breast-conserving surgery. A structured PubMed, Embase, Cochrane, and Web of Science search was performed. Endpoints studied were feasibility, completeness of ablation, timing of the sentinel node biopsy (SNB), imaging modalities, and treatment-related complications. A total of 24 articles were retrieved, and the level of evidence varied (2B-4). Mainly phase II studies with a treat-and-resect protocol were analyzed. Up to 100% completeness of ablation was reported for radiofrequency ablation (RFA), cryosurgery, and focused ultrasound (FUS). The oncologic results need further evaluation. Dynamic contrast enhanced MRI seems to be the best method for monitoring treatment response (77% sensitivity, 100% specificity). Ultrasound is suitable for guiding probes into the tumor. There is no consensus on the timing of the SNB. All studies on minimally invasive ablative modalities published so far show that these techniques are feasible and safe. At this stage only T1 tumors should be ablated in a clinical trial setting; it is unclear which of the modalities is most suitable.


In Vivo Cell Tracking Using Two-Photon Microscopy.
Recently we have explored and developed approaches imaging using confocal/two-photon microscopy, which enables simultaneous high-resolution assessment of specifically fluorescently marked cells in conjunction with structural components of the tissues visualized via harmonic generated signals. This approach uses commercially available confocal and two-photon laser microscope and automated user-interactive image analysis methods based on commercially available software packages allowing easy implementation in usual microscopy facilities.


The Use of Legendre and Zernike Moment Functions for the Comparison of 2-D PAGE Maps.
The comparison of 2-D maps is not trivial, the main difficulties being the high complexity of the sample and the large experimental variability characterizing 2-D gel electrophoresis. The comparison of maps from control and treated samples is usually performed by specific software, providing the so-called spot volume dataset where each spot of a specific map is matched to its analogous in other maps, and they are described by their optical density, which is supposed to be related to the underlying protein amount. Here, a different approach is presented, based on the direct comparison of 2-D map images: each map is decomposed in terms of moment functions, successively applying the multivariate tools usually adopted in image analysis problems. The moments calculated are then treated with multivariate classification techniques. Here, two types of moment functions are presented (Legendre and Zernike moments), while linear discriminant analysis and partial least squares discriminant analysis are exploited as classification tools to provide the classification of the samples. The procedure is applied to a sample dataset to prove its effectiveness.


Maturation of the response of human fetal pancreatic explants to glucose.
The release of insulin from the human pancreas in response to glucose is known to be either poor or absent in the fetus, whereas in the infant and adult, the response is much greater. The maturation of this response was examined systematically in this study using pancreases that were initially obtained at 14-20 weeks gestation and maintained either in culture alone or by passaging them in diabetic nude mice. Stimulation with glucose was carried out in vitro using tissue of ages ranging from 14 to 58 weeks. A response to glucose was initially seen at 25 weeks and this dramatically increased in the fetal tissue that had reached an age of 55 weeks or more. One of the nude mice used for passage developed normoglycaemia and when the pancreatic implant of age 52 weeks was removed, diabetes recurred. Our findings support the idea of the use of human fetal pancreatic tissue in the treatment of diabetes mellitus.


Minimally invasive single-vessel coronary artery bypass with the internal thoracic artery and early postoperative angiography: midterm results of a prospective study in 120 consecutive patients.
This prospective study was undertaken to determine the role of the minimally invasive direct coronary artery bypass with early postoperative angiography and midterm follow-up in 120 consecutive patients with single-vessel coronary artery disease. Minimal access (6 to 10 cm), without complete sternotomy and no cardiopulmonary bypass, was used. The lesions were located at the proximal left anterior descending coronary artery in 95% of the patients. Routine coronary angiography was performed before discharge. Postoperative angiography was performed in 104 (90.4%) of those 115 patients who had coronary revascularization concluded by the mini-access method. The internal thoracic artery patency rate was 98.1% (95.2% grade A). Two (1.7%) patients presented with perioperative myocardial infarction, which led to the single in-hospital death (0.8%). Of the remaining 119 patients, 113 (95.0%) were asymptomatic. The event-free probability was 94.9% and the actuarial survival was 98.3% with 42 months of follow-up. For selected patients with single-vessel coronary artery disease and no major myocardial dysfunction, minimally invasive direct coronary artery bypass is a safe operation and a less invasive alternative to conventional coronary artery bypass grafting.


The role of cross-linking structures to the formation of one-dimensional nano-organized polyaniline and their Raman fingerprint.
In the present work, the resonance Raman, UV-vis-NIR and scanning electron microscopic (SEM) data of nanorods (about approximately 300 nm in diameter) and nanofibers (about approximately 93 nm in diameter) of PANI are presented and compared. The PANI samples were synthesized in aqueous media with dodecybenzenesulfonic acid (DBSA) and beta-naphtalenesulfonic acid (beta-NSA) as dopants, respectively. The presence of bands at 578, 1400 and 1, 632 cm(-1) in the Raman spectra of PANI-NSA and PANI-DBSA shows that the formation of cross-linking structures is a general feature of the PANI chains prepared in micellar media. It is proposed that these structures are responsible for the one-dimensional PANI morphology formation. In addition, the Raman band at 609 cm(-1) of PANI fibers is correlated with the extended PANI chain conformation.


The cost implications of a polypill for primary prevention in the TIPS-3 trial.
The International Polycap Study 3 (TIPS-3) trial demonstrated that a polypill containing cholesterol- and multiple blood-pressure-lowering drugs reduces cardiovascular events by 20% compared with placebo in people without cardiovascular disease. The polypill plus aspirin led to a 31% relative risk reduction in cardiovascular disease events compared with double placebo. We report regional variations in costs and affordability of a polypill based on the TIPS-3 trial. Countries were categorized using World Bank economic groups: lower-middle-income, upper-middle-income, and high-income countries. Country-specific costs were obtained for hospitalization events, procedures, and non-study medications (2019 US dollars). Polypill price was based on the cheapest equivalent substitute (CES) for each component. For the polypill vs. placebo, the difference in cost over the 4.6 years of the trial was $291 [95% confidence interval (CI): $243-339] per participant in lower-middle-income countries, $1068 (95% CI: $992-1144) in upper-middle-income countries, and $48 (95% CI: -$271 to $367) in high-income countries. Results were similar for the polypill plus aspirin vs. a double placebo. In both cases, the polypill was affordable in all groups using monthly household capacity to pay or a threshold of 4% of the gross national income per capita. The use of a polypill (CES) in TIPS-3 increases costs in lower-middle-income countries and upper-middle-income countries but is affordable in countries at various economic levels and is cost neutral (dominant) in high-income countries.


The role of multidetector CT in the evaluation of the left atrium and pulmonary veins anatomy before and after radio-frequency catheter ablation for atrial fibrillation. Preliminary results and work in progress. Technical note.
Radio-frequency catheter ablation (RFCA) of the distal pulmonary veins is increasingly being used to treat recurrent or refractory atrial fibrillation that doesn't respond to pharmacologic therapy or cardioversion. Successful RFCA of atrial fibrillation depends on the pre-procedural understanding of the complex anatomy of the distal pulmonary veins and the left atrium. Aim of this paper is to describe the technical main features that characterise the multidetector helical computed tomography in the evaluation of this anatomic region before and after RFCA procedure. The 3D post-processing techniques useful for pre-RFCA planning are straightforward.


Physicochemical properties, antioxidant activities and in vitro sustained release behaviour of co-encapsulated liposomes as vehicle for vitamin E and β-carotene.
In this study the potential of liposomes as a vitamin E (VE) and β-carotene (βC) delivery system was examined. The co-encapsulated liposomes of βC and VE (L-VE-βC) were prepared and characterized. Their antioxidant properties were evaluated by free radical scavenging activities of 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), hydroxyl radical and lipid peroxidation assay. The in vitro sustained release behaviour was then investigated and discussed. VE and βC were co-encapsulated in liposomes with high encapsulation efficiency, up to 92.49% and 86.16% for βC and VE, respectively. The antioxidant activities of L-VE-βC samples were significantly higher than that of single loaded liposome. Among different ratios of VE/βC, L-VE-βC at 5:3 exhibited the highest radical scavenging rates, with 66.80%, 56.58% and 34.39% for DPPH, ABTS and OH radical, respectively. L-VE-βC samples also had a good ability to inhibit lipid peroxidation, especially the sample with ratios of VE/βC at 5:3 and 3:1. In simulated gastrointestinal release, L-VE-βC exhibited an excellent sustained release behaviour in SGF with the accumulated rate at about 20%, while the release rate in SIF increased to over 80%, where they should be absorbed. The release kinetics analysis indicated that βC was released in the Higuchi model in stomach, and the Korsmeyr-Peppas model in intestine. Compared to single loaded liposomes, the combined-loaded liposomes exhibited higher antioxidant activity and bioavailability, suggesting the potential applications in functional foods. © 2022 Society of Chemical Industry.


Factor structure of DSM-5 PTSD symptoms in trauma-exposed adolescents: Examining stability across time.
This study investigated the latent structure of DSM-5 PTSD symptoms using two-wave longitudinal data collected from a sample of adolescents exposed to an explosion accident. Two waves of surveys were conducted approximately 3 and 8 months after the accident, respectively. A total of 836 students completed the baseline survey, and 762 students completed the follow-up survey. The results of confirmatory factor analyses(CFA) indicated that a seven-factor hybrid model composed of intrusion, avoidance, negative affect, anhedonia, externalizing behaviors, anxious arousal and dysphoric arousal factors yielded significantly better data fit at both waves than the other models including the DSM-5 four-factor model, the six-factor anhedonia and externalizing behaviors models. Furthermore, the results of CFA invariance tests supported the longitudinal invariance of the model. Implications and limitations in terms of these results are discussed.


Deciphering the molecular landscape of microcephaly in 87 Indian families by exome sequencing.
Microcephaly is a frequent feature of neurodevelopmental disorders (NDDs). Our study presents the heterogeneous spectrum of genetic disorders in patients with microcephaly either in isolated form or in association with other neurological and extra-neural abnormalities. We present data of 91 patients from 87 unrelated families referred to our clinic during 2016-2020 and provide a comprehensive clinical and genetic landscape in the studied cohort. Molecular diagnosis using exome sequencing was made in 45 families giving a yield of 51.7%. In 9 additional families probable causative variants were detected. We identified disease causing variations in 49 genes that are involved in different functional pathways Among these, 36 had an autosomal recessive pattern, 8 had an autosomal dominant pattern (all inherited de novo), and 5 had an X-linked pattern. In 41 probands where sequence variations in autosomal recessive genes were identified 31 were homozygotes (including 16 from non-consanguineous families). The study added 28 novel pathogenic/likely pathogenic variations. The study also calls attention to phenotypic variability and expansion in spectrum as well as uncovers genes where microcephaly is not reported previously or is a rare finding. We here report phenotypes associated with the genes for ultra-rare NDDs with microcephaly namely ATRIP, MINPP1, PNPLA8, AIMP2, ANKLE2, NCAPD2 and TRIT1.


A lipoteichoic acid fraction of Enterococcus hirae activates cultured human monocytic cells via a CD14-independent pathway to promote cytokine production, and the activity is inhibited by serum components.
To elucidate the cellular activation mechanisms of lipoteichoic acid (LTA) compared with those of lipopolysaccharide (LPS), a quantitatively major LTA fraction, QM-1M, was prepared from hot phenol-water extracts of Enterococcus hirae (ATCC 9790) by hydrophobic octyl-Sepharose chromatography and by ion-exchange membrane (QMA-Mem Sep 1010) chromatography as a 60% 1-propanol- and 1 M NaCl-eluted fraction. Unlike the reference Escherichia coli LPS, QM-1M did not demonstrate any ability to induce cytokines in a human whole blood culture system in this study, whereas QM-1M induced a few cytokines such as interleukin (IL)-8 and tumor necrosis factor-alpha in human monocytic THP-1 cell and human peripheral mononuclear cell (PBMC) cultures in the absence of serum. Fetal calf and human sera decreased the above cytokine induction by QM-1M in THP-1 and PBMC cultures, whereas sera increased activities of the reference LPS. IL-8 induction in the absence of serum in response to QM-1M was demonstrated to proceed through a CD14-independent pathway unlike the reference LPS.


Septicemia after transurethral prostatectomy.
Septicemia occurred in 18 of 1,604 patients subjected to transurethral resection (TUR) of the prostate. Six patients died postoperatively, 4 of septicemia. In 11 patients septicemia was provoked by TUR in the presence of urinary infection and in the absence of appropriate antibiotic cover. Septicemia was provoked by catheter removal in 2 similarly infected patients. In the remaining 5 patients the urine was sterile at operation but became infected prior to catheter removal, and this maneuver precipitated septicemia.


The effect of single and concomitant pathogen infections on condition and fecundity of the wild rabbit (Oryctolagus cuniculus).
We assessed the effect of two pathogens (myxoma virus and Eimeria stiedae) and five macroparasites (gastrointestinal helminth species) of the wild rabbit (Oryctolagus cuniculus) upon total host body mass and abdominal fat level. Additionally, we assessed the effects of these organisms on the number of foetuses in adult females during the peak breeding period. Both mass of abdominal fat and total body mass of the rabbit were negatively associated with myxoma virus infection and increasing helminth species richness. Total body mass was also negatively associated with the protozoan parasite E. steidae. No relationship was found between any of the parasites/pathogens and the number of foetuses in adult females, although only relatively small sample sizes were available for this section of the analysis. Increasing host body mass was positively associated with number of foetuses and we propose that mass reduction caused by the pathogen and parasite species could also have the consequence of reducing foetal number.


Influence of the carbon source on Gordonia alkanivorans strain 1B resistance to 2-hydroxybiphenyl toxicity.
The viability of bacteria plays a critical role in the enhancement of fossil fuels biodesulfurization efficiency since cells are exposed to toxic compounds such as 2-hydroxybiphenyl (2-HBP), the end product of dibenzothiophene (DBT) biodesulfurization. The goal of this work was to study the influence of the carbon source on the resistance of Gordonia alkanivorans strain 1B to 2-HBP. The physiological response of this bacterium, pre-grown in glucose or fructose, to 2-HBP was evaluated using two approaches: a growth inhibition toxicity test and flow cytometry. The results obtained from the growth inhibition bioassays showed that the carbon source has an influence on the sensitivity of strain 1B growing cells to 2-HBP. The highest IC50 value was obtained for the assay using fructose as carbon source in both inoculum growth and test medium (IC50-48 h = 0.464 mM). Relatively to the evaluation of 2-HBP effect on the physiological state of resting cells by flow cytometry, the results showed that concentrations of 2-HBP >1 mM generated significant loss of cell viability. The higher the 2-HBP concentration, the higher the toxicity effect on cells and the faster the loss of cell viability. In overall, the flow cytometry results highlighted that strain 1B resting cells grown in glucose-SO4 or glucose-DBT are physiologically less resistant to 2-HBP than resting cells grown in fructose-SO4 or fructose-DBT, respectively.


Effects of osteopontin inhibition on radiosensitivity of MDA-MB-231 breast cancer cells.
Osteopontin (OPN) is a secreted glycophosphoprotein that is overexpressed in various tumors, and high levels of OPN have been associated with poor prognosis of cancer patients. In patients with head and neck cancer, high OPN plasma levels have been associated with poor prognosis following radiotherapy. Since little is known about the relationship between OPN expression and radiosensitivity, we investigated the cellular and radiation induced effects of OPN siRNA in human MDA-MB-231 breast cancer cells. MDA-MB-231 cells were transfected with OPN-specific siRNAs and irradiated after 24 h. To verify the OPN knockdown, we measured the OPN mRNA and protein levels using qRT-PCR and Western blot analysis. Furthermore, the functional effects of OPN siRNAs were studied by assays to assess clonogenic survival, migration and induction of apoptosis. Treatment of MDA-MB-231 cells with OPN siRNAs resulted in an 80% decrease in the OPN mRNA level and in a decrease in extracellular OPN protein level. Transfection reduced clonogenic survival to 42% (p = 0.008), decreased the migration rate to 60% (p = 0.15) and increased apoptosis from 0.3% to 1.7% (p = 0.04). Combination of OPN siRNA and irradiation at 2 Gy resulted in a further reduction of clonogenic survival to 27% (p < 0.001), decreased the migration rate to 40% (p = 0.03) and increased apoptosis to 4% (p < 0.005). Furthermore, OPN knockdown caused a weak radiosensitization with an enhancement factor of 1.5 at 6 Gy (p = 0.09) and a dose modifying factor (DMF10) of 1.1. Our results suggest that an OPN knockdown improves radiobiological effects in MDA-MB-231 cells. Therefore, OPN seems to be an attractive target to improve the effectiveness of radiotherapy.


The introduction of poliovirus RNA into cells via lipid vesicles (liposomes).
Large unilamellar vesicles (LUV) composed of phosphatidylserine are capable of encapsulating poliovirus ribonucleic acid (RNA) and delivering it efficiently to cells in an infectious form. The biological activity of vesicle-entrapped poliovirus RNA was 1-2 x 10(4) plaque forming units/nanogram (pfu/ng) and appeared to be enhanced by ribonuclease treatment of the vesicle preparations (infectivity = 1-2 x 10(5) pfu/ng). Vesicle-mediated RNA infection produced equivalent titers in primate and nonprimate cells. Moreover, the data strongly suggest that the ratio of molecules per infectious unit is close to one when the RNA is properly delivered to the cell. A comparative study of LUV and multilamellar vesicles (MLV) indicates that LUV deliver their contents to the cell cytoplasm much more efficiently than MLV. LUV-entrapped poliovirus RNA produced infectious titer 10-100 fold higher than comparable RNA preparations delivered to cells by other techniques.


Procyanidins alleviates morphine tolerance by inhibiting activation of NLRP3 inflammasome in microglia.
The development of antinociceptive tolerance following repetitive administration of opioid analgesics significantly hinders their clinical use. Evidence has accumulated indicating that microglia within the spinal cord plays a critical role in morphine tolerance. The inhibitor of microglia is effective to attenuate the tolerance; however, the mechanism is not fully understood. Our present study investigated the effects and possible mechanism of a natural product procyanidins in improving morphine tolerance via its specific inhibition on NOD-like receptor protein3 (NLRP3) inflammasome in microglia. CD-1 mice were used for tail-flick test to evaluate the degree of pain. The microglial cell line BV-2 was used to investigate the effects and the mechanism of procyanidins. Reactive oxygen species (ROS) produced from BV-2 cells was evaluated by flow cytometry. Cell signaling was measured by western blot assay and immunofluorescence assay. Co-administration of procyanidins with morphine potentiated its antinociception effect and attenuated the development of acute and chronic morphine tolerance. Procyanidins also inhibited morphine-induced increase of interleukin-1β and activation of NOD-like receptor protein3 (NLRP3) inflammasome. Furthermore, procyanidins decreased the phosphorylation of p38 mitogen-activated protein kinase, inhibited the translocation of nuclear factor-κB (NF-κB), and suppressed the level of reactive oxygen species in microglia. Procyanidins suppresses morphine-induced activation of NLRP3 inflammasome and inflammatory responses in microglia, and thus resulting in significant attenuation of morphine antinociceptive tolerance.


Diverse β subunits of heterotrimeric G proteins are present in thyroid plasma membranes.
The functioning of heterotrimeric G protein α subunits in the transduction of hormonal signals to appropriate intracellular responses is well recognized. Much less is known about the distribution of isoforms and functions of G protein β subunits. Here, using specific antibodies, we documented that in plasma membranes of the thyroid cell line Nthy-ori 3-1 all Gβ isoforms-Gβ(1), Gβ(2), Gβ(3), Gβ(4) and Gβ(5) are present, while the Gβ(3) occurs in minute amount. In plasma membrane fraction isolated from pooled postoperative thyroids of patients with nodular goiter and Graves' disease, the Gβ(1), Gβ(2), Gβ(4) and Gβ(5) subunits were found, whereas Gβ(3) could not be detected. Competition studies revealed that the Gβ(2) is the principal Gβ subunit in membranes from cultured thyroid cells, originated from normal thyroid, as well as in membranes from patients' thyroids. This suggests that Gβ(2) subunit cooperates with Gα(s) subunit, the most active of the Gα variants, during stimulation of adenylate cyclase which constitutes the main route of physiological thyroid stimulation.


Results of large-caliber internal urethrotomy.
Thirty-five patients undergoing internal urethrotomy for urethral stricture disease were reviewed retrospectively. Eight patients had conventional urethrotomies (less than 36 F) while 27 had large-caliber urethrotomies (greater than 40 F). Large-caliber urethrotomy tends to give longer symptom-free intervals immediately postoperatively, but long-term results show little difference between the two groups.


Surface marker cluster translation, rotation, scaling and deformation: Their contribution to soft tissue artefact and impact on knee joint kinematics.
When recording human movement with stereophotogrammetry, skin deformation and displacement (soft tissue artefact; STA) inhibits surface markers' ability to validly represent the movement of the underlying bone. To resolve this issue, the components of marker motions which contribute to STA must be understood. The purpose of this study is to describe and quantify which components of this marker motion (cluster translation, rotation, scaling and deformation) contribute to STA during the stance phase of walking, a cutting manoeuvre, and one-legged hops. In vivo bone pin-based tibio-femoral kinematics of six healthy subjects were used to study skin marker-based STA. To quantify how total cluster translation, rotation, scaling and deformation contribute to STA, a resizable and deformable cluster model was constructed. STA was found to be greater in the thigh than the shank during all three movements. We found that the non-rigid (i.e. scaling and deformation) movements contribute very little to the overall amount of error, rendering surface marker optimisation methods aimed at minimising this component superfluous. The results of the current study indicate that procedures designed to account for cluster translation and rotation during human movement are required to correctly represent the motion of body segments, however reducing marker cluster scaling and deformation will have little effect on STA.


Evidence for an organic cation-proton antiport system in brush-border membranes isolated from the human term placenta.
Uptake of guanidine, an endogenous organic cation, into brush-border membrane vesicles isolated from human term placentas was investigated. Initial uptake rates were manyfold greater in the presence of an outward-directed H+ gradient ([pH]o greater than [pH]i) than in the absence of a H+ gradient ([pH]o = [pH]i). Guanidine was transiently accumulated inside the vesicles against a concentration gradient in the presence of the H+ gradient. The H+ gradient-dependent stimulation of guanidine uptake was not due to a H+-diffusion potential because an ionophore (valinomycin or carbonylcyanide p-trifluoromethoxyphenylhydrazone)-induced inside-negative membrane potential failed to stimulate the uptake. In addition, uphill transport of guanidine could be demonstrated even in voltage-clamped membrane vesicles. The H+ gradient-dependent uptake of guanidine was inhibited by many exogenous as well as endogenous organic cations (cis-inhibition) but not by cationic amino acids. The presence of unlabeled guanidine inside the vesicles stimulated the uptake of labeled guanidine (trans-stimulation). These data provide evidence for the presence of an organic cation-proton antiporter in human placental brush-border membranes. Kinetic analysis of guanidine uptake demonstrated that the uptake occurred via two saturable, carrier-mediated transport systems, one being a high affinity, low capacity type and the other a low affinity, high capacity type. Studies on the effects of various cations on the organic cation-proton antiporter and the Na+-H+ exchanger revealed that these two transport systems are distinct.


Why Z-drugs are used even if doctors and nurses feel unable to judge their benefits and risks-a hospital survey.
Many patients receive Z-drugs for hospital-associated sleep problems, in spite of well-known risks. The aim of this study was to learn more about the attractiveness of Z-drugs, seen from the doctors' and nurses' perspective. Using a standardized questionnaire, doctors (63/116) and nurses (73/243) in a German general hospital were surveyed about the risks and benefits of Z-drugs, compared with benzodiazepines. "Reduced time to get to sleep" was perceived by doctors (51%) and nurses (53%) to be a strong benefit of Z-drugs; "confusion" and "falls" were perceived by ca. 10% of doctors and ca. 15% of nurses to be a frequent problem. Compared with benzodiazepines, respondents more often answered "unable to judge" for Z-drugs; e.g. for doctors, 18% (benzodiazepines) vs. 45% (Z-drugs) were unable to judge "improved daytime functioning" and 12% (benzodiazepines) vs. 37% (Z-drugs) were unable to judge "falls." Z-drugs seem to be attractive because experiential knowledge overemphasizes their benefits and fails to take risks such as drug-related falls and confusion into account. Difficulties to judge a drug's risk-benefit ratio do not prevent doctors and nurses from using them. Interventions for reducing Z-drug usage should incorporate local quality assurance data about relevant patient risks.


Addressing the conundrum of multimorbidity in heart failure: Do we need a more strategic approach to improve health outcomes?
There is clear evidence across the globe that the clinical complexity of patients presenting to hospital with the syndrome of heart failure is increasing - not only in terms of the presence of concurrent disease states, but with additional socio-demographic risk factors that complicate treatment. Management strategies that treat heart failure as the main determinant of health outcomes ignores the multiple and complex issues that will inevitably erode the efficacy and efficiency of current heart failure management programmes. This complex problem (or conundrum) requires a different way of thinking around the complex interactions that underpin poor outcomes in heart failure. In this context, we present the COordinated NUrse-led inteNsified Disease management for continuity of caRe for mUltiMorbidity in Heart Failure (CONUNDRUM-HF) matrix that may well inform future research and models of care to achieve better health outcomes in this rapidly increasing patient population.


SynLethDB 2.0: a web-based knowledge graph database on synthetic lethality for novel anticancer drug discovery.
Two genes are synthetic lethal if mutations in both genes result in impaired cell viability, while mutation of either gene does not affect the cell survival. The potential usage of synthetic lethality (SL) in anticancer therapeutics has attracted many researchers to identify synthetic lethal gene pairs. To include newly identified SLs and more related knowledge, we present a new version of the SynLethDB database to facilitate the discovery of clinically relevant SLs. We extended the first version of SynLethDB database significantly by including new SLs identified through Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) screening, a knowledge graph about human SLs, a new web interface, etc. Over 16 000 new SLs and 26 types of other relationships have been added, encompassing relationships among 14 100 genes, 53 cancers, 1898 drugs, etc. Moreover, a brand-new web interface has been developed to include modules such as SL query by disease or compound, SL partner gene set enrichment analysis and knowledge graph browsing through a dynamic graph viewer. The data can be downloaded directly from the website or through the RESTful Application Programming Interfaces (APIs). Database URL: https://synlethdb.sist.shanghaitech.edu.cn/v2.


Ivermectin alters reproductive success, body condition and sexual trait expression in dung beetles.
Ivermectin is a very common parasiticide used in livestock. It is excreted in the dung and has negative effects on survival and reproduction of dung-degrading organisms, including dung beetles. Here we exposed the dung beetle Euoniticellus intermedius to different concentrations of ivermectin in the food and evaluated reproductive success and the expression of traits associated with survival and reproduction under laboratory conditions. It is the first time the effects of ivermectin were evaluated on offspring physiological condition and the expression of a secondary sexual trait. We also registered the number of emerged beetles, sex ratio and body size of emerged adult beetles. Besides reducing the number of emerged beetles and body size, as found in the same and other insects, ivermectin at high doses reduced muscle mass while at intermediate doses it increased lipid mass. Ivermectin changed offspring sex ratio and at high doses increased the size of male horn, which is an important trait defining the male mating success. Our results highlight the importance of regulating parasiticide usage in livestock in order to maintain ecosystem services provided by dung beetles and confirm that contaminants impose new environmental conditions that not only impact on wild animal survival, but also on evolutionary processes such as sexual selection.


Prospective analysis of toxicity in patients treated with strut-adjusted volume implant for early-stage breast cancer.
We report the toxicity of patients treated with strut-adjusted volume implant (SAVI) for accelerated partial breast irradiation treated at our institution. Patients treated from January 2013 to July 2015 with SAVI planned for 10 b.i.d. fractions for a total dose of 34 Gy were included. Acute and late toxicities were prospectively collected on patients in followup and graded by the Common Terminology Criteria for Adverse Events, version 4.0. A total of 132 patients were included, with 1 patient having synchronous breast cancer treated in each breast. Median followup was 20.0 months (range, 2.7-37.4 months). The median age at diagnosis was 61 years (range, 41-83 years). Forty-two lesions (32%) were in situ, 88 lesions (66%) were Stage 1, and 3 (2%) lesions were Stage 2. The median planning target volume was 58.2 cc (range, 24.2-109.9 cc), median V150 was 26.3 cc (range, 11.5-47.5 cc), and median V200 was 13.0 cc (range, 6.3-26.1 cc). On a pain scale of 0-10 (10 = worst pain), pain was worst on Day 2 of treatment, with an average score of 0.46. There was one acute skin infection; there were three late skin infections, two of which was Grade 3. Other late toxicities were Grade 1 or 2: hyperpigmentation (44%), telangiectasia (0.8%), seroma (9%), fat necrosis (5%), and fibrosis (12%). Crude local recurrence rate was 4%. SAVI is a safe treatment option for patients who are candidates for accelerated partial breast irradiation. Local control seems to be excellent, but longer followup is needed.


Interictal epileptiform discharges vary across age groups.
To investigate whether the occurrence and morphology of interictal epileptiform discharges (IEDs) in scalp-EEG change by age. 10,547 patients who had a standard or sleep deprived EEG recording reported using the SCORE standard were included. 875 patients had at least one EEG with focal IEDs. Focal IED morphology was analyzed by age using quantitative measures in EEGLAB and by visual classification based on the SCORE standard. We present distributions of IED measures by age group, with medians, interquartiles, 5th and 95th percentiles. Focal IEDs occurred most frequently in children and elderly. IED morphology and localization depended on age (p < 0.001). IEDs had higher amplitudes, sharper peaks, larger slopes, shorter durations, larger slow-wave areas and wider distributions in children. These morphological characteristics diminished and the IEDs became more lateralized with increasing age. Spike asymmetry was stable across all age groups. IEDs have age-dependent characteristics. A spike detector, human or computer, should not operate with the same set of thresholds for patients at various age. With increasing age, focal IEDs are less sharp, have lower amplitudes, have less prominent slow-waves and they become more lateralized. Our findings can help EEG readers in detecting and correctly describing IEDs in patients of various age. EEG readers should always consider patient age when interpreting interictal epileptiform discharges.


Sex ratio from germination through maturity and its reproductive consequences in the liverwort Sphaerocarpos texanus.
The dioecious winter ephemeral liverwort, Sphaerocarpos texanus disperses spore tetrads consisting of two males and two females. I examined the subsequent sex ratio of S. texanus at different stages in its life cycle to detect possible mechanisms affecting deviations from a 1:1 sex ratio and the effect of sex ratio on reproductive success. As S. texanus occurs in pure male, pure female and mixed sex clumps, I examined the proportions and sizes of these, the reproductive success of pure female and mixed sex clumps in the field and the sex ratio of germinating plants in a growth chamber. In both the field and the growth chamber the most abundant clump type was pure female followed by mixed sex and pure male clumps. These abundance patterns suggest that males have a lower survival rate than females before emergence and this lower survival rate continues through the gametophytic stage. This disadvantage may be due to the higher susceptibility of males to environmental conditions, to their competitive inferiority to females, and/or to differential resource allocation to the sexes within the spore tetrad. The female biased sex ratio at germination is consistent with predictions from sex ratio theory. Further my field data indicate that males may gain a survival benefit from growing in a mixed sex clump and both males and females benefit reproductively when they occur in mixed sex clumps.


Validation of gout diagnosis in electronic primary care medical records: A population-based study.
The main objective of the study was to see the concordance between the diagnosis of gout recorded in primary care electronic medical records and the ACR/EULAR 2015 classification criteria. A cross-sectional study was conducted using electronic medicals records in 7 primary care centres of Barcelona. Patients' data to study clinical diagnose and management was gathered from the primary care electronic medical records of the Catalonian health institute (Institut Català de la Salut, ICS) and phone interview. Patients were considered to have gout if they scored 8 or more points on the EULAR/ACR 2015 classification criteria for gout. In total, 70.9% of the patients with a gout diagnosis met ACR/EULAR 2015 criteria. Adding a hyperuricemia in a blood test in the EMR increased the percentage to 78.9%. 29.8% of the gout patients were not receiving urate-lowering therapy. 62.3% of the treated patients did not achieve the target uricemia (< 6mg/dL). The majority of gout patients from primary care electronic medical records fulfil ACR/EULAR gout criteria. This database can be used for observational studies. In most of the gout patients the urate target was not achieved.


Structure, physiological role, and specific inhibitors of human thymidine kinase 2 (TK2): present and future.
Human mitochondrial thymidine kinase (TK2) is a pyrimidine deoxynucleoside kinase (dNK) that catalyzes the phosphorylation of pyrimidine deoxynucleosides to their corresponding deoxynucleoside 5'-monophosphates by gamma-phosphoryl transfer from ATP. In resting cells, TK2 is suggested to play a key role in the mitochondrial salvage pathway to provide pyrimidine nucleotides for mitochondrial DNA (mtDNA) synthesis and maintenance. However, recently the physiological role of TK2turned out to have direct clinical relevance as well. Point mutations in the gene encoding TK2 have been correlated to mtDNA disorders in a heterogeneous group of patients suffering from the so-called mtDNA depletion syndrome (MDS). TK2 activity could also be involved in mitochondrial toxicity associated to prolonged treatment with antiviral nucleoside analogues like AZT and FIAU. Therefore, TK2 inhibitors can be considered as valuable tools to unravel the role of TK2 in the maintenance and homeostasis of mitochondrial nucleotide pools and mtDNA, and to clarify the contribution of TK2 activity to mitochondrial toxicity of certain antivirals. Highly selective TK-2 inhibitors having an acyclic nucleoside structure and efficiently discriminating between TK-2 and the closely related TK-1 have already been reported. It is actually unclear whether these agents efficiently reach the inner mitochondrial compartment. In the present review article,structural features of TK2, MDS-related mutations observed in TK2 and their role in MDS will be discussed. Also, an update on novel and selective TK2 inhibitors will be provided.


Repatriation of a patient with COVID-19 contributed to the importation of an emerging carbapenemase producer.
Patients hospitalised abroad can become colonised with multidrug-resistant bacteria and import them to their home countries. In this study, we characterised an OXA-484 carbapenemase-producing Escherichia coli strain from a Swiss patient infected by SARS-CoV-2 and repatriated from India. At admission to Switzerland (April 2021), the patient undertook a nasopharyngeal swab to search for SARS-CoV-2 and a rectal swab to detect multidrug-resistant bacteria. Both SARS-CoV-2 and E. coli isolates were whole-genome sequenced and analysed for phylogenetic relatedness. The patient was infected with the SARS-CoV-2 B.1.617.2 lineage (VOC Delta), a lineage that began to be reported across Switzerland at that time. He was also colonised with a sequence type 410 (ST410) E. coli strain (L3452210II) producing OXA-484, a single amino acid variant of OXA-181. The blaOXA-484 gene was carried by a 51.5 kb IncX3 plasmid identical to those described in blaOXA-181-harbouring ST410 E. coli strains. Core genome analysis showed that L3452210II was identical (ΔSNV ≤23) to two ST410 OXA-484 producers recently reported in Qatar and Germany, but differed from other ST410 OXA-181 producers reported worldwide. The patient was infected by an emerging SARS-CoV-2 variant and also imported an E. coli producing OXA-484, an OXA-48-like carbapenemase not yet reported in Switzerland. The genetic background of L3452210II indicated that blaOXA-484 shared the same plasmid as blaOXA-181, but its bacterial host differed from most of the pandemic OXA-181-producing ST410 strains reported previously. This case description underlines that the COVID-19 crisis can contribute to the worldwide spread of emerging carbapenemase producers.


Association of Val158Met polymorphism in COMT gene with attention-deficit hyperactive disorder: An updated meta-analysis.
The results of published articles on the relationship between the Val158Met polymorphism in the (Catechol-O-methyltransferase) COMT gene and the susceptibility of attention-deficit hyperactive disorder (ADHD) are controversial. We conducted an updated meta-analysis of case-control studies to assess the relationship between Val158Met polymorphism in COMT gene and ADHD susceptibility. A comprehensive literature search was conducted to identify all the case-control studies on the relationship between the COMT gene Val158Met polymorphism and ADHD susceptibility. According to the heterogeneity test results among studies evaluated with I, the fixed effect model or random effect model was selected as the pooling method. Meta-regression as well as sensitive analysis were used to explore possible causes of between-study heterogeneity. The funnel plot and Harbord test were used to estimate publication bias. Finally, seventeen studies that met the inclusion criteria were included. The Val158Met genotype distributions of COMT gene in controls were in Hardy-Weinberg equilibrium in all studies. In general, there was no significant association between the COMT gene Val158Met polymorphism and ADHD susceptibility in dominant, recessive, and codominant models. The recessive genetic model (I = 60.8%) showed strong heterogeneity among studies, and still no significant association was found after sensitivity analysis. Subgroup analysis stratified by ethnicity (Asian and Caucasian) also showed that there was no significant association in the above-mentioned three models. This updated meta-analysis indicated that the Val158Met polymorphism in the COMT gene may not be related to the risk of ADHD. Further researches are needed to confirm these results.


Bone marrow mesenchymal stem cells ameliorated kidney fibrosis by attenuating TLR4/NF-κB in diabetic rats.
Diabetic nephropathy (DN) is a chronic inflammatory complication of diabetes mellitus, which becomes the most common cause of end-stage renal disease (ESRD). Recently, bone marrow mesenchymal stem cells (BMSCs) are considered as a promising therapy for DN. However, the protective mechanism of BMSCs on DN remains unclear. This study was done to explore the effect of a bone marrow stromal cell (BMSCs) transplant on DN rats and rat glomerular mesangial cells in high-glucose concentration. Diabetic rats were induced by a single intraperitoneal injection of streptozotocin (STZ) 65 mg/kg, then 4 × 106 BMSCs were transplanted in diabetic rats as the treatment group. Six weeks after BMSCs transplantation, blood serum creatinine (Scr) and blood urea nitrogen (BUN) were used to test renal function. Renal pathological examination was observed by HE staining, Masson staining, PAS staining and immunohistochemistry. The results demonstrated that BMSCs could dramatically improve renal function and collagen accumulation by reducing Scr, BUN, collagen I and IV expression and histopathological abnormalities in the diabetic kidneys. Furthermore, BMSCs could significantly attenuate the expression of TLR4/NF-κB and MCP-1 in vitro and in vivo (P < 0.05, vs diabetic groups). This study reported a novel finding that BMSCs play a protective role in inhibition of inflammatory and fibrotic cytokines by down-regulating TLR-4/NF-κB expression under diabetic condition.


Evaluation of pesticide pollution in the Gualeguay Basin: An extensive agriculture area in Argentina.
The current agricultural production model was established in the 1990s based on the use of genetically modified organisms and agrochemicals, mainly pesticides. Despite pesticide spread and prevalence, data on the associated concentrations in surface watercourses are comparatively scarce. The aim of this work was to evaluate to what extent the >20 years of agricultural activity with the use of pesticides has impacted on the Gualeguay-River basin, with respect to the different stream orders: the tributary streams and main channel. Thirteen sites within the lower Gualeguay basin were sampled once every season (autumn, winter, spring, and summer) in 2017-2018. The samples were analyzed by gas chromatography time-of-flight mass-spectrometry (GC-TOF-MS) and ultraperformance liquid chromatography tandem mass-spectrometry (UPLC-MS/MS). The most frequently detected pesticide was glyphosate along with its metabolite (aminomethyl)phosphonic acid (AMPA), at 82 % and 71 % of surface water samples and 97 % and 92 % of bottom sediments, respectively; followed by atrazine in 73 % of the water samples. The concentrations of these compounds, each in their respective matrices, did not present sufficient statistically significant differences for differentiating a tributary stream from the main channel. Regardless of glyphosate's affinity for the suspended particulate and bottom sediments, over the entire basin the soluble fraction contributed on average to >80 % of the total concentration in surface water. Despite not being so frequently detected, certain insecticides, mostly deltamethrin, were likewise detected at concentrations above their water-quality guidelines for the protection of aquatic life, even in samples from the main channel. Upon comparison of the pesticide profiles of extensive- and horticultural-production systems in the country, atrazine emerged as a prime candidate to be used as a tracer of extensive agriculture contamination in the environment. Further research is required to establish to what degree pesticides used in agriculture and mobilized by watercourses have an impact on their associated wetland ecosystems.


Resveratrol as a new type of DNA-cleaving agent.
The first demonstration of DNA cleavage by resveratrol '3,5,4'-trihydroxy-trans-stilbene' is presented. Resveratrol mediated relaxation of pBR322 at micromolar concentrations in the presence of Cu2+. Evidence is provided that resveratrol is capable of binding to DNA, and that the Cu(2+)-dependent DNA damage is more likely caused by a copper-peroxide complex rather than by a freely diffusible oxygen species.


Laser-assisted delivery of vitamin C, vitamin E, and ferulic acid formula serum decreases fractional laser postoperative recovery by increased beta fibroblast growth factor expression.
Laser-assisted drug delivery is an emerging technology to achieve greater penetration by existing topical medications to reach desired targets in the tissue. The objective of this research was to study whether laser-assisted delivery of Vitamin C, E, and Ferulic immediately postoperatively of fractional ablative laser could improve wound healing. Secondary objectives were to evaluate the potential molecular markers involved in this wound-healing process. A double blinded, prospective, single center, randomized split face trial of Vitamin C, E, and Ferulic topical formula #740019 to decrease postoperative recovery time in fractional ablative laser resurfacing for photo damage. Fifteen healthy men and women of ages 30-55 years were treated with the Vitamin C, E, and Ferulic acid serum to one side of face and vehicle to the other side of face, within 2 minutes immediately after fractional ablative CO2 laser surgery and daily during the healing process. Patients were evaluated daily on days 1-7 using photographs, patient questionnaires, and molecular evaluation. Clinically, postoperative Vitamin C, E, and Ferulic delivery resulted in decreased edema versus vehicle on postoperative day 7 and decreased erythema versus vehicle on postoperative days 3 and 5. Molecularly, the expression of basic fibroblast growth factor (bFGF) was significantly increased at day 5 on the lesion treated with Vitamin C, E, and Ferulic acid serum compared to vehicle control on the other side. This is first study to show that Vitamin C, E, and Ferulic acid correlate with more rapid wound healing post-fractional ablative laser. Elevated bFGF could be involved in the Vitamin C, E, and Ferulic acid-induced rapid wound healing.


Inhibition of chemokine-like factor 1 improves blood-brain barrier dysfunction in rats following focal cerebral ischemia.
Disruption of blood-brain barrier (BBB) and subsequent edema are major contributors to the pathogenesis of ischemic stroke, and the current clinical therapy remains unsatisfied. Chemokine-like factor 1 (CKLF1), as a novel C-C chemokine, plays important roles in immune response. The expression of CKLF1 increased after focal cerebral ischemia and inhibition of CKLF1 activity showed neuroprotective effect by alleviating infiltration of neutrophil and neuron apoptosis in cerebral ischemia. However, few studies have focused on the role of CKLF1 on BBB integrity. The objective of present study was to investigate the role of CKLF1 on BBB integrity by applying anti-CKLF1 antibodies in rat focal cerebral ischemia and reperfusion model. Brain water content, Evans blue leakage and the expression of aquaporin-4 (AQP-4), matrix metalloproteinase-9 (MMP-9), Zonula Occludens-1 (ZO-1) and Occludin were measured. After treatment with anti-CKLF1 antibody, brain water content and Evans blue leakage in ipsilateral hemisphere were decreased in a dose-dependent manner at 24h after reperfusion, but not changed in contralateral hemisphere. Anti-CKLF1 antibody reduced the expression of AQP-4 and MMP-9, and upregulated the expression of ZO-1 and Occludin. These results suggest that CKLF1 is involved in BBB disruption after reperfusion. Inhibition of CKLF1 protects against cerebral ischemia by maintaining BBB integrity, possibly via inhibiting the expression of AQP-4 and MMP-9, and increasing the expression of tight junction protein.


Corporate social responsibility and firm performance nexus: Moderating role of CEO chair duality.
This study aims to explore the link between corporate social responsibility (CSR) and firm performance in the presence of the moderating role of CEO chair duality. It is widely believed that CSR initiatives and firm performance are largely influenced by psychological factors and the behavior of the decision maker (manager/CEO). Hence, CEO chair duality may play an instrumental role in shaping CSR initiatives to enhance firm performance. For empirical investigation, the study used the dynamic panel data method with generalized method of moment (GMM) parameters. The study considered 131 firms listed on the Pakistan Stock Exchange (PSX), yielding 1508 firm-year observations, over the period 2006 to 2020. Our results reveal that the impact of CSR on book-based and market-based measures differs due to the asymmetry of information in the market. The market discounts CEO chair duality due to the concentration of power and translates it into negative impact of CSR on firm performance. Thus, firms should not only improve CSR activities but also take steps to reduce asymmetry in markets because the impact on book-based measures and market-based measures of performance are not consistent. Society should also play a role to convince firms in a better way to take CSR initiatives. The perception of transparency should also be improved as CEO chair duality is being negatively seen by the market.


Enhancement in Curie Temperature of Yttrium Iron Garnet by Doping with Neodymium.
The effect of the substitution of Y3+ by Nd3+ on the structural and magnetic properties of neodymium-doped yttrium iron garnet, NdxY3-xFe₅O12 with x in the range of 0⁻2.5, is presented. Oxide powders of Fe₂O₃, Nd₂O₃, and Y₂O₃ were mixed in a stoichiometric ratio and milled for 5 h using high-energy ball milling, before being uniaxially pressed at 900 MPa and annealed at 1373 K for 2 h to obtain NdxY3-xFe₅O12 (0 ≤ x ≤ 2.5). It was found that the mechanical milling of oxides followed by annealing promotes the complete structural formation of the garnet structure. Additionally, the X-ray diffraction patterns confirm the complete introduction of Nd3+ into the garnet structure with a neodymium doping concentration (x) of 0⁻2.0, which causes a consistent increment in the lattice parameters with the Nd3+ content. When x is higher than 2.0, the yttrium orthoferrite is the predominant phase. Besides, the magnetic results reveal an increase in the Curie temperature (583 K) as the amount of Nd3+ increases, while there was enhanced saturation magnetization as well as modified remanence and coercivity with respect to non-doped YIG.


Protein-Pacing and Multi-Component Exercise Training Improves Physical Performance Outcomes in Exercise-Trained Women: The PRISE 3 Study.
The beneficial cardiometabolic and body composition effects of combined protein-pacing (P; 5-6 meals/day at 2.0 g/kg BW/day) and multi-mode exercise (resistance, interval, stretching, endurance; RISE) training (PRISE) in obese adults has previously been established. The current study examines PRISE on physical performance (endurance, strength and power) outcomes in healthy, physically active women. Thirty exercise-trained women (>4 days exercise/week) were randomized to either PRISE (n = 15) or a control (CON, 5-6 meals/day at 1.0 g/kg BW/day; n = 15) for 12 weeks. Muscular strength (1-RM bench press, 1-RM BP) endurance (sit-ups, SUs; push-ups, PUs), power (bench throws, BTs), blood pressure (BP), augmentation index, (AIx), and abdominal fat mass were assessed at Weeks 0 (pre) and 13 (post). At baseline, no differences existed between groups. Following the 12-week intervention, PRISE had greater gains (p < 0.05) in SUs, PUs (6 ± 7 vs. 10 ± 7, 40%; 8 ± 13 vs. 14 ± 12, 43% ∆reps, respectively), BTs (11 ± 35 vs. 44 ± 34, 75% ∆watts), AIx (1 ± 9 vs. -5 ± 11, 120%), and DBP (-5 ± 9 vs. -11 ± 11, 55% ∆mmHg). These findings suggest that combined protein-pacing (P; 5-6 meals/day at 2.0 g/kg BW/day) diet and multi-component exercise (RISE) training (PRISE) enhances muscular endurance, strength, power, and cardiovascular health in exercise-trained, active women.


A novel electrochemical biosensor based on horseradish peroxidase immobilized on Ag-nanoparticles/poly(l-arginine) modified carbon paste electrode toward the determination of pyrogallol/hydroquinone.
A novel electrochemical biosensor for the determination of pyrogallol (PG) and hydroquinone (HQ) has been constructed based on the poly l-arginine (poly(l-Arg))/carbon paste electrode (CPE) immobilized with horseradish peroxidase (HRP) and silver nanoparticles (AgNPs) through the silica sol-gel (SiSG) entrapment. The electrochemical properties of the biosensor were characterized by employing the electrochemical techniques. The proposed biosensor showed a high sensitivity and fast response toward the determination of PG and HQ around 0.18V. Under the optimized conditions, the anodic peak current of PG and HQ was linear with the concentration range of 8μM to 30×10(-5)M and 1-150μM. The limit of detection (LOD) and limit of quantification (LOQ) were found to be 6.2μM, 20μM for PG and 0.57μM, 1.92μM for HQ respectively. The electrochemical impedance spectroscopy (EIS) studies have confirmed that the occurrence of electron transfer at HRP-SiSG/AgNPs/poly(l-Arg)/CPE was faster. Moreover the stability, reproducibility and repeatability of the biosensor were also studied. The proposed biosensor was successfully applied for the determination of PG and HQ in real samples and the results were found to be satisfactory.


The socio-demographic profile of hanging suicides in Ireland from 1980 to 2005.
This paper provides a comparison of the socio-demographic profile of hanging suicides and suicides by other means in Ireland from January 1st 1980 to December 31st 2005. Data on 9674 suicides occurring in that time frame was provided by the Central Statistics Office of Ireland (CSO). 4031 (42%) of these deaths involved suicide by 'hanging, suffocation or strangulation' (HSS), with the remainder being suicides by other means. Binary logistic regressions were used to examine six potential risk factors for suicide across the two groups: Gender, marital status, employment in the agricultural sectors, residential location (urban/rural) and age were entered in Block 1 of the analysis, with year of death (pre 1994 vs. post 1994) added in a second block. Results indicate that those dying through hangings were statistically more likely to be male (OR=3.1, 95% CI=2.8-3.5), single (OR=1.3, 95% CI=1.2-1.4), rural-dwelling (OR=1.1, 95% CI=1.0-1.2), agri-employed (OR=1.3, 95% CI=1.1-1.4) and to have died since 1994 (OR=2.3, 95% CI=2.1-2.5). The magnitude of the group effect was moderate for all but the gender and time period comparisons. Hanging suicide victims (m=37.7, sd=16.7) were also significantly younger than other suicide victims (mean=42.72, sd=16.7), although the size of the effect was small (r=.16). Overall the six variables explained 6% of the variance in the criterion variable.


A Critical Look at Student Evaluations of Teaching.
Student evaluations of teaching are used at many schools and colleges of pharmacy as the primary, often exclusive, means of assessing the quality of instruction and instructor performance. As such, they can be pivotal in annual performance evaluations and rank and tenure decisions. However, serious concerns have been raised about these ubiquitous surveys and how, or even if, they should be used to measure the quality of instruction or the performance of the instructor. This commentary discusses concerns that have been raised about using student evaluations of teaching scores to assess teaching performance and offers recommendations for how they can be better interpreted and used in schools and colleges of pharmacy.


Activation of trkA induces differentiation and inhibits the growth of JK-GMS Askin tumor cells.
Peripheral primitive neuroectodermal tumor (PNET) and Ewing's sarcoma (ES) constitute a unique group of small round cell tumors in childhood and young adults that are characterized by the same chromosomal translocation t(11;22)(q24;q12). Recently, the expression of neurotrophin receptors has been found in various human tumors including PNET/ES, but the functional significance of these receptor expressions has not been documented in PNET/ES. In the present study, we investigated the biologic effects of trkA neurotrophin receptor activation by nerve growth factor (NGF) in a newly established Askin tumor cell line, JK-GMS, which constitutively expresses a high level of trkA. The activation of trkA induced differentiation and inhibited the growth of JK-GMS cells, which was characteristically associated with down-regulation of c-myc and N-myc mRNA expression. NGF did not exert significant changes in two different PNET/ES cell lines, CADO-ES1 and RD-ES, which did not express detectable levels of trkA. The biologic effects mediated by NGF were abrogated by treatment of the cells with K-252a, and the treatment with brain-derived neurotrophic factor did not affect the biologic behavior of JK-GMS cells, indicating that the effects are trkA specific. The results observed were quite similar to those of neuroblastoma cells, another childhood tumor of neural crest origin. Overall findings strongly suggest that the trkA-mediated signaling pathway plays a crucial role in controlling the basic biologic properties of JK-GMS cells.


Electromagnetic chirality: from fundamentals to nontraditional chiroptical phenomena.
Chirality arises universally across many different fields. Recent advancements in artificial nanomaterials have demonstrated chiroptical responses that far exceed those found in natural materials. Chiroptical phenomena are complicated processes that involve transitions between states with opposite parities, and solid interpretations of these observations are yet to be clearly provided. In this review, we present a comprehensive overview of the theoretical aspects of chirality in light, nanostructures, and nanosystems and their chiroptical interactions. Descriptions of observed chiroptical phenomena based on these fundamentals are intensively discussed. We start with the strong intrinsic and extrinsic chirality in plasmonic nanoparticle systems, followed by enantioselective sensing and optical manipulation, and then conclude with orbital angular momentum-dependent responses. This review will be helpful for understanding the mechanisms behind chiroptical phenomena based on underlying chiral properties and useful for interpreting chiroptical systems for further studies.


Bone mesenchymal stem cell therapy for ovariectomized osteoporotic rats: a systematic review and meta-analysis.
Previous studies have found that bone mesenchymal stem cells (BMSCs) were capable of self-replication, multi-differentiation, and regeneration. The aim of this study was to carry out a systematic review and meta-analysis of the efficacy of BMSC therapy for ovariectomized rats. The PubMed, Embase, Web of Science, China National Knowledge Infrastructure, VIP, and Chinese Sinomed databases were searched systematically from their initiation date to October 5, 2018. Two researchers independently screened the literatures, which used the bone mineral density (BMD), total bone volume by total tissue volume (BV/TV) (%), and trabecular thickness/spacing (Tb/Sp) as the outcome measures. Five eligible studies were selected. In the BMSC treatment groups, the BMD values and normalized BV/TV values remarkably increased. In addition, in the BMSCs plus other treatment groups, the BMD and Tb/Sp values significantly increased. This study showed that BMSCs could accelerate callus maturity, ossification and restore mechanical properties of bones in osteoporotic fractures.


The role of p-Stat3 Y705 immunohistochemistry in glioblastoma prognosis.
In spite of the multimodal treatment used today, glioblastoma is still the most aggressive and lethal cerebral tumour. To increase survival in these patients, novel therapeutic targets must be discovered. Signal transducer and activator of transcription 3 (Stat3), a transcription factor that controls normal cell differentiation and survival is also involved in neoplastic celltransformation. In this study we evaluated the immunohistochemical expression of pY705-Stat3 in patients with primary glioblastoma and determined its prognostic role by correlating it with survival. This retrospective study included 94 patients diagnosed with glioblastoma. We determined the localization, number of positive cells, and marker intensity for pY705-Stat3 in these patients with the use of immunohistochemistry. The prognostic role was determined by correlating pY705-Stat3 expression on formalin-fixed paraffin-embedded tumour tissues with the patient's survival in univariate and multivariate COX regressions. We found a statistically significant difference in survival between the patients with more than 20% pY705-Stat3 positive cells and those with less than 20% pY705-Stat3 positive cells (8.9 months median survival versus 13.7 months medial survival, p < 0.001). On multivariate analyses with the COX proportional hazards regression model including pY705-Stat3 expression, age and relapse status, pY705-Stat3 status was an independent prognostic factor in glioblastoma (P < 0.001). The results obtained show that the immunohistochemical expression of pY705-Stat3 correlates with survival in glioblastoma. This study identifies Stat3 as a possible target for existing or new developed Stat3 inhibitors.


Oxidative stability and radical scavenging activity of extra virgin olive oils: an electron paramagnetic resonance spectroscopy study.
The oxidative stability of extra virgin olive oils (EVOO) from the Greek island of Crete was evaluated by electron paramagnetic resonance (EPR) spectroscopy and the spin trapping technique. The spin trap N-t-butyl-alpha-phenylnitrone (PBN) was added to the olive oil samples and the production of free radicals was monitored during heating at 70 degrees C. Induction time for the accelerated oxidation of virgin olive oils at 70 degrees C was determined. The EPR results were compared with the oxidative stability values provided by the Rancimat method at 110 degrees C and high linear correlations were found (r=0.922). EPR spin trapping provides a sensitive and rapid method for evaluating the oxidative stability of EVOO. The same samples of Greek extra virgin olive oils were also examined for their radical scavenging activity (RSA) toward the stable galvinoxyl radical by EPR spectroscopy. The decrease of the intensity of the EPR signal upon incubation time was followed. Both oxidative stability and radical scavenging activity of EVOO samples were correlated to their content in polyphenols and tocopherols.


Neurological pathologies in acute acquired comitant esotropia.
Acute acquired comitant esotropia (AACE) is an uncommon subtype of esotropia characterized by sudden and usually late onset of a relatively large angle of comitant esotropia with diplopia in older children and adults. A literature survey regarding neurological pathologies in AACE was conducted using databases (PubMed, MEDLINE, EMBASE, BioMed Central, the Cochrane Library, and Web of Science) in order to collect data for a narrative review of published reports and available literature. The results of the literature survey were analyzed to provide an overview of the current knowledge of neurological pathologies in AACE. The results revealed that AACE with unclear etiologies can occur in many cases in both children and adults. Functional etiological factors for AACE were found to be due to many reasons, such as functional accommodative spasm, the excessive near work use of mobile phones/smartphones, and other digital screens. In addition, AACE was found to be associated with neurological disorders, such as astrocytoma of the corpus callosum, medulloblastoma, tumors of the brain stem or cerebellum, Arnold-Chiari malformation, cerebellar astrocytoma, Chiari 1 malformation, idiopathic intracranial hypertension, pontine glioma, cerebellar ataxia, thalamic lesions, myasthenia gravis, certain types of seizures, and hydrocephalus. Previously reported cases of AACE with unknown etiologies have been reported in both children and adults. However, AACE can be associated with neurological disorders that require neuroimaging probes. The author recommends that clinicians should perform comprehensive neurological assessments to rule out neurological pathologies in AACE, especially in the presence of nystagmus or abnormal ocular and neurological indications (e.g., headache, cerebellar imbalance, weakness, nystagmus, papilloedema, clumsiness, and poor motor coordination).


A mobile application tool for standing posture analysis: development, validity, and reliability.
Using mobile application for postural assessments has been drawing a rising interest due to widespread use of smartphones. Although there are some mobile applications in use, validated mobile tools for accurate postural assessment are still warranted. This study aimed to develop Fizyoprint mobile application tool to assess standing posture and investigate the validity and reliability of the application in young adults. A convenience sample of 20 young adults (12 men and 8 women with a mean age of 21.3 ± 2.2 years) and 2 physiotherapists as raters participated in the study. The participant's digital images were obtained from the anterior, posterior, and right lateral sides. The raters selected the anatomic reference points by using digital markers in the app screen, and the Fizyoprint application, with Turkish language option, calculated a total of 26 posture variables, including 11 distance and 15 angle variables. Each participant was assessed twice (1-week interval) by 2 raters with Fizyoprint. Inter- and intra-rater reliabilities were estimated using the intraclass correlation coefficient. The BioTonix™ posture analysis system was used for validation. A total of 80.7% (21 variables) indicated acceptable to excellent intra-rater reliability results. A total of 57.7% (15 variables) were found to be acceptable to excellent for inter-rater measurements. The results confirmed the validity of the Fizyoprint application for testing the standing posture. Fizyoprint application is a new, valid, free mobile tool with acceptable concordance with BioTonix™ postural analysis system for assessing standing posture. Further studies are warranted to test the current application in different populations and musculoskeletal conditions.


[Plasma-cell granuloma of the kidney pelvis].
To report a rare case of plasma cell granuloma of the renal pelvis. To our knowledge, only five cases have been reported in the literature. Clinicopathological description of a case of plasma cell granuloma of the renal pelvis with light chain immunohistochemical study. A young male patient with a radiologically benign mass in the right renal pelvis extending into the upper calices that caused hematuria is described. The diagnosis was suggested during the intraoperative study of the mass that was suggested by pyelotomy (conservative surgery). Immunohistochemical study confirmed the initial diagnosis. Although this condition is rare, plasma cell granuloma, an inflammatory pseudotumor, can occur in the urinary tract and should be considered in the differential diagnosis of mass lesions. Histopathological diagnosis requires a complete study of the entire tumor and the use of immunohistochemical techniques to discard plasmacytic non-Hodgkin lymphoma or neoplastic plasma cell proliferation.


Increased accumulation of N-isopropyl-(I-123) p-iodoamphetamine in the left auditory area in a schizophrenic patient with auditory hallucinations.
A schizophrenic patient with auditory hallucinations is reported in which IMP markedly accumulated in the left superior temporal and inferior parietal lobes which correspond to the left primary and secondary cortical auditory areas and angular gyrus, respectively.


A molecular mechanism that links Hippo signalling to the inhibition of Wnt/β-catenin signalling.
The Hippo signalling pathway has emerged as a key regulator of organ size, tissue homeostasis, and patterning. Recent studies have shown that two effectors in this pathway, YAP/TAZ, modulate Wnt/β-catenin signalling through their interaction with β-catenin or Dishevelled, depending on biological contexts. Here, we identify a novel mechanism through which Hippo signalling inhibits Wnt/β-catenin signalling. We show that YAP and TAZ, the transcriptional co-activators in the Hippo pathway, suppress Wnt signalling without suppressing the stability of β-catenin but through preventing its nuclear translocation. Our results show that YAP/TAZ binds to β-catenin, thereby suppressing Wnt-target gene expression, and that the Hippo pathway-stimulated phosphorylation of YAP, which induces cytoplasmic translocation of YAP, is required for the YAP-mediated inhibition of Wnt/β-catenin signalling. We also find that downregulation of Hippo signalling correlates with upregulation of β-catenin signalling in colorectal cancers. Remarkably, our analysis demonstrates that phosphorylated YAP suppresses nuclear translocation of β-catenin by directly binding to it in the cytoplasm. These results provide a novel mechanism, in which Hippo signalling antagonizes Wnt signalling by regulating nuclear translocation of β-catenin.


Topical vs Intravenous Tranexamic Acid in Reducing Blood Loss After Bilateral Total Knee Arthroplasty: A Prospective Study.
Total knee arthroplasty (TKA) results in substantial postoperative blood loss with increased morbidity. Despite various studies proving the efficacy of tranexamic acid (TXA), no consensus exists on the routes of administration. Seventy consecutive patients with knee arthritis undergoing simultaneous bilateral TKA, who were eligible and fulfilled the criteria, were taken up for this study. They were randomly allocated by a computer-generated random number table, either to receive intravenous TXA (IVTXA; group 1) or topical TXA (TTXA; group 2) in a prospective, double-blinded study. The primary outcome measures were total blood loss and total drain output. The secondary outcome measures were number of blood units transfused and clinical and functional outcomes as evaluated by the Knee Society Score, Western Ontario and McMaster Universities Arthritis Index score, visual analog score, and wound score. Both groups were similar in age, sex, and body mass index, and no statistical significance was observed. There was statistically significant difference between IVTXA and TTXA groups in mean postoperative total blood loss (P < .001), postoperative hemoglobin (P < .001) with a higher drop of hemoglobin in the former, total drain output (P < .001), and allogeneic blood transfusion (P < .001). No complication was observed in either group. Significant difference was observed in the Western Ontario and McMaster Universities Arthritis Index score at 12 weeks and 6 months (P = .015 and .007) and Knee Society Score at 6 and 12 months (P = .050 and .045, respectively). However, no significant difference was found at 6 weeks. TTXA is better than IVTXA in reducing blood loss and clinical outcome after simultaneous bilateral TKA.


Prevalence of psychiatric disorders among heroin users who received methadone maintenance therapy in Taiwan.
Many patients under methadone maintenance treatment are present with comorbid psychiatric symptoms. We wish to examine the prevalence of psychiatric disorders among heroin users who received methadone maintenance therapy (MMT) in Taiwan. By combining the National Health Insurance Research database and Center for Disease Control database, 18,271 heroin users who received MMT were defined as the subject group and after matching age and sex, 73,084 patients were randomly selected as the control group. The 1 year prevalence of any psychiatric disorder, any psychotic disorder, neurotic and other nonpsychotic disorder among MMT patients and control group were 13.14% versus 2.50% (OR 5.89, CI 5.53-6.27), 4.21% versus 1.29% (OR 3.38, CI 3.07-3.72), and 9.89% versus 1.31% (OR 8.25, CI 7.62-8.94), respectively. The prevalence of any co-morbid psychiatric disorder among MMT patients is almost six times higher than the control group. A thorough psychiatric screening and appropriate aggressive intervention should be incorporated into an effective methadone treatment program.


Enzymatic reduction of acetophenone derivatives with a benzil reductase from Pichia glucozyma (KRED1-Pglu): electronic and steric effects on activity and enantioselectivity.
A recombinant ketoreductase from Pichia glucozyma (KRED1-Pglu) was used for the enantioselective reduction of various mono-substituted acetophenones. Reaction rates of meta- and para-derivatives were consistent with the electronic effects described by σ-Hammett coefficients; on the other hand, enantioselectivity was determined by an opposite orientation of the substrate in the binding pocket. Reduction of ortho-derivatives occurred only with substrates bearing substituents with low steric impact (i.e., F and CN). Reactivity was controlled by stereoelectronic features (C[double bond, length as m-dash]O length and charge, shape of LUMO frontier molecular orbitals), which can be theoretically calculated.


Macromolecule absorption and cortisol secretion in newborn calves derived from in vitro produced embryos.
Earlier reports indicate that calves derived from in vitro produced (IVP) embryos are more susceptible to neonatal disease than calves produced after artificial insemination (AI) or natural mating. The aims of the present study were to investigate whether calves born after IVP embryos show an altered macromolecule absorption (immunoglobulin G (IgG) and porcine serum albumin (PSA)) compared with AI calves and whether the macromolecule absorption could be related to the degree of acidosis or to the cortisol secretion around birth. Hence, IgG and PSA absorption in control AI calves (n=7) was compared with that in two groups of IVP calves (IVP-defined: SOFaa embryo culture with polyvinyl alcohol, n=6; IVP-serum: SOFaa embryo culture with serum and co-culture, n=8). The calves were fed colostrum (40ml/kg) at 2, 6 and 12h after birth. At 24h after birth, both AI and IVP calves had achieved a level of plasma IgG sufficient to provide passive immunization (>15mg/ml). When the values were adjusted for the varying colostral IgG contents and the degree of acidosis, the IVP-defined calves had significantly lower peak plasma IgG concentrations than the AI calves at 18-24h after birth (P<0.04). However, when the macromolecule marker (PSA), was fed to all calves at 2 and 12h after birth the resulting plasma PSA levels were significantly lower in the AI calves compared with the IVP calves during the whole observation period (P<0.0001). Calves with a moderate neonatal acidosis (mean pH<7.2 during the first 30min after birth) had reduced peak plasma IgG concentration at 18-24h after birth (P<0.02) compared to calves without acidosis. The basal and ACTH-stimulated cortisol levels were lower in the newborn IVP-defined calves than in the AI calves (P<0.05) and the IVP-serum calves (P<0.002). Cortisol levels shortly after birth correlated positively with birth weight (r=0.60, P<0.0001) and with gestation length (r=0.34, P<0.04). Since, the IVP calves absorbed sufficient amounts of IgG from colostrum to acquire sufficient passive immunity, we conclude that the lower viability described in IVP offspring probably is not caused by an impaired passive immunization. IVP-defined calves had significantly lower absorption efficiency of IgG compared with AI calves, whereas absorption of a non-Ig macromolecule (PSA) was higher for IVP than AI calves. This might indicate a more selective absorption in AI calves in favor of IgG. Acidosis around birth affected immunoglobulin absorption negatively. IVP-defined calves had significantly lower cortisol levels the first 3h after birth and during an ACTH-challenge and a lower IgG absorption efficiency, which might indicate a mild degree of organ dysmaturity in these calves.


Sequence of centromere separation: characterization of multicentric chromosomes in a rat cell line.
The B1 cell line of rat cerebral endothelium origin exhibits several dicentric and multicentric chromosomes. These chromosomes, unlike multicentrics in mouse (Vig and Zinkowski 1986) do not show premature centromere separation. All centromeres deposit kinetochore proteins and appear to be functional. Even the centromeres which fail to migrate to the poles during anaphase and make side arm bridges bind to spindle microtubules. Some multicentric chromosomes show kinetochores spaced apart with intervening stretches of euchromatin while others are located adjacent to each other thus exhibiting tandem repeats and forming a "compound" kinetochore (Brinkeley et al. 1984). Also, unlike mouse multicentric chromosomes in which different pericentric regions and the centromeres replicate at different times, the rat chromosomes appear to replicate all pericentric and centric regions in a given multicentric simultaneously. The present studies indicate that centromeres in rat and mouse replicate during the last part of the S-phase and in continuation with the pericentric heterochromatin.


Surgical resident research productivity over 16 years.
General surgery training has changed over the past decade due to the 80-hour work week and increasing demands on the surgery faculty to generate clinical revenue with ever decreasing reimbursements. The purpose of this study was to evaluate surgery resident productivity over the years and the surgery resident's contribution to clinical and basic research literature. A PubMed literature search of all graduating chief residents (n = 95) over a 16-y period from a single university-based general surgery program were evaluated. Number and types of publications (clinical paper versus basic science paper) were analyzed for each resident. A cohort of residents graduating from the years 1990 to 1996 (n = 42) were deemed the early group and a cohort of residents graduating from the years 1999 to 2005 (n = 41) were deemed the late group. Residents graduating in 1997 and 1998 were deemed the washout group. From 1990 to 2005, there were 95 graduates with 204 published articles. Resident research time ranged from 0 to 2 y, with most residents spending 1 y of research time. In the early group, residents averaged 2.0 +/- 0.4 papers versus the late group where each resident published 2.6 +/- 0.5 papers (P = NS). In the early group, 24.4% of the papers were basic science in nature as opposed to the late group where 27.7% of the papers were with a basic science topic (P = NS, chi(2) analysis). Resident research productivity at a single university-based program with an elective research time does not appear to be deteriorating over time. A majority of research performed by residents is clinically oriented; however. basic science research does not appear to be decreasing. Careful scrutiny to resident research productivity is needed to ensure productive future academic surgeons.


Patterns of fungal diversity in New Zealand Nothofagus forests.
The development of protocols for the conservation of fungi requires knowledge of the factors controlling their distribution, diversity, and community composition. Here we compare patterns of variation in fungal communities across New Zealand's Nothofagus forests, reportedly the most myco-diverse in New Zealand and hence potentially key to effective conservation of fungi in New Zealand. Diversity of leaf endophytic fungi, as assessed by culturing on agar plates, is assessed for three Nothofagus sp. growing in mixed stands from four sites. Host species was found to have a greater influence on fungal community assemblage than site. The leaf endophyte communities associated with Nothofagus solandri and Nothofagus fusca (both Nothofagus subgenus Fuscopora), were more similar to each other than either were to the community associated with Nothofagus menziesii (Nothofagus subgenus Lophozonia). The broad taxonomic groups isolated, identified on the basis of internal transcribed spacer (ITS) sequences, were similar to those found in similar studies from other parts of the world, and from an earlier study on the endophyte diversity in four podocarp species from New Zealand, but there were few matches at species level. Average levels of endophyte species diversity associated with single Nothofagus species and single podocarp species were similar, despite historical literature and collection data recording more than twice as many fungal species on average from the Nothofagus species. The significance of these findings to fungal conservation is discussed.


Targeted Drug Delivery and Theranostic Strategies in Malignant Lymphomas.
Malignant lymphomas represent the most common type of hematologic malignancies. The first clinically approved TDD modalities in lymphoma patients were anti-CD20 radioimmunoconjugates (RIT) 131I-tositumomab and 90Y-ibritumomab-tiuxetan. The later clinical success of the first approved antibody-drug conjugate (ADC) for the treatment of lymphomas, anti-CD30 brentuximab vedotin, paved the path for the preclinical development and clinical testing of several other ADCs, including polatuzumab vedotin and loncastuximab tesirine. Other modalities of TDD are based on new formulations of "old" cytostatic agents and their passive trapping in the lymphoma tissue by means of the enhanced permeability and retention (EPR) effect. Currently, the diagnostic and restaging procedures in aggressive lymphomas are based on nuclear imaging, namely PET. A theranostic approach that combines diagnostic or restaging lymphoma imaging with targeted treatment represents an appealing innovative strategy in personalized medicine. The future of theranostics will require not only the capability to provide suitable disease-specific molecular probes but also expertise on big data processing and evaluation. Here, we review the concept of targeted drug delivery in malignant lymphomas from RIT and ADC to a wide array of passively and actively targeted nano-sized investigational agents. We also discuss the future of molecular imaging with special focus on monoclonal antibody-based and monoclonal antibody-derived theranostic strategies.


Persistent retention of acetic acid is associated with complete tumour necrosis in patients with hepatocellular carcinoma undergoing percutaneous acetic acid injection.
Ultrasound (US)-guided percutaneous acetic acid injection therapy (PAIT) is effective for patients with hepatocellular carcinoma (HCC). This study aimed to determine the occurrence and predictive value of persistent intra-tumoral retention of acetic acid after PAIT. We prospectively studied 60 (52 M, mean age 68 +/- 10 years) patients with 72 HCC nodules (45 < or = 3 cm) treated with PAIT. The presence of post-treatment persistent retention of acetic acid, defined as a homogeneous and highly hyperechoid mass in US appearance 3 days after completion of the treatment, was correlated with the treatment response. The mean size of the treated tumour was 2.9 +/- 1.0 cm (range 1.5-5 cm). Thirty (42%) HCC nodules showed complete tumour necrosis demonstrated by contrast-enhanced dynamic CT. Complete response was found in 22 (69%) of 32 nodules showing persistent intra-tumoral retention of acetic acid (P < 0.001). Small (< or = 3 cm) tumour size was also significantly associated with complete tumour necrosis (P = 0.001). There were no significant differences of the injection volume and treatment sessions between those with and without complete tumour necrosis in either small or large (> 3 cm) HCC (P > 0.1). Multivariate logistic regression analysis showed that persistent retention of acetic acid (odds ratio (OR) 10.4, 95% confidence interval (CI) 3.1-34.7; P < 0.001) and tumour size < or = 3 cm (OR 6.8, 95%, CI 1.8-25.8; P = 0.002) were independent factors predicting complete tumour necrosis. The presence of persistent retention of acetic acid is associated with a favourable response and may predict complete tumour necrosis after PAIT.


Endoscopic Treatment for Large Multifocal Upper Tract Urothelial Carcinoma.
We reviewed the oncologic and surgical outcomes of endoscopic treatments for low grade upper tract urothelial carcinoma, and assessed the prognostic significance of tumor size, location and multifocality. We retrospectively reviewed all patients who underwent endoscopic treatment for low grade upper tract urothelial carcinoma at our institution between 2014 and 2019. Tumors were treated with a dual laser generator, which alternately produces holmium and neodymium lasers. A stringent ureteroscopic followup protocol was conducted. We looked for an association between outcome and tumor size, location or multifocality, and for predictive factors for time to local recurrence and progression. The cohort included 59 patients (62 renal units), 27% of tumors were multifocal and 40% were >2 cm. The median followup time was 22 months (IQR 11-41), and the median number of ureteroscopies was 5.5 (4-9). Local recurrence was observed in 46 renal units (74.1%) at a median of 6.5 months after initial surgery. Four patients (6.4%) developed disease progression and were referred for radical surgery: 2 had pathological progression and 2 had a rapid and high volume local recurrence, and 1 later developed metastatic disease. The progression-free rate was 93.2%. Tumor location in kidney (p=0.03, HR 1.95) and multifocality (p=0.005, HR 3.25) significantly predicted time to local recurrence. No factor predicted time to progression. Ureteroscopic treatment of large, multifocal, low grade upper tract urothelial carcinoma is feasible, does not involve significant complications and has good short-term oncologic outcomes, with a 93.2% progression-free survival rate. Tumors located in the kidney and multifocality yielded shorter time to local recurrence but not progression.


The expression of β-galactosidase during long-term cultured goat skin fibroblasts and the effect of donor cell passage on in vitro development of nuclear transfer embryos.
The present study aimed to detect the expression of β-galactosidase during long-term cultured goat skin fibroblasts and investigate the effects of donor goat age, sex, and cell passage on senescence and the effects of donor cell passage on in vitro development of nuclear transfer embryos. The results showed that, in the same cell passage, more β-galactosidase-positive cells were detected in cells from older donors than younger donors. Irrespective of the donor age, the number of positive cells was higher in later passages from passages 20 to 50. In the same passage from 20 to 50, the β-galactosidase-positive rate was higher in cells from 5-yr female goat than 5-yr male goat. Using fibroblasts from male goats at various passages as donor cells, reconstructed embryos had similar fusion and cleavage rates, but the blastocyst rate was higher for cells at passages 10 and 20 than passage 30. In conclusion, donor goat age and cell passage had significant effects on the β-galactosidase-positive rate; also, cells from 5-yr female goat had a higher β-galactosidase-positive rate than those from 5-yr male goat, and the donor cell passage affected the developmental potential of nuclear transfer embryos.


The cardiovascular protective effect and mechanism of calycosin and its derivatives.
Cardiovascular disease is the main cause of mortality and morbidity in the world, especially in developing countries. Drug therapy is one of the main ways to treat cardiovascular diseases. Among them, great progress has been made in the treatment of cardiovascular diseases with traditional Chinese medicine. In terms of experimental research, the mechanism of traditional Chinese medicine in the treatment of cardiovascular diseases has been thoroughly discussed in vitro and in vivo. In terms of clinical treatment, traditional Chinese medicine with flavonoids, saponins and alkaloids as the main effective components has a definite effect on the treatment of cardiovascular diseases such as arrhythmia, myocardial ischemia, angina pectoris and myocardial infarction, with high safety and good application prospects. With the further research on the effective ingredients, mechanism and adverse reactions of traditional Chinese medicine, it will be beneficial to the effectiveness of traditional Chinese medicine, reduce side effects and promote the modernization of traditional Chinese medicine. Calycosin and its derivatives, the main bioactive flavonoids in Astragalus membranaceus have multiple biological effects, such as antioxidant, pro-angiogenesis, anti-tumour, and anti-inflammatory effects. Based on the above biological effects, calycosin has been shown to have good potential for cardiovascular protection. The potent antioxidant effect of calycosin may play an important role in the cardiovascular protective potential. For injured cardiac myocytes, calycosin and its derivatives can alleviate the cell damage mainly marked by the release of myocardial enzymes and reduce the death level of cardiac myocytes mainly characterized by apoptosis through various mechanisms. For vascular endothelial cells, calycosin also has multiple effects and multiple mechanisms, such as promoting vascular endothelial cell proliferation, exerting vasodilating effect and directly affecting the synthesis function of endothelial cells. The present review will address the bioactivity of calycosin in cardiovascular diseases such as protective effects on cardiac myocytes and vascular endothelial cells and elucidate main mechanism of calycosin and its derivatives to exert the above biological effects.


BCL-2 family proteins modulate radiosensitivity in human malignant glioma cells.
Radiotherapy is the standard treatment for glioblastoma. Here, we assessed the radiosensitivity of 12 human malignant glioma cell lines in vitro and correlated these data with irradiation-induced cell cycle changes, chemosensitivity profiles and BCL-2 family protein expression. Irradiation at 3 Gy failed to cause major cell cycle perturbations. Radioresistance was associated with collateral sensitivity to the topoisomerase II inhibitors, teniposide and doxorubicin. High levels of BCL-XL and low levels of BAX were independently linked to radioresistance. Ectopic expression of a BAX transgene induced radiosensitization in the LN-18 cell line. Thus, BCL-2 family protein expression modulates radiosensitivity in human glioma cells and targeted alterations in BCL-2 family protein expression are a promising strategy to improve the therapeutic efficacy of radiotherapy for gliomas.


Atypical Presentation of Aneurysmal Subarachnoid Hemorrhage: Incidence and Clinical Importance.
The symptoms of sudden severe headache and/or diminished consciousness characterize the onset of aneurysmal subarachnoid hemorrhage (SAH). However, several studies have suggested that some patients show an atypical presentation at the onset: symptoms lacking sudden headache and diminished consciousness. The aim of this study was to investigate the incidence and clinical features of cases with atypical onset. Retrospective observational study based on the data collected prospectively from all patients with SAH admitted to our hospital was performed. Cases with a sudden headache at the onset were classified as the headache onset group, and cases with onset symptoms other than headache were classified as the atypical onset group. The clinical parameters were compared between the two groups. Of the 368 patients with SAH, 75 (20.4%) showed diminished consciousness from onset, 279 (75.8%) comprised the headache onset group, and 14 (3.8%) comprised the atypical onset group. The main symptoms in the atypical onset group were nausea or vomiting, vertigo or dizziness, and neck pain or back pain. The rate of misdiagnosis of SAH and the rate of rebleeding after misdiagnosis were higher in the atypical onset group (P = .045 and P = .043, respectively). The interval from onset to diagnosis was longer in the atypical onset group (P = .033). The atypical onset group demonstrated a more severe clinical grade on admission (P = .009), a lower rate of ruptured aneurysm repair (P < .001), and a poorer outcome (P = .003). Atypical onset is rare but has a great impact on the clinical course through rebleeding exacerbated by misdiagnosis or delayed diagnosis, resulting in poor outcomes.


The effect of measurement error in risk factors that change over time in cohort studies: do simple methods overcorrect for 'regression dilution'?
The attenuation of the relationship between disease and a risk factor subject to error through 'regression dilution' is well recognized, and researchers often make attempts to adjust for its effects. However, the adjustment methods most often adopted in cohort studies make an implicit assumption that the relationship is driven exclusively by current error-free levels of the risk factor and not by past levels. Here we investigate the bias that is introduced if this assumption is invalid. We model disease risk at a particular time in terms of error-free levels of the risk factor at that time and in past periods, and summarize the 'life-course' risk factor-disease relationship using crude current level, history adjusted current level and lifetime level associations. Using systolic blood pressure data from the Framingham Heart Study we show the impact of measurement error on these associations and investigate the biases that can occur with simple correction methods. A simple 'ratio of ranges' type correction factor overestimates the lifetime level association by 29% in the presence of a relatively modest dependency of current risk on past levels (levels 5 years ago half as predictive of current risk as current levels). Simple methods of correction for regression dilution bias can lead to substantial overcorrection if the risk factor-disease relationship is not short term.