Acute pain management.
We encounter patients with acute pain many times each day, and few aspects of veterinary practice offer such an opportunity to help so many in such a profoundly rewarding way. As emphasized here and elsewhere, we now have excellent tools with which to help these animals, and the biggest impediment to optimal treatment of their pain is often our own difficulty in recognizing its presence. Perhaps the single most important aspect of treating acute pain is to cultivate an ability to see past our personal biases and expectations which may limit treatment and to rediscover the common sense we had about pain before we entered the profession. By rededicating ourselves to seeking out, preventing, and relieving pain, we not only perform a vital service for our patients but also elevate our profession even as we reap financial and spiritual rewards for our efforts. What could be better?


Ferritin confers protection against iron-mediated neurotoxicity and ferroptosis through iron chelating mechanisms in MPP+-induced MES23.5 dopaminergic cells.
Ferritin is the main iron storage protein and plays an important role in maintaining iron homeostasis. In a previous study, we reported that apoferritin exerted a neuroprotective effect against MPTP by regulation of brain iron metabolism and ferroptosis. However, the precise cellular mechanisms of extracellular ferritin underlying this protection are not fully elucidated. Ferritin was reported to be localized in different intracellular compartments, cytoplasm or released outside cells. Here we demonstrated that the intracellular iron increased after iron treatment in primary cultured astrocytes. These iron-loaded astrocytes released more ferritin in order to buffer extracellular iron. Using co-culture system of primary cultured astrocytes and MES23.5 dopaminergic cells, we showed that ferritin released by astrocytes could enter MES23.5 dopaminergic cells. And primary cultured astrocytes protected MES23.5 dopaminergic cells against 1-methyl-4-phenylpyridinium ion (MPP+)-induced neurotoxicity and ferroptosis. In addition, we found that exogenous Apoferritin or Ferritin pretreatment could significantly inhibit MPP+-induced cell damage by restoring the cell viability and mitochondrial transmembrane potential (ΔΨm). Furthermore, exogenous Apoferritin and Ferritin might also protect MES23.5 dopaminergic cells against MPP+ by decreasing reactive oxygen species (ROS) and inhibiting the increase of the labile iron pool (LIP). This suggests that astrocytes increased ferritin release to respond to iron overload, which might inhibit iron-mediated oxidative damage and ferroptosis of dopamine (DA) neurons in Parkinson's disease (PD).


Effectiveness of Everolimus Versus Endocrine Monotherapy or Chemotherapy Among HR+/HER2- mBC Patients With Multiple Metastatic Sites.
This review compared the real-world effectiveness of everolimus-based therapy versus endocrine monotherapy or chemotherapy in postmenopausal hormone receptor positive (HR+)/ human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) patients with multiple metastatic sites. This retrospective chart review examined a nationwide sample of postmenopausal HR+/HER2- mBC women with ≥2 non-lymph-node metastatic sites. Patients must have initiated everolimus-based therapy (monotherapy or combination therapy including everolimus), endocrine monotherapy (any endocrine agent), or chemotherapy (monotherapy or combination with another chemotherapeutic or endocrine agent) for mBC between July 1, 2012 and August 15, 2013 after nonsteroidal aromatase inhibitor failure. Progression-free survival and time on treatment were compared using Kaplan-Meier analysis and Cox proportional hazard models, adjusting for line of therapy and baseline characteristics. One hundred patients received everolimus-based therapy, 79 received endocrine monotherapy, and 86 received chemotherapy. Everolimus-based therapy was associated with significantly longer progression-free survival and time on treatment than endocrine monotherapy and chemotherapy. Among HR+/HER2- mBC patients with multiple metastatic sites, everolimus-based therapy was associated with better real-world effectiveness than endocrine monotherapy or chemotherapy.


Changes in perceived attentional function in women following breast cancer surgery.
After treatment for breast cancer, many women experience cognitive problems, as determined by objective neuropsychological tests. However, the ecological validity of these tests has been questioned. This study explored the trajectory of perceived attentional function from before to 24 months after surgery in women with breast cancer and examined the effect of adjuvant treatment on this perceived attentional function. Women with breast cancer (N = 200) were assessed for perceived cognitive function by measuring attentional function using the attentional function index (AFI). Covariates included anxiety, depression, fatigue, and sleep disturbance. Perceived attentional function declined in 54% of women at 1 month after surgery. At 1 and 2 years after surgery, 41 and 30% of women, respectively, still perceived this decline. The mean AFI decreased to the lowest point 1 month after surgery, but improved gradually afterward, taking about 1 year to return to the pre-surgery level. Decreases in perceived attentional function were associated with increases in anxiety, depression, fatigue, and sleep disturbance. After controlling for baseline differences and covariates, mean AFI scores were not associated with adjuvant treatment. Perceived cognitive function deteriorated after surgery but improved over time. It was not associated with adjuvant cancer treatment.


Method development for determination of polyhalogenated carbazoles in industrial waste through gas chromatography/triple quadrupole tandem mass spectrometry.
Polyhalogenated carbazoles (PHCZs) are dioxin-like compounds that are ubiquitous in the environment. However, their unintentional emissions from industrial sources have received little attention and there is no method available for determination of PHCZs in industrial waste. This research develops a method for determination of PHCZs in industrial waste. In this research, a glass column packed with activated silica serves as a rapid and efficient clean-up pretreatment for purification. An isotope dilution gas chromatography/triple quadrupole tandem mass spectrometry method was established for simultaneous determination of eleven PHCZs in industrial samples. The regression coefficients of the standard curves for the congeners were all >0.99. The method detection limit ranged from 1.46 to 3.82 ng/mL for liquid samples and from 0.009 to 0.021 ng/g for solid samples. The precision described by the relative standard deviation ranged from 2.4% to 18.4% for liquid samples and from 5.5% to 35.8% for solid samples. The recovery ranges for the liquid and solid samples were 82%-123% and 83%-137%, respectively. 3-Chlorocarbazole (3-CCZ) and 36-dichlorocarbazole (36-CCZ) can be detected in both chemical bottom liquid from vinyl chloride production and fly ash from medical waste incineration by this method. An efficient method is established for determination of PHCZs from industrial waste. The discovery of 3-CCZ and 36-CCZ highlights the importance of identification of potential industrial sources of PHCZs and clarification of their contribution to environmental risks. Our method could be applied to investigate industrial emission of PHCZs.


The Duplex Interaction of Microbiome with Chemoradiation and Immunotherapy: Potential Implications for Colorectal Cancer.
Gut microbiota has the ability to modify the metabolism of wide array of therapeutic drugs. Current treatment modalities used in colorectal cancer have a narrow therapeutic index with a side effects profile that decreases tolerance to these treatments and adversely affects treatment outcome. Harnessing the gut microbiota ability to modify oncotherapeutic drugs metabolism and hence efficacy, could be potentially used to improve treatment outcomes in colorectal cancer patients. This review will shed lights on important findings from recent microbiome interaction studies which would hopefully serve as a useful tool to guide future translative colorectal cancer research. Recent advances in microbiome studies have revealed an interesting aspect of gut microbes carcinogenic properties in dysbiotic gut environment. Microbiota niche in colorectal cancer can also modify efficacy and toxicity profile of different oncotherapeutic treatment modalities from chemoradiotherapy to immunotherapy. Conversely, each of these treatment modalities has numerous effects on the gastrointestinal flora, causing changes in the gut microbial community that affects host morbidity and mortality. Symbiotic gut microbiota is an incredible functioning organ that maintains essential aspects of our homeostasis and immunity. According to the recent body of literature, they also can modify efficacy of many therapeutic drugs including oncotherapy. Considering that unexplainable variable treatment outcomes as well as variable tolerance to treatment have been observed in colorectal cancer patients, studying gut microbiota modulatory effects on oncotherapy might be a feasible approach to explain this phenomenon.


A novel methylation signature predicts radiotherapy sensitivity in glioma.
Glioblastoma (GBM) is the most common and malignant cancer of the central nervous system, and radiotherapy is widely applied in GBM treatment; however, the sensitivity to radiotherapy varies in different patients. To solve this clinical dilemma, a radiosensitivity prediction signature was constructed in the present study based on genomic methylation. In total, 1044 primary GBM samples with clinical and methylation microarray data were involved in this study. LASSO-COX, GSVA, Kaplan-Meier survival curve analysis, and COX regression were performed for the construction and verification of predictive models. The R programming language was used as the main tool for statistical analysis and graphical work. Via the integration analysis of methylation and the survival data of primary GBM, a novel prognostic and radiosensitivity prediction signature was constructed. This signature was found to be stable in prognosis prediction in the TCGA and CGGA databases. The possible mechanism was also explored, and it was found that this signature is closely related to DNA repair functions. Most importantly, this signature could predict whether GBM patients could benefit from radiotherapy. In summary, a radiosensitivity prediction signature for GBM patients based on five methylated probes was constructed, and presents great potential for clinical application.


Towards Asymmetrical Methylene Blue Analogues: Synthesis and Reactivity of 3-N'-Arylaminophenothiazines.
The search for new ways to obtain analogues of the well-known Methylene Blue dye is an important synthetic task. Herein, we proposed and developed an approach to the synthesis of 3-N'-arylaminophenothiazines and asymmetrical 3,7-di(N'-arylamino)phenothiazines. This approach included the optimization of synthetic strategy by quantification analysis of the positive charge distribution in the cation of 3-N'-arylaminophenothiazine derivative. The obtained experimental data are confirmed by DFT studies. Two synthetic routes for asymmetrical phenothiazine diarylamino derivatives were suggested and verified. The developed convenient and versatile synthetic approach makes it easy to obtain aromatic Methylene Blue isostructural analogues with various substituents. As a result, a series of novel 3-N'-arylaminophenothiazines and asymmetrical 3,7-di(N'-arylamino)phenothiazines containing ester, tert-butoxycarbonyl, sulfonic acid, hydroxyl and amine groups were obtained in high yields.


Food restriction reduces brain damage and improves behavioral outcome following excitotoxic and metabolic insults.
Food restriction (FR) in rodents is known to extend life span, reduce the incidence of age-related tumors, and suppress oxidative damage to proteins, lipids, and DNA in several organ systems. Excitotoxicity and mitochondrial impairment are believed to play major roles in the neuronal degeneration and death that occurs in the brains of patients suffering from both acute brain insults such as stroke and seizures, and chronic neurodegenerative conditions such as Alzheimer's, Parkinson's, and Huntington's diseases. We now report that FR (alternate-day feeding regimen for 2-4 months) in adult rats results in resistance of hippocampal neurons to excitotoxin-induced degeneration, and of striatal neurons to degeneration induced by the mitochondrial toxins 3-nitropropionic acid and malonate. FR greatly increased the resistance of rats to kainate-induced deficits in performance in water-maze learning and memory tasks, and to 3-nitropropionic acid-induced impairment of motor function. These findings suggest that FR not only extends life span, but increases resistance of the brain to insults that involve metabolic compromise and excitotoxicity.


nr0b1 (DAX1) mutation in zebrafish causes female-to-male sex reversal through abnormal gonadal proliferation and differentiation.
Sex determinations are diverse in vertebrates. Although many sex-determining genes and pathways are conserved, the mechanistic roles of these genes and pathways in the genetic sex determination are not well understood. DAX1 (encoded by the NR0B1 gene) is a vertebrate specific orphan nuclear receptor that regulates gonadal development and sexual determination. In human, duplication of the NR0B1 gene leads to male-to-female sex reversal. In mice, Nr0b1 shows both pro-testis and anti-testis functions. We generated inheritable nr0b1 mutation in the zebrafish and found the nr0b1 mutation caused homozygous mutants to develop as fertile males due to female-to-male sex reversal. The nr0b1 mutation did not increase Caspase-3 labeling nor tp53 expression in the developing gonads. Introduction of a tp53 mutation into the nr0b1 mutant did not rescue the sex-reversal phenotype. Further examination revealed reduction in cell proliferation and abnormal somatic cell differentiation in the nr0b1 mutant gonads at the undifferentiated and bi-potential ovary stages. Together, our results suggest nr0b1 regulates somatic cell differentiation and cell proliferation to ensure normal sex development in the zebrafish.


Selection of CD4+CD8+ thymocytes by complex formation with medulla-derived epithelial cells.
The role of lymphostromal complexes in T-cell differentiation is far from elucidated, mainly because a clear association of a particular stromal cell type with a distinct thymocyte subset has never been identified. Using an in vitro system, detecting the adherence of thymocytes to a thymic medullary epithelial cell line (E-5), we showed that the phenotype of these thymocytes was that of cortical type: Thy-1hi, LFA-1+, PNAhi, CD4+CD8+, MEL-14-/lo, IL-2R-, CD3-/lo, and TcR V beta 8-/lo. They were enriched in cells in G2/M at the time of complex formation, showed a higher basal proliferation in culture, and did not respond to PHA, IL-2 and only marginally to Con A. These data show that complex formation with mouse thymic medullary epithelium selects for CD4+CD8+ thymocytes, as shown by the marked decrease in CD4+CD8-/CD4-CD8+ thymocytes, and the incapacity of CD4-CD8- thymocytes to adhere.


Dopamine agonist inhibits vascular endothelial growth factor protein production and secretion in granulosa cells.
Dopamine receptor 2 agonists (D2-ags) inhibit vascular endothelial growth factor (VEGF) secretion in luteinized granulosa cells (LGCs) both in vitro and in vivo. However, the mechanism of D2 regulation of the VEGF/VEGF Receptor 2 (VEGFR-2) pathway remains to be elucidated. We sought to determine the effects of D2 signaling on VEGF transcription and translation in LGCs, with the expectation of identifying potential D2-ag-based therapies for ovarian hyperstimulation syndrome (OHSS). LGCs from egg donors were cultured with chorionic gonadotropin (hCG) in the presence of Actinomycin-D (ActD) or Brefeldin-A (BFA) to evaluate the effects of a D2-ag, cabergoline (Cb2), on VEGF secretion. The contribution of the conventional Gi/Go, Gz and AKT/β-Arrestin pathways in the VEGF regulation was assessed by adding pertussis toxin (PTX), phorbol 12-myristate 13-acetate (PMA), or wortmannin (WT). While Cb2 inhibited VEGF secretion by interfering with VEGF peptide translation and secretion, inhibition of conventional D2 transduction pathways did not reverse Cb2-mediated inhibition of VEGF secretion. The effects of D2-ag on VEGF translation and secretion are mediated by D2 signaling pathways that have yet to be described. We found that D2-ag inhibits VEGF secretion at the post-transcriptional level, suggesting that D2-ag treatment should be combined with therapies that inhibit VEGF transcription, such as the employment of LH or GnRH for triggering ovulation, to improve the efficacy of OHSS prevention.


Admission deep venous thrombosis of lower extremity after intertrochanteric fracture in the elderly: a retrospective cohort study.
The purpose of this study was to investigate the incidence, location, and related factors of deep venous thrombosis (DVT) of the bilateral lower extremities after intertrochanteric fractures in the elderly. Retrospective analysis was performed on the elderly patients with intertrochanteric fracture who were admitted from January 2017 to December 2019. At admission, patients receive routine ultrasound Doppler scanning of bilateral lower extremities to detect DVT; those with DVT were assigned to the case group and those without DVT to the control group. Patient data on demographics, comorbidities, injury-related data, and laboratory test results at admission were extracted. Logistic regression analyses were conducted to identify the independent risk factors associated with DVT. Five hundred seventy-eight patients were included, among whom 116 (20.1%) had DVT. Among those with DV, 70.7% (82/116) had DVT of the distal type, 24 (29.6%) had DVT of the proximal type, and 10 (10.4%) had mixed DVT. In 76.7% (89/116) of patients, DVT occurred in the fractured extremity, 9.5% (11/116) in the bilateral and 13.8% (16/116) in the non-fractured extremity. Multivariate analyses identified obesity, delay to admission, increased D-dimer level (> 1.44 mg/L) and reduced albumin (< 31.7 g/L) as independent factors. Admission incidence of DVT was high in elderly patients with intertrochanteric fractures, especially the proximal DVT. Identification of associated risk factors is useful for individualized assessment risk of DVT and early targeted interventions.


Effectiveness of Dimethyl Fumarate in Patients With Relapsing Multiple Sclerosis Switching After Suboptimal Response to Glatiramer Acetate, Including Patients With Early Multiple Sclerosis: Subgroup Analysis of RESPOND.
This post hoc subset analysis of RESPOND evaluated the effectiveness of dimethyl fumarate (DMF) 240 mg twice daily in patients with relapsing multiple sclerosis (RMS) after suboptimal response to glatiramer acetate (GA; "first switch" patients), including patients with early MS ("early MS switch" patients). Patients had discontinued GA due to suboptimal response and initiated DMF treatment within 60 days after enrollment. Relapse data were collected from medical records. First switch patients had had one prior approved MS therapy (GA) before initiating DMF treatment. Early MS switch patients were first switch patients with baseline Patient-Reported Expanded Disability Status Scale (PR-EDSS) score ≤ 3.5, ≤ 1 relapses in the past 1 year, or both. Among first switch patients (n = 231), the annualized relapse rate (ARR) was 0.48 (95% confidence interval [CI] 0.40-0.58) for 12 months before DMF initiation and 0.11 (95% CI 0.06-0.18) for 12 months after DMF initiation, a 78% decrease in ARR. Among early MS switch patients with baseline PR-EDSS score ≤ 3.5 (n = 120), ≤ 1 relapses in the prior year (n = 219), or both (n = 114), the ARRs (95% CIs) for 12 months before DMF initiation were 0.47 (0.37-0.59), 0.37 (0.32-0.44), and 0.39 (0.31-0.49), respectively; values for 12 months after DMF initiation were 0.06 (0.02-0.19), 0.09 (0.05-0.17), and 0.06 (0.02-0.20), respectively, an 87, 75, and 83% decrease in ARR. The proportion of patients relapse-free 12 months after DMF initiation versus 12 months before were 94 versus 59% in first switch patients, and 97 versus 58%, 94 versus 63%, and 97 versus 61% in early MS switch patients in the PR-EDSS score ≤ 3.5, ≤ 1 relapses in the prior year, or PR-EDSS score ≤ 3.5 and ≤ 1 relapses subgroups, respectively. After 12 months of DMF treatment, most patient-reported outcomes scores showed significant improvement. DMF may be an effective treatment option in first switch and early MS switch patients with RMS who experience a suboptimal response to GA. ClinicalTrials.gov identifier: NCT01903291.


Preliminary results of the laparoscopic adjustable gastric banding procedure by a new generation of silicone band: MIDBAND.
The surgical treatment of morbid obesity by laparoscopic adjustable gastric banding has become a "gold standard" in Europe. Currently, five types of silicone bands are used in the majority of countries performing bariatric surgery. The MIDBAND was introduced to the European market in 2000. It is placed around the stomach using the Pars Flaccida technique described by Forsell. A prospective multicentric study on 113 cases was carried out to evaluate technical feasibility, complications, and the midterm weight loss outcomes (2 years). The percentage of excess body weight loss was 52.58% at 2 years. Perioperative mortality was nil and the complication rate was low (slippage <2%). These encouraging results require longer-term studies to validate this procedure.


Measurement Reliability and Diagnostic Accuracy of Virtual Monoenergetic Dual-Energy CT in Patients with Colorectal Liver Metastases.
To compare dual-energy CT virtual monoenergetic images (VMI) and standard reconstructions for reliability of quantitative size measurements and diagnostic accuracy for the detection of colorectal liver metastases (CRLM). We retrospectively included 98 patients (mean age, 61.1±11.5 years) with colorectal cancer, of whom 49 subjects had CRLM. All patients underwent a portal-venous phase dual-energy CT examination. Standard linearly-blended reformats and 40-keV VMI were reconstructed. For both reconstruction techniques, two blinded readers performed measurements of CRLM twice in a preset sequence. Three additional radiologists independently assessed all liver lesions in terms of dignity (benign vs. malignant). Sensitivity, specificity and diagnostic accuracy were calculated on a per-patient basis using MRI as reference standard. Readers scored the suitability for metric measurements and their diagnostic confidence using 5-point Likert scales. Inter-rater agreement was evaluated using intraclass correlation coefficient (ICC). Inter-rater agreement for lesion size measurements was higher for 40-keV VMI (ICC, 0.88) compared to standard linearly-blended series (ICC, 0.80). Sensitivity and diagnostic accuracy for the detection of CRLM were significantly higher for VMI at 40-keV compared to standard reconstructions (90.6% vs. 80.6%, and 89.1% vs. 81.3%; p < 0.001). Reader scores indicated that 40-keV VMI were more suitable for metric lesion measurements and provided greater diagnostic confidence compared to standard reformats (median, 5 vs. 3, and 5 vs. 4; both p < 0.001). Low-keV VMI reconstructions improve reliability of quantitative size measurements and diagnostic accuracy for the assessment of CRLM compared to standard linearly-blended images.


Impact of renal sinus protrusions on achieving trifecta in robot-assisted partial nephrectomy.
The objective of this work is to assess the relationship between the morphological characteristics of a central tumour and the perioperative outcomes of robot-assisted partial nephrectomy (RAPN). We retrospectively analysed the data from 186 patients with central tumours involving the renal sinus, who underwent RAPN in a single-centre study between February 2015 and June 2022. All cases were assigned a RENAL nephrometry score based on preoperative images. The shape of the protruding portion of the tumour was classified into four types: 'flat', 'spherical', 'single-hump', and 'complex-hump', and was independently assessed by two readers. The trifecta is defined as the warm ischemia time within 25 min, negative surgical margins, and no major postoperative complications. Univariate and multivariate analyses were performed to identify the factors associated with the failing trifecta. Trifecta was achieved in 113 cases (60.8%), and the achievement rate in flat, spherical, single-hump, and complex-hump types was 83.3%, 74.5%, 64.3%, and 21.3%, respectively. Prolonged warm ischemia time was the primary cause of the failure to achieve the trifecta. The rate of positive surgical margins and upstage to pathological T3a was greater for complex humps while the rate of major complications and postoperative GFR preservation did not differ between shapes. On multivariate analysis for failing trifecta achievement, the complex-hump protrusion was found to be an independent positive predictor (odds ratio: 15.8; p < 0.001), whereas the height and width of protrusion were not significantly related. The degree of difficulty varied among central tumours, and it was not possible to precisely measure it with existing scoring systems. Complex-hump protrusions strongly correlate with failure to achieve the trifecta. Preoperative assessment of the morphology of protrusion is useful for predicting outcomes.


Physical exercise for negative symptoms of schizophrenia: Systematic review of randomized controlled trials and meta-analysis.
The negative symptoms of schizophrenia contribute strongly to functional impairment but are inadequately treated by antipsychotic medication. Several studies have suggested that physical exercise could reduce the negative symptoms. We conducted a systematic review and a meta-analysis of randomized controlled trials (RCTs) examining the effectiveness of physical exercise interventions in improving the negative symptoms of schizophrenia using different databases and trial registries. Seventeen RCTs were included in the meta-analysis (n = 954 patients). Overall, the results revealed a significant beneficial effect of physical exercise on negative symptoms. We conducted a subgroup analysis differentiating between aerobic interventions (12 RCTs) and non-aerobic interventions (5 RCTs). Aerobic exercise reduced negative and positive symptoms, while this was not the case for non-aerobic interventions. A sensitivity analysis including only studies with a low risk of bias confirmed the effect on negative but not on positive symptoms. Aerobic exercise had a beneficial effect on negative symptoms, albeit with a small effect size. The conclusions are limited by the fact that the included studies did not assess patients for predominant or primary negative symptoms. Given the important role of exercise for physical health, the additional effects on negative symptoms are promising and justify further research to disentangle the effects on primary and secondary negative symptoms.


Multi-factor settlement prediction around foundation pit based on SSA-gradient descent model.
With the rise of machine learning, a lot of excellent algorithms are used for settlement prediction. Backpropagation (BP) and Elman are two typical algorithms based on gradient descent, but their performance is greatly affected by the random selection of initial weights and thresholds, so this paper chooses Sparrow Search Algorithm (SSA) to build joint model. Then, two sets of land subsidence monitoring data generated during the excavation of a foundation pit in South China are used for analysis and verification. The results show that the optimization effect of SSA on the gradient descent model is remarkable and the stability of the model is improved to a certain extent. After that, SSA is compared with GA and PSO algorithms, and the comparison shows that SSA has higher optimization efficiency. Finally, select SSA-KELM, SSA-LSSVM and SSA-BP for further comparison and it proves that the optimization efficiency of SSA for BP is higher than other kind of neural network. At the same time, it also shows that the seven influencing factors selected in this paper are feasible as the input variables of the model, which is consistent with the conclusion drawn by the grey relational analysis.


The impact of cationic solid lipid nanoparticles on human neutrophil activation and formation of neutrophil extracellular traps (NETs).
Cationic solid lipid nanoparticles (cSLNs) are extensively employed as the nanocarriers for drug/gene targeting to tumors and the brain. Investigation into the possible immune response of cSLNs is still lacking. The aim of this study was to evaluate the impact of cSLNs upon the activation of human polymorphonuclear neutrophil cells (PMNs). The cytotoxicity, pro-inflammatory mediators, Ca(2+) mobilization, mitogen-activated protein kinases (MAPKs), and neutrophil extracellular traps (NETs) as the indicators of PMN stimulation were examined in this work. The cSLNs presented a diameter of 195 nm with a zeta potential of 44 mV. The cSLNs could interact with the cell membrane to produce a direct membrane lysis and the subsequent cytotoxicity according to lactate dehydrogenase (LDH) elevation. The interaction of cSLNs with the membrane also triggered a Ca(2+) influx, followed by the induction of oxidative stress and degranulation. The cationic nanoparticles elevated the levels of superoxide anion and elastase by 24- and 9-fold, respectively. The PMN activation by cSLNs promoted the phosphorylation of p38 and Jun-N-terminal kinases (JNK) but not extracellular signal-regulated kinases (ERK). The imaging of scanning electron microscopy (SEM) and immunofluorescence demonstrated the production of NETs by cSLNs. This phenomenon was not significant for the neutral SLNs (nSLNs), although histones in NETs also increased after treatment of nSLNs. Our results suggest an important role of cSLNs in governing the activation of human neutrophils.


Simple physical model of coronary vasodilation.
The coronary diastolic pressure-flow relationship was studied in two groups of dogs; in one group coronary circulation was characterized by normal tone of vascular smooth muscle, while in the other group, complete relaxation of smooth muscle fibres was produced by intravenous infusion of dipyridamole. The coronary flow (CF) was measured in both groups for several values of mean aortic blood pressure (ABP), the variations being obtained by means of a 10 s arterial haemorrhage. The measured CF versus ABP data were found to be well represented by best fit curves calculated by power regression methods. These curves were quite different in the presence and absence of dipyridamole infusion. A simple physical model is proposed for analysis of these curves; the model is based on the Poiseuille equation, modified to take into proper account the variations of the vessel radii under different ABP values during ventricular diastole. These variations are expressed by means of Laplace and Hooke's laws by equating wall tension due to APB, to the sum of tensions due to elastic and smooth muscle forces. Analysis of CF versus APB curves, performed on the basis of this model, shows that to account for the large change of coronary bed conductance observed under dipyridamole infusion one must assume not only that the smooth muscle tone is absent but also that some relevant variations occur in the whole coronary bed, thus pointing to possible recruitment of new blood vessel paths.


Adefovir is effective to promote development of immunity to donor origin hepatitis B virus in an allogeneic transplant recipient: a case report.
Hepatitis B infection is a serious health problem in endemic areas particularly among immunocompromised patients. The more profound immunosuppression in recipients of hematopoietic stem cell transplantations (HCT) can lead to more complicated hepatitis B virus (HBV)-related events. Despite the high risk of recipient infection allogeneic HCT donors with HBV infection are not excluded in the absence of an alternative donor. A 25 year-old man with severe aplastic anemia underwent allogeneic HCT from his HLA-identical sibling. The patient was hepatitis B naive and had normal liver function tests. However the donor had hepatitis B surface antigen (HbsAg) positivity, and collected stem cells were positive for HBV DNA (1 × 10(4) copies/mL). Lamivudine was initiated to treat the patient prior to transplantation. Forty days after the HCT, the patient displayed hepatitis B surface antibody (HBsAb), hepatitis B core antibody (HBcAb), and hepatitis B e antibody (HBeAb), with HBV-DNA negativity. Cyclosporine was tapered and finally stopped at day + 256. On day +368, 112 days after the cessation of cyclosporine HBV reactivation was detected with an HBV-DNA level of 10 × 10(4) copies/mL despite lamivudine. After demonstration of the YMDD mutation, adefovir dipivoxil was combined with lamivudine. The HBV-DNA became negative; AST ALT levels decreased to normal levels after a month of combination therapy. In conclusion adefovir was effective to treat lamivudine-resistant HBV infection in an allogeneic HCT recipient.


Euphorbia leaf extract-assisted sustainable synthesis of Au NPs supported on exfoliated GO for superior activity on water purification: reduction of 4-NP and MB.
In the present work, the effect of graphene oxide (GO) architecture and synthesis of gold nanoparticles (AuNPs) on the surface of GO by using Euphorbia leaf extract was investigated. The as-synthesized catalyst was utilized for reduction of 4-nitrophenol (4-NP) and methylene-blue (MB). The ethanol/water extract of the leaves of Euphorbia was found as a non-toxic, suitable, eco-friendly natural reducing agent in one-step generation of Au nanoparticles onto the GO. The catalyst was characterized by different analysis such as atomic force microscopy, powder X-ray diffraction, field emission scanning electron microscopy, energy dispersive X-ray spectroscopy, SEM-mapping, transmission electron microscopy, and atomic absorption spectrometry. The high catalytic performance of the surfactant exfoliated gold-GO (SE-AuNPs/GO) towards the reduction of 4-NP to 4-aminophenol (4-AP) and reduction of MB to leucomethylene blue (LMB) under mild conditions, in water and at room temperature, was exhibited. Graphical abstract.


EuroEcho-Imaging 2014: highlights.
The annual meeting of the European Association of Echocardiography (EuroEcho-Imaging) was held in Vienna, Austria. In the present paper, we present a summary of the 'Highlights' session.


Pancreatic stellate cell activation by ethanol and acetaldehyde: is it mediated by the mitogen-activated protein kinase signaling pathway?
Pancreatic fibrosis is a characteristic feature of alcoholic chronic pancreatitis. Recent studies suggest that activated pancreatic stellate cells (PSCs) are the major cell-type involved in pancreatic fibrogenesis. Cultured PSCs become activated when exposed to ethanol or its metabolite acetaldehyde (as indicated by increased alpha-smooth muscle actin [alpha-SMA] expression and increased collagen synthesis). However the intracellular signaling mechanisms responsible for ethanol- or acetaldehyde-induced PSC activation remain to be fully elucidated. One of the major signaling pathways known to regulate protein synthesis in mammalian cells is the mitogen-activated protein kinase (MARK) pathway. To examine the effects of ethanol and acetaldehyde on the MAPK pathway (by assessing the activities of the 3 major subfamilies (extracellular-regulated kinases 1 and 2 [ERK 1/2], JNK and p38 kinase) in PSCs and to examine the role of p38 kinase in mediating the ethanol- and acetaldehyde-induced increase in alpha-SMA expression in activated rat PSCs. Rat PSCs were incubated with ethanol (50 mM) or acetaldehyde (200 microM) for 15 min, 30 min, 60 min, and 24 h; and activities of ERK 1/2, JNK, and p38 kinase were assessed in cell lysates using kinase assays and Western blot. In addition, rat PSCs were treated with the specific p38 MAPK inhibitor SB203580 in the presence or absence of ethanol or acetaldehyde for 24h, and activation of the downstream protein kinase MAPKAP kinase-2 (an indicator of p38 MAPK activity) was assessed by Western blot. Specific inhibitors were also used to inhibit the activity of ERK 1/2 and JNK. Following inhibition of the above signaling pathways, alpha-SMA expression by PSCs was assessed by Western blot. Ethanol and acetaldehyde increased the activation of all 3 subfamilies (ERK 1/2, JNK and p38 kinase) of the MAPK pathway in PSCs. Treatment of PSCs with SB203580 abolished the ethanol- and acetaldehyde-induced increase in p38 MAPK activity and also prevented the induction of alpha-SMA expression in PSCs. However, inhibition of ERK 1/2 and JNK had no effect on ethanoland acetaldehyde-induced alpha-SMA expression in PSCs. (1) The MAP kinase pathway is induced in PSCs after exposure to ethanol or acetaldehyde and this induction is sustained for at least 24h. (2) The p38 MAPK pathway mediates the activation (as indicated by increased alpha-SMA expression) of PSCs by ethanol or acetaldehyde.


[Metformin and malignant neoplasms: a possible mechanism of antitumor action and prospects for use in practice].
Metformin is a first-line antidiabetic drug for the treatment of type 2 diabetes mellitus (DM2); its molecular target is AMP-activated protein kinase (AMPK), which is involved in many metabolic processes. Metformin not only reduces blood glucose levels and improves insulin sensitivity, but also inhibits lipolysis and reduces cardiovascular risk in patients with DM2. In recent years, it has been proven that metformin slows down the aging process, stimulates hair growth, eliminates cognitive impairment, and also has an antitumor effect. Most basic studies have shown that metformin inhibits the growth of tumor cells and promotes cellular apoptosis, while clinical studies show contradictory results. This discrepancy can be explained by the difference in the concentration of metformin between basic and clinical studies. The maximum daily dose of metformin for patients with DM2 is 2500 mg / day, and the dose used in basic research was much higher. Metformin directly activates the AMPK signaling pathway, inhibits the production of reactive oxygen species, induces the activation of mTORC1, inhibits cyclin D1, which leads to a reduction in the risk of the occurrence and development of malignant neoplasms. In addition, metformin indirectly inhibits tumor growth, proliferation, invasion and metastasis by reducing the concentration of glucose in the blood, insulin resistance, as well as by reducing inflammation and affecting the tumor microenvironment. Glycolysis plays an important role in the energy metabolism of tumors, and metformin is able to have an inhibitory effect on it. Currently, studies of the mechanism of antitumor effects of metformin are becoming more extensive and in-depth, but there are still some contradictions.


Intraoperative radiation therapy for gastric cancer.
From among 115 patients who were treated by intraoperative radiation therapy (IORT), 94 patients were classified according to the histologic findings. The control 127 patients who were treated by operation alone during the same period were also histologically classified, and survivals were compared between the two groups. No difference in the survivals of patients with stage I was observed for the two groups. On the other hand, the survivals of patients with stages II through IV who were treated by IORT increased by nearly 10% to 20% at 5 years. A comparative study was also performed on the survivals between patients treated by IORT and those treated by operation alone according to the presence or absence of the serosal invasion and the grade of the lymph node metastasis. The number of patients treated by IORT in whom the serosal invasion and the lymph node metastasis were histologically examined was 57. The 171 control patients who underwent operation alone were examined histologically in the same fashion, and survivals for the two groups were compared. IORT did not afford any benefit if the lymph node metastasis was limited within n1 group or serosal invasion was not found. On the other hand, the 5-year survival rates for patients who were treated by IORT increased by nearly 10% when the serosal invasion was observed and by nearly 18% when n2 and n3 lymph node metastases were found.


Reduced analgesic effects of morphine after bilateral lesions of the locus coeruleus in rats.
Noradnenaline-depleting lesions involving the locus coerulcus markedly reduced morphine analgesia. Rats were tested for analgesia using the tail-compression method. The results indicate that locus coeruleus plays an important role in analgesic action of morphine.


Intranuclear iron deposition in hepatocytes and renal tubular cells in mice treated with ferric nitrilotriacetate.
Cytoplasmic and intranuclear iron depositions were observed in the livers and kidneys of male and female ddY mice treated for 4-12 weeks with ferric nitrilotriacetate (Fe-NTA), a known renal carcinogen that acts through the production of free radicals. The intranuclear iron deposition consisted of a spherical aggregation of ferritin particles of approximately 10 nm diameter, as revealed by immunohistochemical staining and electron microscopy. Although the incidence of renal tumours was greater in the males than in the females, the incidence of iron depositions did not differ with gender. The most abundant intranuclear iron depositions were observed in the animals treated with Fe-NTA for the longest duration (12 weeks). These findings suggest that the intranuclear production and propagation of free radical reactions are prevented by the trapping of iron in a chemically inert iron form of ferritin.


A new real time PCR-based assay for diagnosing Renibacterium salmoninarum in rainbow trout (Oncorhynchus mykiss) and comparison with other techniques.
Bacterial Kidney Disease of salmonid is caused by a slow-growing gram-positive bacterium, Renibacterium salmoninarum. This bacterium lives both extra-cellular and intra-cellular in the host. Serological and molecular diagnostic methods to detect the bacterium major surface protein antigen p57 have been developed. In the present work, a newly developed quantitative Reverse Transcriptase-PCR (RT-QPCR), using self-quenched fluorescent primer (Lux), a nested PCR (NPCR), a commercial ELISA and recently commercially available Immune-chromatographic strip test(IC-Strip) were compared for their ability to detect BKD in kidney tissue samples obtained from experimentally infected fish. ELISA test resulted to be rapid, simple and indicative for the bacterial load. The IC-Strip test had similar characteristics for bacterial detection. Both tests are a good option for rapid and relatively inexpensive screening studies, despite the one and two log decrease in bacterial detection limits compared to NPCR and RT-QPCR, respectively. The use of Lux primers in the newly developed RT-QPCR revealed to be a cost-effective alternative to other fluorescence-based PCR techniques. The option of generating a melting temperature curve with the real time PCR instrument confirmed the specificity of the PCR product. The RT-QPCR technique had the advantage of detecting low numbers of viable bacterial mRNA which implied a higher capacity of detecting chronically infected animals. For instance, some fish in the group infected by cohabitation had very low bacterial load and were only detected by this technique.


Demographic variation in the Australian desert cassia under grazing pressure.
Demographic variation was examined in 3 populations of the Australian desert shrub Cassia nemophila which vary in their grazing histories. Age-specific life tables were constructed from 50 years of observations on mortality and recruitment at the Koonamore Vegetation Reserve in South Australia. Population projection matrix models were used to examine population responses to grazing pressure. The predicted population growth rates, reproductive values and stable age distributions are evaluated and compared with observed results. Grazing by sheep or rabbits, in high populations, prevents shrub recruitment and causes local population extinction. However, where protected from sheep and with low rabbit pressure, Cassia populations have increased. Current sheep grazing practices and rabbit population levels if continued will have a drastic affect on Cassia populations and other shrub species, and on the structure and composition of the Australian arid shrublands in general.


Loss of the xeroderma pigmentosum group B protein binding site impairs p210 BCR/ABL1 leukemogenic activity.
Previous studies have demonstrated that p210 BCR/ABL1 interacts directly with the xeroderma pigmentosum group B (XPB) protein, and that XPB is phosphorylated on tyrosine in cells that express p210 BCR/ABL1. In the current study, we have constructed a p210 BCR/ABL1 mutant that can no longer bind to XPB. The mutant has normal kinase activity and interacts with GRB2, but can no longer phosphorylate XPB. Loss of XPB binding is associated with reduced expression of c-MYC and reduced transforming potential in ex-vivo clonogenicity assays, but does not affect nucleotide excision repair in lymphoid or myeloid cells. When examined in a bone marrow transplantation (BMT) model for chronic myelogenous leukemia, mice that express the mutant exhibit attenuated myeloproliferation and lymphoproliferation when compared with mice that express unmodified p210 BCR/ABL1. Thus, the mutant-transplanted mice show predominantly neutrophilic expansion and altered progenitor expansion, and have significantly extended lifespans. This was confirmed in a BMT model for B-cell acute lymphoblastic leukemia, wherein the majority of the mutant-transplanted mice remain disease free. These results suggest that the interaction between p210 BCR/ABL1 and XPB can contribute to disease progression by influencing the lineage commitment of lymphoid and myeloid progenitors.


Predictors of Mental Health Literacy and Information Seeking Behavior Toward Mental Health Among University Students in Resource-Limited Settings.
This paper investigated mental health literacy level and information seeking behavior, and mental health-related information sources in limited-resource settings, in the case of Ethiopian university students. A cross-sectional, self-administered web-based survey was conducted among Dilla University students, from 1 January to 29 February 2022, with a total of 780 respondents. We presented descriptive statistics using mean, standard deviations, and proportions. Bivariate and multivariate logistic regression were employed to identify factors associated with mental health literacy and information seeking behavior of students. Further, path analysis was also employed. The result showed 71 (9.1%) respondents had a diagnosed history of mental illness. Overall, 397 (50.9%) respondents were identified as having adequate mental health literacy and 420 (53.8%) sought mental health information. In multivariate analysis, mental health literacy was significantly associated with: being female (AOR = 2.8; 95% CI (1.5-5.4)), higher digital health literacy (AOR=2.8; 95% CI (1.5-5.4), seeking mental health-related information (AOR=1.6; 95% CI: (1.1-2.5)), having family with mental illness, and students in health-related programs (AOR = 2.1; 95% CI (1.0-4.2)). Furthermore, health-related programs, level of mental health literacy, exposure to mental health problems in the family, and were associated with information seeking behavior regarding mental health. Further, path analysis revealed significant positive associations of information seeking behavior and digital health literacy with mental health literacy. The result indicated the status of university students' mental health literacy level and information seeking behavior were low and inadequate. This study suggests the need to improve students' digital health competencies by designing mental health literacy programs by collaboration of different stakeholders, and mental health literacy programs need to optimize access to internet and online resources in the university settings.


Genomic and mutational profiling of ductal carcinomas in situ and matched adjacent invasive breast cancers reveals intra-tumour genetic heterogeneity and clonal selection.
The mechanisms underlying the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) of the breast are yet to be fully elucidated. Several hypotheses have been put forward to explain the progression from DCIS to IDC, including the selection of a subpopulation of cancer cells with specific genetic aberrations, and the acquisition of new genetic aberrations or non-genetic mechanisms mediated by the tumour microenvironment. To determine whether synchronously diagnosed ipsilateral DCI and IDCs have modal populations with distinct repertoires of gene copy number aberrations and mutations in common oncogenes, matched frozen samples of DCIS and IDC were retrieved from 13 patients and subjected to microarray-based comparative genomic hybridization (aCGH) and Sequenom MassARRAY (Oncocarta v 1.0 panel). Fluorescence in situ hybridization and Sanger sequencing were employed to validate the aCGH and Sequenom findings, respectively. Although the genomic profiles of matched DCI and IDCs were similar, in three of 13 matched pairs amplification of distinct loci (ie 1q41, 2q24.2, 6q22.31, 7q11.21, 8q21.2 and 9p13.3) was either restricted to, or more prevalent in, the modal population of cancer cells of one of the components. Sequenom MassARRAY identified PIK3CA mutations restricted to the DCIS component in two cases, and in a third case the frequency of the PIK3CA mutant allele reduced from 49% in the DCIS to 25% in the IDC component. Despite the genomic similarities between synchronous DCIS and IDC, our data provide strong circumstantial evidence to suggest that in some cases the progression from DCIS to IDC is driven by the selection of non-modal clones that harbour a specific repertoire of genetic aberrations.


Halothane for status asthmaticus in the intensive care unit--a case report.
A case report is presented demonstrating the beneficial beta2 stimulating effect of halothane in a patient with status asthmaticus unresponsive to adequate conventional therapy. Twenty-four hours after the commencement of therapy, 0.5 per cent of 1.0 per cent halothane was administered for one hour with sustained reductions in peak inspiratory airway pressure and increases in dynamic and static effective compliances.


The association between the type of progesterone supplementation and miscarriage risk in women who have had a positive pregnancy test following embryo transfer: a retrospective cohort study.
The purpose of this study was to identify if switching from intramuscular (IM) to vaginal progesterone compared to staying on IM progesterone after a positive pregnancy test following embryo transfer (ET) is associated with miscarriage risk. A retrospective cohort study was performed in a private university-affiliated fertility clinic and included women aged 18-50 years with a positive pregnancy test following ET. The two groups studied were: women who stayed on IM progesterone following a positive pregnancy test and those who switched to vaginal progesterone after a positive test. The main outcome measured was risk of miscarriage < 24 weeks gestation as a proportion of non-biochemical pregnancies. 1988 women were included in the analysis. Among the baseline characteristics, the presence of prior miscarriages as well as prior failed ETs, and frozen cycles (vs fresh) as type of transfer were associated with IM progesterone use (p values ≤ 0.01). As per miscarriage risk < 24 weeks, 22.4% (274/1221) of patients in the IM progesterone group experienced a miscarriage compared with 20.7% (159/767) in the vaginal progesterone group (OR 0.90; 95% CI 0.73-1.13). A multivariable logistic regression model revealed an adjusted OR (aOR) of 0.97 (95% CI 0.77-1.22). This study suggests that switching from IM to vaginal progesterone after a positive pregnancy test following an ET is not associated with miscarriage risk. Considering that IM progesterone imposes substantial discomfort, this study offers reassurance and some flexibility in treatment protocols. Further prospective studies are necessary to corroborate the results of this study.


Protein Arrays II: Antigen Arrays.
Antigen arrays are fabricated using various antigens such as DNA, histones, synthetic peptides, recombinant proteins, or cell extracts to detect autoantibodies in autoimmune diseases, alloantibodies in transplantation, drug-induced antibodies or cancer-induced antibodies in blood or cell culture supernatant. In this protocol, we will provide a step-by-step executable procedure to perform antigen arrays, including antigen preparation and printing, blocking, sample loading, array detection, imaging, and data analysis.


Differences in Optical Coherence Tomography Assessment of Bruch Membrane Opening Compared to Stereoscopic Photography for Estimating Cup-to-Disc Ratio.
To compare the vertical and horizontal cup-to-disc ratio (VCDR, HCDR) by an updated optical coherence tomography (OCT) Bruch membrane opening (BMO) algorithm and stereoscopic optic disc photograph readings by glaucoma specialists. Reliability analysis. A total of 195 eyes (116 glaucoma and 79 glaucoma suspect) of 99 patients with stereoscopic photographs and OCT scans of the optic discs taken during the same visit were compared. Optic disc photographs were read by 2 masked glaucoma specialists for VCDR and HCDR estimation. Intraclass correlation coefficient (ICC) and Bland-Altman plots were used to assess the agreement between photograph reading and OCT in estimating CDR. OCT images computed significantly larger VCDR and HCDR than photograph reading before and after stratifying eyes based on disc size (P < .001). The difference in CDR estimates between the 2 methods was equal to or greater than 0.2 in 29% and 35% of the eyes for VCDR and HCDR, respectively, with a mean difference of 0.3 in each case. The ICCs between the readers and OCT ranged between 0.50 and 0.63. The size of disagreement in VCDR correlated weakly with cup area in eyes with medium (r2 = 0.10, P = .008) and large (r2 = 0.09, P = .007) discs. OCT and photograph reading by clinicians agree poorly in CDR assessment. The difference in VCDR between the 2 methods was depended on cup area in medium and large discs. These differences should be considered when making conclusions regarding CDRs in clinical practice.


Iron corrosion by novel anaerobic microorganisms.
Corrosion of iron presents a serious economic problem. Whereas aerobic corrosion is a chemical process, anaerobic corrosion is frequently linked to the activity of sulphate-reducing bacteria (SRB). SRB are supposed to act upon iron primarily by produced hydrogen sulphide as a corrosive agent and by consumption of 'cathodic hydrogen' formed on iron in contact with water. Among SRB, Desulfovibrio species--with their capacity to consume hydrogen effectively--are conventionally regarded as the main culprits of anaerobic corrosion; however, the underlying mechanisms are complex and insufficiently understood. Here we describe novel marine, corrosive types of SRB obtained via an isolation approach with metallic iron as the only electron donor. In particular, a Desulfobacterium-like isolate reduced sulphate with metallic iron much faster than conventional hydrogen-scavenging Desulfovibrio species, suggesting that the novel surface-attached cell type obtained electrons from metallic iron in a more direct manner than via free hydrogen. Similarly, a newly isolated Methanobacterium-like archaeon produced methane with iron faster than do known hydrogen-using methanogens, again suggesting a more direct access to electrons from iron than via hydrogen consumption.


Prognostic implications of pericardial and pleural effusion in patients with cardiac amyloidosis.
Pericardial and pleural effusion are common findings in patients with cardiac amyloidosis (CA). It is not known, whether effusions correlate with right ventricular (RV) function in these patients. Furthermore, data on the prognostic significance of pleural and pericardial effusion in CA is scarce. Patients with transthyretin (ATTR) and light chain (AL) CA were included in a clinical registry. All patients underwent transthoracic echocardiography at baseline. The presence of pericardial and pleural effusion was determined in every patient. The clinical endpoint was defined as cardiac death or heart failure hospitalization. In total, 143 patients were analysed. Of these, 85 patients were diagnosed with ATTR and 58 patients with AL. Twenty-four patients presented with isolated pericardial effusion and 35 with isolated pleural effusion. In 19 patients, both pericardial and pleural effusion were found and in 65 patients no effusion was present at baseline. The presence of pleural effusion correlated well with poor RV function, measured by global RV free-wall strain (p = 0.007) in patients with AL, but not in ATTR. No such correlation could be found for pericardial effusion in either amyloidosis subtype. Patients with AL presenting with pleural effusion had worse outcomes compared to patients with pericardial effusion alone or no effusion at baseline. In the ATTR group, there was no difference in outcomes according to presence and type of effusion. More than 50% of patients with CA presented with pleural and/or pericardial effusions. While pleural effusion was clearly associated with poor RV function in AL, we were not able to detect this association with pericardial effusion.


Improved pantograph clutches fabricated intraorally.
A technique that improves intraorally made autopolymerizing resin pantograph clutches has been presented. The resulting clutches are comfortable and stable. Even after removing and reinserting the clutches several times, retention is sufficient to support the weight of the pantograph. Mandibular clutches have sufficient retention for accurate hinge axis location. If necessary, the same clutches can easily be relined for tracings during and after treatment. Replacing the relining material will adapt the clutches to changes in tooth contour that may occur as a result of treatment.


Molecular Mechanisms of Dielectrically Controlled Resolution (DCR).
It is widely believed that the chiral discrimination process is solely dependent on the stereochemistryof the relevant molecules. However, through systematic studies on several resolution systems with popularchiral selectors, we have discovered a new fact that triggers modification of this prevailing conceptof chiral resolution. The studies have demonstrated that one enantiomer of a chiral selector can recognizeboth enantiomers of a target molecule in different solvent systems with different dielectric constants.The phenomenon was termed dielectrically controlled resolution (DCR). Since DCR was observed in differentresolution systems and was not too specific to a particular system, DCR was expected to widely occurin various resolution systems. We have investigated the molecular mechanism underlying this interestingphenomenon based on X-ray analysis of the relevant diastereomeric salts. The disclosed mechanism clearlyindicates that a chiral selector can inherently recognize both enantiomers of a target moleculeand only the dielectric property of the solvent employed in the resolution process governs the selectionof the enantiomer.


Determination of As(III) by anodic stripping voltammetry following double deposition and stripping steps at two gold working electrodes.
The double deposition and stripping steps were proposed to minimize interference and increase the sensitivity in anodic stripping voltammetry of As(III). Two working electrodes of drastically different surface areas were used for the measurements. Arsenic was first deposited at the gold film electrode of a large surface area. When the deposition step at this electrode finished, the electrode was moved at a short distance to the second electrode consisting of four gold microelectrodes. The arsenic stripped from the first electrode was partially deposited at the microelectrodes and the analytical signal was obtained by its oxidation. Due to double deposition of arsenic the interference of Cu(II) was minimized and the detection limit of As(III) was lowered by one order of magnitude. The calibration graph was linear from 5×10(-10) to 1×10(-8) mol L(-1) following deposition time of 300 s at the first and the second electrode.


Nonaccommodative esotropia after cataract extraction in a patient with previous accommodative esotropia.
We report a case of nonaccommodative esotropia developing after bilateral cataract surgery that corrected the preexisting hyperopia in a patient with accommodative esotropia since childhood. The esotropia required surgical correction despite the good visual acuity after the cataract surgery. In patients with preexisting strabismus, there is a possibility of decompensation of adaptive binocular mechanisms after cataract surgery and refractive procedures.


Current perspectives on parathyroid hormone (PTH) and PTH-related protein (PTHrP) as bone anabolic therapies.
Osteoporosis is characterized by low bone mineral density and/or poor bone microarchitecture leading to an increased risk of fractures. The skeletal alterations in osteoporosis are a consequence of a relative deficit of bone formation compared to bone resorption. Osteoporosis therapies have mostly relied on antiresorptive drugs. An alternative therapeutic approach for osteoporosis is currently available, based on the intermittent administration of parathyroid hormone (PTH). Bone anabolism caused by PTH therapy is mainly accounted for by the ability of PTH to increase osteoblastogenesis and osteoblast survival. PTH and PTH-related protein (PTHrP)-an abundant local factor in bone- interact with the common PTH type 1 receptor with similar affinities in osteoblasts. Studies mainly in osteoporosis rodent models and limited data in postmenopausal women suggest that N-terminal PTHrP peptides might be considered a promising bone anabolic therapy. In addition, putative osteogenic actions of PTHrP might be ascribed not only to its N-terminal domain but also to its PTH-unrelated C-terminal region. In this review, we discuss the underlying cellular and molecular mechanisms of the anabolic actions of PTH and the similar potential of PTH-related protein (PTHrP) to increase bone mass and improve bone regeneration.


Development of a 3D printing process of bolus using BolusCM material for radiotherapy with electrons.
This work presents the optimized parameters of 3D printing for print bolus using BolusCM material. Printing parameters were selected of the homogeneity and absence of air gaps. The dosimetric features of printed bolus were measured with a plane-parallel ionization chamber and EBT3 radiochromic film. Measured features were compared with those estimated with Monte Carlo methods. BolusCM shows good characteristics to be used as bolus material in radiotherapy with electrons, where the printing process allows personalizing the bolus in function of patient characteristics. The material low-cost, the 3D printing and the dosimetric features are few of the advantages of using BolusCM material in radiotherapy with electrons in skin cancer treatment.


Glomerular clusterin expression is increased in diabetic nephropathy and protects against oxidative stress-induced apoptosis in podocytes.
Clusterin, a glycoprotein encoded by the CLU gene, is expressed in many tissues, including the kidney, and clusterin expression is upregulated in the glomeruli of patients with various forms of kidney disease. Here, we investigated the role of clusterin in diabetic nephropathy (DN). In this study, we found that glomerular clusterin expression was increased in both patients with DN and streptozotocin-induced diabetic mice and that it co-localised with the podocyte marker WT1, indicating clusterin is expressed in podocytes. In our in vitro analysis, we found no significant change in CLU mRNA expression in podocytes following stimulation with high glucose and angiotensin II; in contrast, CLU mRNA expression was significantly upregulated following methylglyoxal stimulation. Methylglyoxal treatment also significantly decreased the mRNA expression of the slit diaphragm markers ZO-1 and NEPH1 and significantly increased the mRNA expression of the oxidative stress marker HO-1. Lastly, we showed that pre-incubating podocytes with recombinant human clusterin protein increased podocyte survival, prevented slit diaphragm damage, and reduced oxidative stress‒induced apoptosis following methylglyoxal stimulation. Taken together, our results indicate that glomerular clusterin is upregulated in DN, and this increase in clusterin expression may protect against oxidative stress-induced apoptosis in podocytes, providing a possible new therapeutic target for DN and other kidney diseases.


Thrombotic microangiopathic syndromes associated with drugs, HIV infection, hematopoietic stem cell transplantation and cancer.
Thrombotic microangiopathy (TMA) has multiple etiologies. In the four disorders described in this review, the primary organ involved is the kidney. Drug-associated TMA can be an acute, immune-mediated disorder or the result of gradual, dose-dependent toxicity. TMA may occur in patients with advanced HIV infection, possibly mediated by angio-invasive infections. TMA following allogeneic hematopoietic stem cell transplantation may also be caused by drug toxicity; the pathogenesis may involve inhibition of vascular endothelial cell growth factor in renal podocytes. Malignancies of many types with systemic microvascular involvement may cause TMA. Recognition that these syndromes may mimic TTP is important to provide appropriate management and to avoid the inappropriate use of plasma exchange treatment.


Thymineless mutagenesis in bacteria.
Experimental evidence indicates that while thymine starvation induces primarily A:T----G:C transitions in bacteria, it also may cause other uncharacterized base substitutions as well as frameshifts and deletions. However, models have been proposed to explain only the induction of point mutations by thymine deprivation. In this study, we demonstrate that thymine nucleotide depletion induces both point mutations in the his-4 and 1acI genes of Escherichia coli and reversion of the frameshift mutations trpE9777, trpA21, trpA540, and trpA9813. Analysis of the 1acI amber spectrum revealed that thymine starvation resulted in G:C----A:T transitions and all possible transversions. A defect in uracil-DNA glycosylase has little effect on the induction of 1acI- mutations but reduces substantially the induction of trpE9777 revertants. These data show that the mutagenic specificity of thymine nucleotide depletion is not limited to A:T----G:C transitions and suggest that removal of uracil from DNA plays a role in the generation of frameshift mutations by thymine deprivation. A model that involves nucleotide misincorporation into DNA and induction of error-prone repair functions in response to thymine starvation is proposed to account for these findings.


Use of quantitative 16S rRNA PCR to determine bacterial load does not augment conventional cerebrospinal fluid (CSF) cultures among children undergoing treatment for CSF shunt infection.
The aim of this study was to develop a quantitative 16S rRNA assay for determination of bacterial nucleic acid load in cerebrospinal fluid (CSF) shunt infection and to compare quantitative 16S rRNA polymerase chain reaction (PCR) findings to those of conventional bacterial culture in patients treated for CSF shunt infection. We developed a quantitative 16S rRNA PCR assay that detected bacterial load across a range of 2.5 × 10(9) down to 2.5 × 10(4) 16S copies/mL CSF under experimental conditions for numerous Gram-positive and Gram-negative organisms. However, when applied to archived CSF samples from 25 shunt infection episodes, correlations between positive bacterial culture and 16S rRNA levels were seen in only half of infections, and 16S rRNA levels dropped precipitously after an initial peak on the first day of sample collection. Bacterial load measured using 16S rRNA PCR does not provide sufficient information beyond bacterial culture to inform CSF shunt infection treatment.


High-Grade Cutaneous Mast Cell Tumour with Widespread Intrathoracic Metastasis and Neoplastic Pericardial Effusion in a Dog.
An 8-year-old neutered male French Bulldog was presented with a 2-day history of intermittent vomiting, reduced appetite and recent rapid development of multiple cutaneous masses over the head and neck regions. On presentation, the patient had a moderate volume of pericardial and bilateral pleural effusion. Echocardiography demonstrated irregular, heterogeneous thickening of the walls of the right ventricle and right atrium, consistent with infiltrative intramyocardial disease. Cytological examination of fine needle aspirates from one of the cutaneous masses confirmed a mast cell tumour. Pericardial fluid analysis revealed a haemorrhagic neoplastic effusion due to mast cell neoplasia. Histopathological and immunohistochemical examination of tissues obtained post mortem confirmed a high-grade cutaneous mast cell tumour with metastasis to the heart, pericardium, mediastinum and spleen. No metastatic disease was present in the submandibular lymph nodes or liver. Immunohistochemistry demonstrated KIT staining pattern 2. There was strong nuclear Ki67 labelling in an average of 65.0 cells per grid and an average of three positive AgNORs per nucleus in neoplastic cells. Polymerase chain reaction for the activating duplication mutation in exons 8 and 11 of c-Kit were negative. To the authors' knowledge, this is the first report of a canine cutaneous mast cell tumour associated with neoplastic pericardial effusion and widespread intrathoracic metastasis.


What are the functional consequences after TBI? The SHEFBIT cohort experience.
To investigate functional outcome after TBI and identify variables that predict outcome in a multiordinal regression model. The results of global outcome studies after Traumatic Brain Injury(TBI) differ widely due to differences in outcome measure, attrition to follow-up and selection bias. Outcome information would inform patients/families, guide service development and target high-risk individuals. prospective cohort of 1322 admissions with TBI, assessed by face to face interviews at 1 yr. Extended Glasgow Outcome Scale (GOSE) by structured questionnaire. At 1 year, outcome was determined in 1207(91.3%). Mean age was 46.9(SD17.3); Almost half(49.2%) had mild injury. At one year, 42.9% achieved Good Recovery but GOSE declined in 11.4% of the cohort compared to 10 weeks including 60(4.9%) deaths. In an ordinal logistic regression, increasing TBI severity, etiology (assault), more prominent CT abnormality, past psychiatric history and alcohol intoxication were independent predictors of worse GOSE. A pseudo-R2 of 0.38 suggested that many unmeasured factors also contribute to TBI outcome. Future work needs to identify other variables that may influence outcome. In a large TBI cohort, there is still considerable functional disability at 1 year. It may be possible to target high-risk groups for rehabilitation.


Impact of COVID-19 lockdown on adolescents in treatment for obesity.
The aim of this study was to evaluate the impact of coronavirus disease 2019 (COVID-19) lockdown on body mass index (BMI) z-score of adolescents treated for obesity, and to assess the correlation between BMI z-score changes and lifestyle variables. This cross-sectional study recruited 66 participants aged 11-18 years with overweight or obesity who attended our obesity clinics before and after the lockdown. We assessed demographic and anthropometric characteristics as well as lifestyle variables. The mean BMI z-score of the participants was stable during this period (p = 0.233). Balanced diet, snacking, and sweet beverage consumption improved in about half of the participants. Having at least one parent at home was associated with a significantly more balanced diet (p = 0.008) and an increase in family activities (p = 0.015). Physical activities decreased (51.5%) and screen time increased for most of the adolescents (86.4%). The BMI z-score decreased significantly when three or more lifestyle habits improved (p<0.001). This study showed that BMI z-scores were stable for a majority of adolescents treated for obesity during the COVID19 lockdown, along with positive and negative changes on weight-related lifestyle habits. This extraordinary period may have created opportunities for lifestyle modification and has emphasized the importance of family support in the management of obesity in adolescents.


Awareness and knowledge of dental erosion among Yemeni dental professionals and students.
This study explored Yemeni dentists' and dental students' knowledge about the associated factors, approaches to diagnosis and preventive methods of dental erosion (DE), as well as any associations between DE awareness and some potentially related variables. A self-administered questionnaire was distributed to general dental practitioners (n = 323) in Sanaa and to fifth year dental students (n = 97) at the University of Science and Technology, Sanaa, Yemen during the period from July to November 2013. Descriptive and logistic regression analyses were conducted. Overall response rate was 79 %. Results indicated that 61 % of respondents learned about DE from dental school, 27 % from their own studies and the rest from continuing education courses and the media. DE was reportedly most frequently seen on incisors by 46 % of respondents and on premolars and molars by 24 %. While 48 % reported DE to be more common in male patients, no gender differences were reported by 20 % of respondents. Acidic drinks were believed to be causative factors for DE by 41 % of dentists and 52 % of students, while 90 % of respondents believed that patients' dietary history is important during DE diagnosis. As preventive measures for DE, reduction of acidic drink consumption was advised by 51 % of respondents while only 37 % advised their patients to use fluoridated toothpastes. Younger respondents (≤35 years) were more likely to identify the commonly-known causative factors for DE (P = 0.024). Twenty-seven percent of the respondents reportedly used an index to grade DE. Dental students were more likely than dentists to use such an index (P <0.001) and to more frequently advise their patients to reduce intake of acidic drinks (P = 0.02) compared to dentists. In-depth knowledge about causative factors, diagnosis and preventive methods of DE was apparent among only half the respondents and approaches to early diagnosis were insufficient. There would appear to be an urgent need for enhancing awareness and knowledge about DE within the Yemeni dental community.


Disruption of global hypothalamic microRNA (miR) profiles and associated behavioral changes in California mice (Peromyscus californicus) developmentally exposed to endocrine disrupting chemicals.
Developmental exposure to endocrine disrupting chemicals (EDCs), e.g., bisphenol A (BPA) or genistein (GEN), causes longstanding epigenome effects. MicroRNAs (miRs) regulate which mRNAs will be translated to proteins and thereby serve as the final checkpoint in epigenetic control. Scant amount is known, however, whether EDCs affect neural miRNA (miR) patterns. We aimed to test the hypothesis that developmental exposure of California mice (Peromyscus californicus) to GEN, BPA, or both chemicals influences hypothalamic miR/small RNA profiles and ascertain the extent such biomolecular alterations correlate with behavioral and metabolic changes. California mice were developmentally exposed to GEN (250 mg/kg feed weight, FW), GEN (250 mg/kg FW)+BPA (5 mg/kg FW), low dose (LD) BPA (5 mg/kg FW), or upper dose (UD) BPA (50 mg/kg FW). Adult offspring were tested in a battery of behavioral and metabolic tests; whereupon, mice were euthanized, brains were collected and frozen, small RNAs were isolated from hypothalamic punches, and subsequently sequenced. California mice exposed to one or both EDCs engaged in one or more repetitive behaviors. GEN, LD BPA, and UD BPA altered aspects of ultrasonic and audible vocalizations. Each EDC exposure led to sex-dependent differences in differentially expressed miR/small RNAs with miR7-2, miR146, and miR148a being increased in all female and male EDC exposed groups. Current findings reveal that developmental exposure to GEN and/or BPA affects hypothalamic miR/small RNA expression patterns, and such changes correlate with EDC-induced behavioral and metabolic alterations. miR146 is likely an important mediator and biomarker of EDC exposure in mammals, including humans.


Iodine Status in Pregnant Women, Lactating Mothers, and Newborns in an Area with More Than Two Decades of Successful Iodine Nutrition.
Pregnant women, lactating mothers, and their newborns constitute the target population for prevention and control of iodine deficiency. Hence, the aim of this study was to evaluate the iodine nutrition status among these vulnerable groups in an area with more than two decades of successful elimination of iodine deficiency. In this cross-sectional study conducted in health care centers of Tehran, 100 pregnant women and 84 lactating mothers and their newborn were randomly selected. Urinary iodine concentration and iodine content of salts were measured using the Sandell-Kolthoff and titration methods, respectively. Urinary iodine concentration <150 μg/L for pregnant women and <100 μg/L for lactating mothers and newborns was considered as iodine nutrition inadequacy, respectively. Median (interquartile range [IQR]) urinary iodine concentration (UIC) was 103 (59-155) μg/L in pregnant women, 77 (42-194) μg/L in lactating mothers, and 198 (84-260) μg/L in newborns. Median (IQR) iodine content of salt was 26 (21-30) ppm and 25 (18-28) ppm in pregnant women and lactating mothers, respectively (P = 0.462). Iodine content of salt was significantly correlated with UIC of pregnant women (r = 0.24, P = 0.019), but no correlation was found among lactating mothers (r = 0.12, P = 0.316). Neonatal UIC was significantly correlated with iodine content of salt consumed by their mothers (r = 0.49, P = 0.001). Despite suboptimal iodine status among subgroups of Tehranian pregnant and lactating women, iodine nutrition status of newborns was within optimal levels, which may be explained by a compensatory mechanism in the mammary glands.


Corticosteroid-serotonin interactions in depression: a review of the human evidence.
It has been suggested that corticosteroid-serotonin interactions are central to the pathophysiology of depression. These interactions have been investigated in healthy and depressed humans, primarily using neuroendocrine techniques. To review the evidence regarding the nature of these interactions in healthy and depressed humans. Electronic searches were performed for relevant papers, employing MEDLINE and Web of Science. To focus the review, we selected only those articles involving (i) assessment of serotonergic function following experimental manipulation of the HPA axis in healthy volunteers; and (ii) assessment of both serotonergic and HPA axis function in clinically depressed subjects. Pre-treatment with hydrocortisone, both acutely and sub-acutely attenuates the GH response to GHRH in healthy subjects. This complicates the interpretation of 5-HT neuroendocrine studies employing GH output as a measure. In depression there is evidence that reduced availability of l-tryptophan impairs HPA axis feedback. There is also evidence that depressed and healthy subjects may adapt differently both to low tryptophan and hypercortisolaemic challenges. There is no consistent evidence of a simple relationship between HPA axis function and 5-HT function in depression. The putative reduction in central 5-HT function has not been shown to be a direct consequence of hypercortisolaemia. Rather, the 5-HT system and HPA axis have complex inter-relationships. Challenges to either system, such as stress or reduced dietary tryptophan, may perturb the other and subjects vulnerable to depression may fail to adapt to such challenges.


A revision of the Tokuhashi revised score improves the prognostic ability in patients with metastatic spinal cord compression.
The Tokuhashi revised score from 2005 (TR2005) is the most recommended prognostic scoring system in patients with metastatic spinal cord compression (MSCC). However, recent studies have questioned its prognostic ability and the need for a new revision has been proposed. We aimed to assess whether a revision of the TR2005 can improve the prognostic ability of the scoring system. In 2011 and 2012, a total of 1143 consecutive patients admitted with MSCC were prospectively included in a 2011 and a 2012 cohort. For the patients admitted in 2011 (n = 544), the components of the TR2005 including primary cancer diagnosis were analyzed regarding the prognostic ability. Based on these findings, a revision of the TR2005 score was defined as the Tokuhashi revised score 2017 (TR2017). The prognostic abilities of the TR2005 and the TR2017 were compared by Kaplan Meyer (KM) curves, and receiver-operating characteristics' (ROC) analysis was compared in a cohort of patients admitted in 2012 (n = 599). KM curves and ROC analysis showed that the TR2017 had better prognostic ability compared to the TR2005. The ROC areas were as follows: <6-months survival, TR2017 = 0.71 and TR2005 = 0.65, and p = 0.003; for ≥6-month survival, TR2017 = 0.71 and TR2005 = 0.65, and p = 0.003; for ≥12-month survival TR2017 = 0.72 and TR2005 = 0.67, and p = 0.0015. The TR2017 can improve the prognostic ability of the TR2005 in patients with MSCC. This could affect the preoperative evaluation of patients suffering from MSCC.


Role of lipoprotein lipase activity on lipoprotein metabolism and the fate of circulating triglycerides in pregnancy.
The mechanism that induces maternal hypertriglyceridemia in late normal pregnancy, and its physiologic significance are reviewed as a model of the effects of sex steroids on lipoprotein metabolism. In the pregnant rat, maternal carcass fat content progressively increases up to day 19 of gestation, then declines at day 21. The decline may be explained by the augmented lipolytic activity in adipose tissue that is seen in late pregnancy in the rat. This change causes maternal circulating free fatty acids and glycerol levels to rise. Although the liver is the main receptor organ for these metabolites, liver triglyceride content is reduced. Circulating triglycerides and very-low-density lipoprotein (VLDL)-triglyceride levels are highly augmented in the pregnant rat, indicating that liver-synthesized triglycerides are rapidly released into the circulation. Similar increments in circulating VLDL-triglycerides are seen in pregnant women during the third trimester of gestation. This increase is coincident with a decrease in plasma postheparin lipoprotein lipase activity, indicating a reduced removal of circulating triglycerides by maternal tissues or a redistribution in their use among the different tissues. During late gestation in the rat, tissue lipoprotein lipase activity varies in different directions; it decreases in adipose tissue, the liver, and to a smaller extent the heart, but increases in placental and mammary gland tissue. These changes play an important role in the fate of circulating triglycerides, which are diverted from uptake by adipose tissue to uptake by the mammary gland for milk synthesis, and probably by the placenta for hydrolysis and transfer of released nonesterified fatty acids to the fetus. After 24 hours of starvation, lipoprotein lipase activity in the liver greatly increases in the rat in late pregnancy; this change is not seen in virgin animals. This alteration is similar to that seen in liver triglyceride content and plasma ketone body concentration in the fasted pregnant rat. In the fasting condition during late gestation, heightened lipoprotein lipase activity is the proposed mechanism through which the liver becomes an acceptor of circulating triglycerides, allowing their use as ketogenic substrates, so that both maternal and fetal tissues may indirectly benefit from maternal hypertriglyceridemia. Changes in the magnitude and direction of lipoprotein lipase activity in different tissues during gestation actively contribute both to the development of hypertriglyceridemia and to the metabolic fate of circulating triglycerides.(ABSTRACT TRUNCATED AT 400 WORDS)


[Acute basophilic leukemia in a 75-year-old man. A clinical and cytological study with a review of the literature].
The authors present a rare clinical case of cytomorphologically and cytochemically confirmed acute basophil leukosis ( ABL ) in a male, aged 75. A comprehensive review of the present-day literature on the problem is made with detailed discussions of the differential diagnostic criteria upon which the diagnosis is made. The discussion emphasized some aspects of the cytomorphological characteristic, not finally solved, and on the nozological belonging of ABL .


Long-Term Outcomes after Thoracic Endovascular Aortic Repair Using Chimney Grafts for Aortic Arch Pathologies: 10 Years of Single-Center Experience.
This study reports the early- and long-term outcomes of the thoracic endovascular aortic repair using the Chimney-Graft technique (ChTEVAR) for the treatment of aortic arch pathologies. From January 2010 to December 2019, patients who underwent aortic ChTEVAR technique in our institution were included. Early, mid, and long-term outcomes in this group of patients were evaluated. Patient follow-up data were obtained by imaging follow-up that are routinely performed after 3-6 months following initial surgery and then at yearly intervals. Aortic arch repair with a ChTEVAR was performed in 54 patients. The 30-day mortality was 18.5% (n = 10). All-cause 30-day mortality was higher in the subgroup of patients operated urgently (33% vs. 14%) without a significant difference (P = 0.141). Permanent neurological deficit (PND) was observed in 15% (8/54 patients); stroke in 11% (6/54), and paraplegia 4% (2/54). During follow-up the primary and primary-assisted chimney-graft patency was 96.8% and 97.8%, respectively. The multivariate analysis identified the age >70 years and the aortic diameter as independent risk factors for elevated mortality during the follow-up (P = 0.015 and 0.001, respectively). The PND was an independent predictor for 30-day mortality (P = 0.014, hazard ratio 13.5, 95% confidence interval 1.7-106.6). The ChTEVAR has noninferior results to other open and endovascular aortic arch repair methods with an acceptable long-term survival especially in elective procedures.


A population-based study on social inequality and barriers to healthcare-seeking with lung cancer symptoms.
Healthcare-seeking with lung cancer symptoms is a prerequisite for improving timely diagnosis of lung cancer. In this study we aimed to explore barriers towards contacting the general practitioner (GP) with lung cancer symptoms, and to analyse the impact of social inequality. The study is based on a nationwide survey with 69,060 individuals aged ≥40 years, randomly selected from the Danish population. The survey included information on lung cancer symptoms, GP contacts, barriers to healthcare-seeking and smoking status. Information about socioeconomics was obtained by linkage to Danish Registers. Descriptive statistics and multivariate logistic regression model were used to analyse the data. "Being too busy" and "Being worried about wasting the doctor's time" were the most frequent barriers to healthcare-seeking with lung cancer symptoms. Individuals out of workforce and individuals who smoked more often reported "Being worried about what the doctor might find" and "Being too embarrassed" about the symptoms. The social inequality in barriers to healthcare-seeking with lung cancer symptoms is noticeable, which emphasises the necessity of focus on vulnerable groups at risk of postponing relevant healthcare-seeking.


First report on spinocerebellar ataxia type 3 (Machado-Joseph disease) in Poland.
Spinocerebellar ataxia type 3 (SCA3; Machado-Joseph disease, MJD) is the most common autosomal-dominant form of genetic ataxia worldwide. However, it has never been reported in Eastern Europe. This letter presents the first three families with SCA3 from Poland and discusses the practical implications of the disease for clinicians.


An HRP study of the central projections from primary sensory neurons innervating the rat masseter muscle.
Retrograde and transganglionic transport of horseradish peroxidase has been used to study the cell bodies of origin and the central projections of neurons innervating the rat masseter muscle. Labeled cell bodies were observed both in the trigeminal ganglion and in the mesencephalic trigeminal nucleus. Major central projections from mesencephalic trigeminal neurons were traced to the supratrigeminal nucleus and to the brainstem reticular formation. Smaller projections from these neurons could be followed to the borders of the solitary tract and hypoglossal nuclei as well as to lamina V of nucleus caudalis and corresponding areas in the dorsal horn at C1-C2 spinal cord segments. Labeling from trigeminal ganglion neurons was observed close to the trigeminal tract in all subdivisions of the trigeminal sensory nuclear complex and in the dorsal horn lamina I at C1 and C2 levels.


A possible role of the cholinergic and purinergic receptor interaction in the regulation of the rat urinary bladder function.
The contractile activation of the upper (dome) and lower (base) parts of the urinary bladder show some differences. Cellular mechanisms that might be responsible for cholinergic effects blocking non-adrenergic non-cholinergic contractions in the base of the rat urinary bladder were investigated. Smooth muscle cells were thus freshly isolated or cultured both from the dome and the base of the rat urinary bladder and the contribution from cholinergic and purinergic pathways to their Ca(2+) homeostasis was examined. The expression of nicotinic acetylcholine (nAChR) and P2X2 purinergic receptors on the cultured cells and on tissue sections was investigated. The ATP-evoked Ca(2+) transients in rat smooth muscle cells did not show any desensitization. However, when ATP was administered together with carbamylcholine (CCh), the latter essentially prevented ATP from evoking Ca(2+) transients in smooth muscle cells from the base (suppression to 12 ± 2.5% of control, n = 57; p < 0.01), but not from the dome (99 ± 5% of control, n = 52; p > 0.05) of the rat urinary bladder. While atropine was unable to modify (6 ± 3% of control, n = 14; p < 0.05), α-bungarotoxin (118 ± 12% of control, n = 20; p > 0.05) blocked the inhibitory effects of CCh. Additionally, α7 subunits of nAChR and P2X2 purinergic receptors were identified using immunocytochemistry, immunohistochemistry, and Western blot in cultured urinary bladder smooth muscle cells, in urinary bladder sections, and in urinary bladder muscle strips, respectively, suggesting that the activation of nAChR modifies the action of ATP.


Gadobutrol for contrast-enhanced magnetic resonance imaging in elderly patients: review of the safety profile from clinical trial, post-marketing surveillance, and pharmacovigilance data.
To assess the safety of gadobutrol administration in elderly patients (≥65 years) by comparing the incidence of adverse drug reactions (ADRs) following gadobutrol-enhanced magnetic resonance imaging (MRI) procedures in elderly patients with that in adults aged 18-64 years. Safety data on gadobutrol administration from clinical trials, post-marketing surveillance (PMS) studies, and pharmacovigilance reports were collected in three databases. In each dataset, absolute and relative frequencies of ADRs between age groups were analysed, along with odds ratios and 95% confidence intervals. Logistic regression was used to identify significant influencing factors on ADRs in the PMS and pharmacovigilance data. Rates of reported ADRs were lower in elderly patients versus adults aged <65 years due to a reduced incidence of non-serious ADRs; this was statistically significant for the clinical trials and pharmacovigilance populations, with a trend in the PMS database. Serious ADRs occurred infrequently in the clinical trials and PMS populations (too low for statistical comparison), and pharmacovigilance data demonstrated a low incidence (<0.005%) in both age groups. This evaluation involving three large databases demonstrated no greater incidence of ADRs following gadobutrol-enhanced MRI in elderly patients (≥65 years) compared with younger adults, with gadobutrol having a favourable safety profile in both age groups.


Climatic niche and flowering and fruiting phenology of an epiphytic plant.
Species have geographic distributions constrained by combinations of abiotic factors, biotic factors and dispersal-related factors. Abiotic requirements vary across the life stages for a species; for plant species, a particularly important life stage is when the plant flowers and develops seeds. A previous year-long experiment showed that ambient temperature of 5-35 °C, relative humidity of >50 % and ≤15 consecutive rainless days are crucial abiotic conditions for Spanish moss (Tillandsia usneoides L.). Here, we explore whether these optimal physiological intervals relate to the timing of the flowering and fruiting periods of Spanish moss across its range. As Spanish moss has a broad geographic range, we examined herbarium specimens to detect and characterize flowering/fruiting periods for the species across the Americas; we used high-temporal-resolution climatic data to assess the availability of optimal conditions for Spanish moss populations during each population's flowering period. We explored how long populations experience suboptimal conditions and found that most populations experience suboptimal conditions in at least one environmental dimension. Flowering and fruiting periods of Spanish moss populations are either being optimized for one or a few parameters or may be adjusted such that all parameters are suboptimal. Spanish moss populations appear to be constrained most closely by minimum temperature during this period.


Feasibility study of short hydration using oral rehydration solution in cisplatin including chemotherapy of lung cancer.
Cisplatin (CDDP) is used as a key anticancer drug for solid cancers, including lung cancer. However, a large quantity of fluid replacement is required to prevent renal dysfunction. This requirement have made outpatient chemotherapies including CDDP administration less popular among the available therapeutic options. We designed a short-term hydration regimen combined with oral rehydration solution (ORS) that has a supplementary water ability equivalent to intravenous electrolyte maintenance infusion and investigated its safety and feasibility in the CDDP including chemotherapy. The subjects received chemotherapy including CDDP administration (60-80 mg/m(2)) for untreated lung cancer were recruited. The intravenous hydration was infused at around 2000 mL on Day 1, and patients drank ORS at a dose of 1000 mL/day for 3 days. Any renal dysfunction, gastrointestinal symptoms or other tolerability variables pertaining to the remaining three cycles of this regimen were analyzed in the patients who were able to continue treatment after the second cycle. The majority (29/35, 82.9 %) of patients completed intake of ORS for 3 days. The mean ± standard deviation of patient body-surface area-adjusted estimated glomerular filtration rate (eGFR), serum creatinine (sCre) and urea nitrogen from the initial therapy to 1 month after the last administration changed from 79.8 ± 11.7-67.0 ± 16.9 mL/min (p = 0.15), 0.70 ± 0.13-0.85 ± 0.27 mg/dL (p = 0.02), and 14.3 ± 3.8-17.1 ± 5.4 mg/dL (p = 0.09), respectively. The CTCAE ver 4.0 grades 1 or 2 adverse events pertaining to renal function after the last administration were 2 (5.7 %)/2 (5.7 %) patients assessed by sCre, and 14 (40.0 %)/12 (34.3 %) patients assessed by eGFR, respectively. There was no patient with ≥3 grade renal dysfunction based on either evaluation. Based on the results of this study, supplementary use of the ORS as a method of short-term hydration may be a feasible regimen for shortening infusion times and improving safety for those undergoing chemotherapy including CDDP administration.


Use of plasma exchange and heparin during cardiopulmonary bypass for a patient with heparin induced thrombocytopenia: a case report.
Patients with documented history of heparin-induced thrombocytopenia (HIT) pose a difficult problem during surgery using cardiopulmonary bypass (CPB). Several alternatives to heparin exist, but these products either are not approved for use in the United States or have more side effects than heparin. We report on a patient with documented heparin-induced antibody and left main coronary artery disease who underwent uneventful coronary artery bypass surgery and recovery by using preoperative plasmaphresis and limited use of porcine intestinal heparin during CPB.