Incidental findings at chest CT: a needs assessment survey of radiologists' knowledge.
To assess practice patterns in evaluating incidental findings at chest computed tomography (CT) to determine the need for further education. A survey was given to 1600 radiologists, presenting four clinical case questions regarding the evaluation/significance of the following incidental findings at chest CT: thyroid lesion; enlarged mediastinal lymph nodes; asymptomatic, small pulmonary embolus; and small lung nodule. The respondents' answers were compared with "truth," as defined by the best evidence available in the medical literature. Additional questions elicited the respondents' demographics and comfort levels in addressing the findings. Analysis of variance models with a Tukey correction for post hoc comparisons and chi-square tests were used to determine if any demographic factors or comfort levels were predictive of higher correct response rates. The overall survey response rate was 28% (445/1600). Correct case response rates ranged from 26% (115/442) to 79% (343/445). Only 6% (28/438) of respondents chose the correct answers for all cases. Up to 80% (353/440) of respondents felt comfortable in addressing findings, and only 57% (252/443) of respondents felt that they needed more training in this area. Fellowship training in cardiothoracic radiology, working in a teaching practice, and subspecialization in abdominal or cardiothoracic radiology were predictive of higher correct response rates. Except for one case question, the comfort level was not predictive of correct response rate. There was considerable variability among radiologists and substantial deviation from best medical practice with regard to the interpretation/evaluation of incidental findings at chest CT, signifying a significant need for further education.


Effect of CO2 insufflation on the number and behavior of air microemboli in open-heart surgery: a randomized clinical trial.
The risks that the presence of air microemboli implies in open-heart surgery have recently been emphasized by reports that their number is correlated with the degree of postoperative neuropsychological disorder. Therefore, we studied the effect of CO2 insufflation into the cardiothoracic wound on the incidence and behavior of microemboli in the heart and ascending aorta. Twenty patients undergoing single-valve surgery were randomly divided into 2 groups. Ten patients were insufflated with CO2 via a gas diffuser, and 10 were not. Microemboli were ascertained by intraoperative transesophageal echocardiography (TEE) and recorded on videotape from the moment that the aortic cross-clamp was released until 20 minutes after end of cardiopulmonary bypass (CPB). The surgeon performed standard de-airing maneuvers without being aware of TEE findings. Postoperatively, a blinded assessor determined the maximal number of gas emboli during each consecutive minute in the left atrium, left ventricle, and ascending aorta. The 2 groups did not differ in the usual clinical parameters. The median number of microemboli registered during the whole study period was 161 in the CO2 group versus 723 in the control group (P<0.001). Corresponding numbers for the left atrium were 69 versus 340 (P<0.001), left ventricle 68 versus 254 (P<0.001), and ascending aorta 56 versus 185 (P<0.001). In the CO2 group, the median number of detectable microemboli after CPB fell to zero 7 minutes after CPB versus 19 minutes in the control group (P<0.001). Insufflation of CO2 into the thoracic wound markedly decreases the incidence of microemboli.


Dorsolateral Prefrontal Cortex and Subcallosal Cingulate Connectivity Show Preferential Antidepressant Response in Major Depressive Disorder.
Major depressive disorder is associated with abnormal connectivity across emotion and reward circuits as well as other established circuits that may negatively impact treatment response. The goal of this study was to perform an exploratory reanalysis of archival data from a clinical trial to identify moderators of treatment outcome of sertraline over placebo. EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care) study participants completed magnetic resonance imaging before randomization to either sertraline or placebo for 8 weeks (n = 279). Seed-based functional connectivity was computed using 4 bilateral seeds (2 spheres defined bilaterally): amygdala, dorsolateral prefrontal cortex (DLPFC), subcallosal cingulate cortex, and ventral striatum. Functional connectivity maps were generated, principal component analysis was performed, linear mixed effects models were used to determine moderators of treatment outcome, and post hoc analyses were used to determine level of connectivity (low and high, -1 and +1 SD from the mean) that was most sensitive to improved depression severity (baseline to week 8) based on treatment. Greater mean reduction in the 17-item Hamilton Rating Scale for Depression score by 8 weeks occurred with sertraline relative to placebo when connectivity in the DLPFC was low (3-way interaction test, p = .05). Conditional on low connectivity in the DLPFC and subcallosal cingulate cortex and high connectivity in the ventral striatum and amygdala, there was on average a 4.8-point greater reduction in the 17-item Hamilton Rating Scale for Depression score with sertraline relative to placebo (p = .003). The level of functional connectivity seeded in both the DLPFC and the subcallosal cingulate cortex networks may play an important role in identifying a favorable response to sertraline over placebo.


[Characteristics of the cells producing thymic chemotactic factor for bone marrow stem cells].
It was shown using complement-dependent cytolysis and monoclonal antibodies against CD4, CD8, and NK1.1 antigens that the cortisone-resistant CD3+4-8-NK1.1(-)-thymocytes spontaneously secreted a chemotactic transmitter inducing the release and directed migration of bone marrow cells. When estimating the general profile of the cytokines of these thymocytes by PCR with revertase, it was demonstrated the cells in question did not express cytokines with colony stimulating activities (SCF, IL-3, or GM-CSF) or cytokines affecting the migration of bone marrow stem elements (IL-2, 4, or 7). In addition, an active expression of gene bcl-2 was detected. Thus, the chemotactic cytokine inducing the release of bone marrow stem elements is a product of the cortisone-resistant long-living CD3+4-8-NK1.1(-)-T-cells of the thymus.


n-3 PUFA Improve Emotion and Cognition during Menopause: A Systematic Review.
Women show an increased risk of cognitive impairment and emotional disorders, such as anxiety and depression, when approaching menopause. Data on risk and protection factors have yielded robust evidence on the effects of lifestyle factors, such as diet, in preserving emotional and cognitive functioning. This review focused on the effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) on anxiety, depression, and cognition during the menopausal transition. This systematic review considered all articles published until 31 December 2021, and the search was performed on two databases, PubMed and Scopus. The fields of interest were "menopause", "n-3 PUFA" and "emotional and cognitive aspects". Out of the 361 articles found on PubMed and 283 on Scopus, 17 met inclusion criteria. They encompassed 11 human and 6 animal studies. Most studies reported relieved depressive symptoms in relation to n-3 PUFA intake. While controversial results were found on anxiety and cognition in humans, n-3 PUFA consistently reduced anxiety symptoms and improved cognition in animal studies. Taken together, n-3 PUFA intake shows beneficial effects on emotional and cognitive behaviours during menopause transition. However, further investigations could increase knowledge about the effectiveness of n-3 PUFA on psychological well-being in this delicate period of feminine life.


Atrial natriuretic peptide modulates N-methyl-D-aspartate-induced hyperexcitability in ethanol-dependent mice.
The role of central nervous atrial natriuretic peptide was investigated for behavioral hyperexcitability in alcohol-dependent mice. Mice were made tolerant to and dependent on ethanol with an ethanol-liquid diet for 14 days. Five hours after withdrawal from ethanol, withdrawal symptoms were analyzed by scoring handling-induced convulsions. N-methyl-D-aspartate (NMDA) induced behavioral seizures in a dose-dependent manner, an effect which was more intensive during the ethanol withdrawal period than in alcohol-naive animals. Intracerebroventricular (i.c.v.) injections of alpha-atrial natriuretic peptide (atrial natriuretic peptide) dose-dependently inhibited, whereas injection of an antiserum against atrial natriuretic peptide potentiated, the seizure-inducing effect of NMDA in ethanol-dependent mice. The main conclusion is that central nervous atrial natriuretic peptide plays a modulatory role in behavioral hyperexcitability during alcohol withdrawal.


24-hour rhythms in oxidative stress during hepatocarcinogenesis in rats: effect of melatonin or alpha-ketoglutarate.
To compare the effects of alpha-ketoglutarate (alpha-KG) and melatonin on 24-h rhythmicity of oxidative stress in N-nitrosodiethylamine (NDEA)-injected Wistar male rats, melatonin (5 mg/kg i.p.) or alpha-KG (2 g/kg through an intragastric tube) was given daily for 20 weeks. In blood collected at 6 time points during a 24-h period, serum activity of aspartate transaminase (AST) and alanine transaminase (ALT) and the levels of alpha-fetoprotein (alpha-FP) were measured as markers of liver function. To assess lipid peroxidation and the antioxidant status, plasma levels of thiobarbituric acid reactive substances (TBARS) and of reduced glutathione (GSH) were measured, together with the activity of erythrocyte superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione S-transferase (GST). NDEA augmented mesor and amplitude of rhythms in AST and ALT activity and plasma alpha-FP levels and mesor values of plasma TBARS, while decreasing mesor values of plasma GSH and erythrocyte SOD, CAT, GPx and GST. Acrophases were delayed by NDEA in all cases except for alpha-FP rhythm, which became phase-advanced. Co-administration of melatonin or alpha-KG partially counteracted the effects of NDEA. Melatonin decreased mesor of plasma TBARS and augmented mesor of SOD activity. The results indicate that melatonin and alpha-KG are effective in protecting from NDEA-induced perturbation of 24-h rhythms in oxidative stress. Melatonin augmented antioxidant defense in rats.


Automatic p wave analysis over 24 hours in patients with paroxysmal or persistent atrial fibrillation.
Patients with atrial fibrillation (AF) often exhibit abnormalities of P wave morphology during sinus rhythm. We examined a novel method for automatic P wave analysis in the 24-hour-Holter-ECG of 60 patients with paroxysmal or persistent AF and 12 healthy subjects. Recorded ECG signals were transferred to the analysis program where 5-10 P and R waves were manually marked. A wavelet transform performed a time-frequency decomposition to train neural networks. Afterwards, the detected P waves were described using a Gauss function optimized to fit the individual morphology and providing amplitude and duration at half P wave height. >96% of P waves were detected, 47.4 +/- 20.7% successfully analyzed afterwards. In the patient population, the mean amplitude was 0.073 +/- 0.028 mV (mean variance 0.020 +/- 0.008 mV(2)), the mean duration at half height 23.5 +/- 2.7 ms (mean variance 4.2 +/- 1.6 ms(2)). In the control group, the mean amplitude (0.105 +/- 0.020 ms) was significantly higher (P < 0.0005), the mean variance of duration at half height (2.9 +/- 0.6 ms(2)) significantly lower (P < 0.0085). This method shows promise for identification of triggering factors of AF.


Effect of sand mining on riparian landcover transformation in Dallung-Kukou catchment of the White Volta basin, Ghana.
Rapid urbanization has increased demand for sand in the construction industry to meet housing and infrastructure needs of urban population. The Dallung-Kukuo catchment of the White Volta River Basin is a major sand mining site for the construction industry in Tamale and other peri-urban communities. On the contrary, the river serves as a major source of water supply to the population. Riparian vegetation is essential to water protection, but research has focused extensively on the impact of sand mining on water quality in the river basin. The present study employed GIS and remote sensing techniques coupled with in-situ vegetation sampling to assess riparian land cover changes from 1990 to 2021. Land cover images of the catchment revealed a 14.9% increase in sand mining area, while river bed area and woodland cover decreased by 0.7% and 20%, respectively, from 1990 to 2021. A comparison of woody plant diversity also showed a higher Shannon diversity index in the unmined area of the riparian zone (3.0) compared to the sand mining area (2.0). Environmental Protection Agency and traditional authorities should intensify monitoring to protect the White Volta basin from unsustainable exploitation.


Impact of allergic rhinitis on quality of life after powered intracapsular tonsillectomy and adenoidectomy.
Allergic rhinitis (AR) has been reported to worsen quality of life (QoL) after adenotonsillectomy. Although powered intracapsular tonsillectomy and adenoidectomy (PITA) has been widely performed, it is not clear whether comorbid AR may worsen QoL in patients who undergo PITA. To evaluate QoL after PITA in relation to AR. Children undergoing PITA for sleep-disordered breathing were enrolled and divided into AR and non-AR groups. QoL was evaluated using serial applications of the Obstructive Sleep Apnea-18 (OSA-18) questionnaire and compared between the two groups. Of 151 enrolled patients, 73 were categorized into the AR and 78 into non-AR groups. After surgery, patients exhibited marked improvement in OSA-18 scores in both groups, with similar results at each follow-up. The degree of improvement in OSA-18 scores was less in the AR group 3 months after surgery; however, this difference was not significant 6 months after surgery. Although comorbid AR may initially appear to impede improvement in QoL after PITA, QoL was improved similarly 6 months after PITA, irrespective of AR status. In children with comorbid AR, PITA could be safely performed to treat sleep-disordered breathing without concerns regarding worsening of QoL.


Effect of indapamide on phosphate metabolism and vascular reactivity.
The effect of indapamide, a nonthiazide diuretic, on urinary electrolytes, renal hemodynamics, and tissue inorganic phosphate was examined in normal anesthetized rats, as well as on vascular reactivity in vitro. Intravenous injections of 0.5 ml/kg of 1 x 10(-5), 1 x 10(-4), and 1 x 10(-3) M indapamide solutions reduced mean arterial pressure from 123 to 114, 130 to 113, and 128 to 114 mm Hg and the plasma phosphate concentrations from 6.4 to 4.2, 6.6 to 4.8, and 7.0 to 4.5 mg/dl, respectively. Similarly, there was a dose-dependent effect of indapamide on fractional excretion of phosphate, which increased from 17 to 44, 24 to 53, and 18 to 75 percent in animals receiving increasing doses of indapamide. This effect of indapamide on the external phosphate balance was associated with significant reduction of kidney cortex and skeletal muscle total inorganic phosphate. In contrast, fractional sodium excretion augmented by 2.6, 2.5, and 2.5 percent, respectively, at each dose of indapamide. This compound also reduced significantly the contractions of strips of rabbit aorta and mesenteric artery elicited by norepinephrine (0.01 to 1.0 micrograms/ml). These results suggest that indapamide-induced reduction of blood pressure could be mediated by an effect of this drug on phosphate balance, and probably on vascular reactivity.


Application of the ANOVA-PCA method to stability studies of reference materials.
Near infrared spectroscopy (NIRS) is an analytical technique that can be very useful for stability studies in particular because of its non destructive analytical capability. However, the spectral interpretation and treatment of this kind of multivariate data remains difficult without the use of chemometrics. In this article, a recent chemometrics method, analysis of variance--principal component analysis (ANOVA-PCA), was used for NIRS stability studies of sunflower and bread wheat external reference materials (ERM). It provided a practical tool for the study of the significance of various storage conditions according to an experimental design. Thus, the effect of the temperature, the nature of the atmosphere in the packaging and the storage duration were tested. ANOVA-PCA highlighted the influence of temperature and storage duration on the stability of the sunflower materials. For the bread wheat materials, the storage conditions did not have a significant effect on stability. Consequently, by applying ANOVA-PCA to near infrared spectral data, the sunflower materials were found to be considered stable for the time length of the study, i.e. 18 months stored in a cold room, while the bread wheat materials were found to be considered stable for the time length of the study, i.e. 12 months under the same conditions.


Interaction between adrenergic and cholinergic nerve terminals in the urinary bladder of rabbit, cat and man.
The influence of muscarinic receptor stimulation (carbachol) and blockade (scopolamine) on the release of 3H-labelled noradrenaline from adrenergic neurons was investigated in isolated detrusor preparations from rabbit, cat and man. A significant influence on the release of 3H from adrenergic nerve terminals was found in the three species with a concentration-dependent decrease and increase induced by carbachol and scopolamine, respectively. Using the alpha 2-adrenoceptor stimulating and blocking agents clonidine and rauwolscine in rabbit and human detrusor preparations, the presence of prejunctionally located inhibitory alpha 2-adrenoceptors could also be demonstrated. The findings indicate the possibility of a functionally important interaction between cholinergic and adrenergic nerves in the urinary bladder mediated via inhibitory muscarinic receptors on adrenergic nerve terminals.


Morphometric analysis of the histology of spontaneous fetal resorption in a murine pregnancy.
Immunopathology of the spontaneous resorption phenomenon in the CBA x DBA/J murine model was explored using morphometric analysis. Accompanying the previously reported presence of natural killer (NK) cells in resorptive feto-placental units we find major changes in tissue morphology indicating that early infiltration of the feto-placental unit by maternal leukocytes plays a direct role with NK cells in fetal demise. Total number of cell nuclei per field and total nuclear area per field were significantly elevated in feto-placental units containing abnormally increased NK cell presence before detectable resorption as early as day 7 of gestation. This difference persisted throughout all stages of early gestation up to and including the final resorption event at day 10 to 12. Increases in cell density were also detected in areas of the embryonic unit not associated with NK infiltration. These results demonstrate that the spontaneous resorption phenomenon in this model involves: (i) Early (day 7-8) cellular infiltration of the decidual-ectoplacental cone junction associated with the presence in this area of NK cells. (ii) Late (day 8-9) cellular infiltration of the ectoplacental cone.


Splenic infarction and spontaneous rupture of the spleen after therapeutic embolization.
Patients with major hematologic disorders who have hypersplenism and alterations in their immune mechanism are subject to a higher incidence of bacteremia after embolization procedures. In certain instances, these infectious complications can be fatal. Medical splenectomy for hematologic disorders is sometimes complicated by massive splenic infarction and spontaneous rupture; spontaneous rupture appears to be a function of both infarct size and underlying infectious complications. Prophylactic measures can be employed to avoid these complications after interventional splenic embolization.


The influence of treatment sequence in the prognostic value of TMPRSS2-ERG as biomarker of taxane resistance in castration-resistant prostate cancer.
TMPRSS2-ERG expression in blood has been correlated with low docetaxel benefit in metastatic castration-resistant prostate cancer (mCRPC). This multicenter study aimed to prospectively asses its role as a taxane-resistance biomarker in blood and retrospectively in tumors, exploring also the impact of prior abiraterone/enzalutamide (A/E) in patients and in vitro. TMPRSS2-ERG was tested by quantitative reverse-transcription PCR. We included 204 patients (137 blood and 124 tumor samples) treated with taxanes. TMPRSS2-ERG expression was correlated with prostate-specific antigen (PSA)-progression-free survival (PFS), radiological-PFS (RX-PFS), and overall survival (OS). Independent association with survival was evaluated by multivariate Cox modeling. In vitro ERG knockdown and combinatorial and sequential experiments with enzalutamide and docetaxel were performed in VCaP cells. Prior A/E (HR 1.8, 95% CI 1.2-2.8) and blood TMPRSS2-ERG detection (HR 2, 95% CI 1.1-3.7) were independently associated to lower PSA-PFS. In patients without prior A/E, blood and tumor TMPRSS2-ERG independently predicted lower PSA-PFS (HR 3.3, 95% CI 1.4-7.9 and HR 1.8, 95% CI 1.02-3.3, respectively) to taxanes. When prior A/E was administered, TMPRSS2-ERG was not associated with outcome. There was a significant interaction between blood TMPRSS2-ERG and prior A/E related to PSA-PFS (p = 0.032) and RX-PFS (p = 0.009). In vitro stable ERG inhibition did not sensitize VCaP cells to docetaxel. Concomitant enzalutamide and taxanes were synergistic, but prior enzalutamide reduced docetaxel cytotoxicity in VCaP cells. Enzalutamide induced the expression of neuroendocrine markers and reduced that of E-cadherin. We conclude that prior hormone-therapy may influence taxanes response and TMPRSS2-ERG prognostic value. Thus, multiple and sequential biomarkers are needed in CRPC follow-up evaluation.


Recent Advances in the Diagnosis and Treatment of Natural Killer Cell Malignancies.
Natural killer (NK)/T-cell lymphomas are aggressive malignancies. Epstein-Barr virus (EBV) infection in lymphoma cells is invariable. NK/T-cell lymphomas are divided into nasal, non-nasal, and disseminated subtypes. Nasal NK/T-cell lymphomas involve the nasal cavity and the upper aerodigestive tract. Non-nasal NK/T-cell lymphomas involve the skin, gastrointestinal tract, testis and other extranodal sites. Disseminated NK/T-cell lymphoma involves multiple organs, rarely presenting with a leukaemic phase. Lymphoma cells are positive for CD3ε (not surface CD3), CD56, cytotoxic molecules and EBV-encoded small RNA. There is a predilection for Asian and Central/South American populations. Genome-wide association studies have identified lymphoma susceptibility loci in Asian patients. Positron emission tomography computed tomography and plasma EBV DNA quantification are crucial evaluations at diagnosis and follow-up. Stage I/II patients typically receive non-athracycline regimens containing asparaginse, together with sequential/concurrent radiotherapy. Anthracycline-containing regimens are ineffective. Stage III/IV patients are treated with asparaginase-containing regimens, followed by allogeneic haematopoietic stem cell transplantation (HSCT) in suitable cases. Autologous HSCT does not improve outcome. In relapsed/refractory patients, novel approaches are needed, involving PD1/PD-L1 targeting, EBV-specific cytotoxic T-cells, and monoclonal antibodies. Small molecules including histone deacetylase inhibitors may be beneficial in selected patients. Future strategies may include targeting of signalling pathways and driver mutations.


Garlic metabolites fail to inhibit the activation of the transcription factor NF-kappaB and subsequent expression of the adhesion molecule E-selectin in human endothelial cells.
The transcription factor NF-kappaB is suggested to play a pivotal role in atherogenesis by regulating the expression of proinflammatory gene products such as adhesion molecules. Garlic is consumed as food or dietary supplement in order to benefit from its antiatherogenic effect. This study addresses the question whether the garlic metabolites diallyldisulfide (DADS) and allylmercaptane (AM) influence the TNF-alpha-induced activation of NF-kappaB and the NF-kappaB-regulated endothelial gene product E-selectin in human umbilical endothelial cells (HUVECs). A putative effect of DADS and AM on NF-kappaB activity was examined by measuring NF-kappaB DNA binding activity by an electrophoretic mobility shift assay (EMSA) and on the NF-kappaB transactivation activity by a luciferase reporter gene assay. In addition, an effect of DADS and AM on the expression of the NF- kappaB-regulated gene product E-selectin was investigated by flow cytometry. We show that neither DADS nor AM (up to 100 micro M) inhibit TNF-alpha (1-10 ng/ml)-induced NF-kappaB DNA binding nor NF-kappaB transactivation activity. The TNF-alpha-induced expression of the endothelial adhesion molecule E-selectin was not reduced in response to DADS or AM. This study suggests that NF-kappaB is not a major target of garlic metabolites such as DADS or AM.


The Impact of Parecoxib on Pain Management for Laparoscopic Cholecystectomy: A Meta-analysis of Randomized Controlled Trials.
The efficacy of parecoxib on pain management for laparoscopic cholecystectomy remains controversial. We conducted a systematic review and meta-analysis to explore the impact of parecoxib on pain management after laparoscopic cholecystectomy. We searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library database results through September 2018 for randomized controlled trials to assess the effect of IV parecoxib versus placebo or noting on pain management after laparoscopic cholecystectomy. This meta-analysis was performed using the random-effect model. Seven randomized controlled trials were included in the meta-analysis. Overall, compared with control group for laparoscopic cholecystectomy, intravenous parecoxib showed no notable impact on pain scores within 2 hours [mean difference (MD), -0.22; 95% confidence interval (CI), -0.82 to 0.38; P=0.48] and 4 hours (MD, -0.33; 95% CI, -1.04 to 0.38; P=0.36), but showed results of significant decrease in pain scores at 6 hours (MD, -0.82; 95% CI, -1.45 to -0.20; P=0.01), 12 hours (MD, -0.69; 95% CI, -1.23 to -0.15; P=0.01), 24 hours (MD, -0.49; 95% CI, -0.89 to -0.10; P=0.01), and postoperative analgesics need (risk ratio, 0.45; 95% CI, 0.30-0.65; P<0.0001). In addition, no increase in nausea and vomiting is observed after parecoxib use compared with control intervention (risk ratio, 0.89; 95% CI, 0.44-0.76; P=0.76). Parecoxib can substantially promote postoperative pain relief in patients with laparoscopic cholecystectomy.


Transanal stapled anastomosis after resection for Hirschsprung's disease.
A treatment of Hirschsprung's disease in an adult is described. It consisted of rectosigmoidectomy, with continuity being restored by means of a transanal end-to-end stapled anastomosis. The implications of this technique are discussed.


An autism-associated mutation in CaV1.3 channels has opposing effects on voltage- and Ca(2+)-dependent regulation.
CaV1.3 channels are a major class of L-type Ca(2+) channels which contribute to the rhythmicity of the heart and brain. In the brain, these channels are vital for excitation-transcription coupling, synaptic plasticity, and neuronal firing. Moreover, disruption of CaV1.3 function has been associated with several neurological disorders. Here, we focus on the de novo missense mutation A760G which has been linked to autism spectrum disorder (ASD). To explore the role of this mutation in ASD pathogenesis, we examined the effects of A760G on CaV1.3 channel gating and regulation. Introduction of the mutation severely diminished the Ca(2+)-dependent inactivation (CDI) of CaV1.3 channels, an important feedback system required for Ca(2+) homeostasis. This reduction in CDI was observed in two major channel splice variants, though to different extents. Using an allosteric model of channel gating, we found that the underlying mechanism of CDI reduction is likely due to enhanced channel opening within the Ca(2+)-inactivated mode. Remarkably, the A760G mutation also caused an opposite increase in voltage-dependent inactivation (VDI), resulting in a multifaceted mechanism underlying ASD. When combined, these regulatory deficits appear to increase the intracellular Ca(2+) concentration, thus potentially disrupting neuronal development and synapse formation, ultimately leading to ASD.


Cross-regulation between G-protein-mediated pathways. Stimulation of adenylyl cyclase increases expression of the inhibitory G-protein, Gi alpha 2.
The hormone-sensitive adenylyl cyclase system is under dual control, receiving both stimulatory and inhibitory inputs. Guanine nucleotide-binding regulatory proteins (G-proteins) transduce signals from cell surface receptors to effectors such as adenylyl cyclase. Hormonal stimulation is propagated via Gs, inhibition by Gi. Persistent (24-h) activation of the stimulatory pathway of adenylyl cyclase by the diterpene forskolin or the beta-adrenergic agonist isoproterenol in S49 mouse lymphoma cells enhanced the effects of somatostatin mediated via the inhibitory pathway of adenylyl cyclase. Stimulating cells with forskolin or isoproterenol for 24 h resulted in a 3-fold increase in the steady-state levels of Gi alpha 2 and a 25% decline in Gs alpha, as quantified by immunoblotting. Within 12 h of stimulation of adenylyl cyclase, Gi alpha 2 mRNA levels increased 4-fold, measured by DNA-excess solution hybridization. Gs alpha mRNA levels, in contrast, increased initially (25%), but then declined to 75% of control. In S49 variants that lack functional protein kinase A (kin-), stimulation by isoproterenol failed to alter Gi alpha 2 expression at either the protein or the mRNA levels. A 3-fold increase in relative synthesis rate and no change in the half-life (approximately 80 h) of Gi alpha 2 was observed in response to forskolin stimulation. Although Gs alpha synthesis increased (70%) modestly in response to forskolin stimulation, the half-life of Gs alpha actually decreased from 55 h in naive cells to 34 h in treated cells. Thus, the two G-protein-mediated pathways controlling adenylyl cyclase display "cross-regulation." Persistent activation of the stimulatory pathway increases Gi alpha 2 mRNA and expression. Transiently elevated Gs alpha mRNA levels are counterbalanced by a reduction in the half-life of the protein.


ABO-incompatible kidney transplantation enabled by non-antigen-specific immunoadsorption.
ABO-incompatible kidney transplantation performed after desensitization with antigen-specific immunoadsorption (IA) results in good outcomes. However, a unique single-use IA device is required, which creates high costs. From August 2005 to August 2010, 19 patients were desensitized for ABO-incompatible living donor kidney transplantation. Six patients treated with a single-use antigen-specific IA device and 12 patients treated with a reusable non-antigen-specific IA device were analyzed. Six patients who received antigen-specific IA had a median of 5 IA treatments and 12 patients with non-antigen-specific IA had a median of 6 IA treatments preoperatively. Median average titer drop in Coombs technique was 1.2 in antigen-specific IA and 1.7 in non-antigen-specific IA. In two patients with antigen-specific IA and four patients with non-antigen-specific IA, additional plasmapheresis treatments were necessary for recipient desensitization. Despite six treatments with antigen-specific IA and 12 plasmapheresis treatments, one patient with a starting isoagglutinin titer of 1:1024 (Coombs) could not be transplanted. The 18-month graft survival rate for the 17 ABO-incompatible living donor kidney transplants was 100%. One male recipient who was desensitized with antigen-specific IA died 44 months after transplantation from sudden cardiac death with a serum creatinine of 1.2 mg/dL. At last follow-up, a median of 13 months after transplantation, median serum creatinine for 16 patients was 1.5 mg/dL, median glomerular filtration rate as estimated by the modification of diet in renal disease formula 54 mL/min/1.73 m, and median urinary protein-to-creatinine ratio 0.1, with no differences between treatments. A reusable non-antigen-specific IA device allows high number of treatments at reasonable cost, and at the same time might deplete human leukocyte antigen-alloantibodies.


Effect of neonatal estrogenization on testosterone metabolism in the prostate and in the epididymis of the rat.
The present experiments were performed in order to analyze whether the administration of estrogens (single injection of 500 micrograms of estradiol benzoate s.c.) to neonatal male rats might modify the weight of the ventral prostate and the epididymis as well as the metabolism of testosterone in these two organs. The metabolism of testosterone was evaluated in vitro using 14C-radiolabelled testosterone as the substrate. The metabolites dihydrotestosterone (DHT), 5 alpha-androstane-3 alpha, 17 beta-diol (3 alpha-diol), 5 alpha-androstane-3 beta,17 beta-diol (3 beta-diol), androstenedione, 5 alpha-androstane-3,17-dione (5-A-dione) and 3 alpha-hydroxy-5 alpha-androstane-17-one (androsterone) were quantified. After neonatal estrogen administration animals were killed on days 22 and 90 of age. The following changes were observed: (1) the body weight, the weight of the testes and of the ventral prostate were lower than in controls on both day 22 and 90; (2) the weight of the epididymides was higher than in controls on day 22 and lower on day 90; (3) in the ventral prostate the in vitro formation of DHT was lower and that of the diols was higher than in control tissue on day 22 of age; (4) the in vitro formation of alpha-reduced metabolites of the 17-keto series (5 alpha-A-dione + androsterone) was higher in ventral prostate of treated animals than in that of controls on day 22; (5) in treated animals, no formation of DHT in the caput epididymis was observed at day 22. On the contrary, at the same age the formation of androstenedione was higher than in controls; on day 90 of age the formation of DHT, androstenedione and the 5 alpha-reduced metabolites of the 17-keto series was identical in caput epididymis of the treated animals and of the controls, while the formation of the diols was higher in the treated than in the controls. The data indicate that neonatal estrogenization may induce important changes in testosterone metabolism in the prostates and in the epididymides of the rat.


Parathyroid hormone-related protein relaxes rat gastric smooth muscle and shows cross-desensitization with parathyroid hormone.
Previously, we reported that parathyroid hormone (PTH) is a potent and effective relaxant of rat gastrointestinal smooth muscle. Since the recently discovered PTH-related protein (PTHrP) has amino-terminal homology with PTH and acts like PTH on bone and kidney, we decided to study the effects of synthetic PTHrP analogs on the isometric tension of rat fundic strips. Rat (r) PTH-(1-34), human (h) PTHrP-(1-34), and [Tyr0]hPTHrP-(1-34) relaxed acetylcholine-stimulated fundic strips in a dose-dependent manner, with an IC50 of 6, 10, and 31 nM, respectively. However, maximal doses of [Tyr0]hPTHrP-(1-34) were considerably less effective than the other two peptides. Addition of rPTH-(1-34) or hPTHrP-(1-34) to a maximally effective dose of [Tyr0]hPTHrP-(1-34) produced no further relaxation, indicating that [Tyr0]hPTHrP-(1-34) also has antagonistic properties. Bovine PTH-(3-34) an established in vitro antagonist of PTH, partially inhibited the relaxant effect of PTHrP. Fundic strips that had been desensitized by preincubation for 30-45 minutes with either rPTH-(1-34) or hPTHrP-(1-34) (330-500 nM) were also insensitive to the relaxant action of either peptide, but in the same preparations, the relaxation produced by vasoactive intestinal peptide was unaffected. These studies indicate that PTHrP and PTH can interact with the same receptor. Whether PTHrP influences gastrointestinal motility in normal or tumor-bearing persons remains to be investigated.


Determination methods for biologically active compounds by ultra-performance liquid chromatography coupled with mass spectrometry: application to the analyses of pharmaceuticals, foods, plants, environments, metabonomics, and metabolomics.
This review summarizes the determination methods for biologically active compounds, such as pharmaceuticals, agrochemicals, and biogenic amines, by ultra-performance liquid chromatography coupled with mass spectrometry. The typical applications using the method are also described in this study, together with the characteristics of the methods.


Enantioselectively functionalised phenytoin derivatives by auxiliary-directed N to C aryl migration in lithiated α-amino nitriles.
Lithiation of N'-arylureas derived from amino nitriles incorporating a (1R,2R)-2-aminocyclohexanol chiral auxiliary leads to diastereoselective migration of the aryl ring to the position α to the nitrile. The resulting N'-lithiated ureas undergo spontaneous cyclisation to iminohydantoins, which may be hydrolysed to give chiral 5,5-diarylhydantoins related to phenytoin, in enantioenriched form.


Surfactant-controlled synthesis of Fe nanorods in solution.
Rodlike Fe particles were prepared by reduction of iron salts with hydrazine hydrate in the presence of CTAB. The as-prepared powders were characterized in detail by conventional techniques such as X-ray diffraction, and scanning electron microscopy, and their magnetic properties were evaluated on a vibrating sample magnetometer.


The effect of digital interventions on related health literacy and skills for individuals living with chronic diseases: A systematic review and meta-analysis.
Chronic diseases are a leading cause of death and disease burden globally. Digital interventions could be an approach to improve patients' ability to find, evaluate, and use health information. The main objective was to conduct a systematic review to determine the effect of digital interventions on digital health literacy for patients living with chronic disease. Secondary objectives were to provide an overviewof the design and delivery characteristics of interventions that impact digital health literacy in people with chronic disease. Randomized controlled trials examining digital health literacy (and related components) for individuals with cardiovascular disease, chronic lung disease, osteoarthritis, diabetes, chronic kidney disease, and HIV were identified. This review was conducted following the PRIMSA guidelines. Certainty was assessed using GRADE and the Cochrane risk of bias tool. Meta-analyses were conducted using Review Manager 5.1. The protocol was registered on PROSPERO (CRD42022375967). 9386 articles were identified and 17 articles representing 16 unique trials were included. Studies evaluated 5138 individuals with one or more chronic conditions (50% women, ages 42 ± 7-71 ± 12 years). The most targeted conditions were cancer, diabetes, cardiovascular disease, and HIV. Interventions included: skills training, websites, electronic personal health records, remote patient monitoring, and education. The effects of the interventions were related to: (i) digital health literacy, (ii) health literacy, (iii) health information skills, (iv) technology skills and access, and (v) self-management and participation in care. A meta-analysis of three studies identified the effect of digital interventions was better than usual care for eHealth literacy (1.22 [CI 0.55, 1.89], p < 0.001). The evidence of the effects of digital interventions on related health literacy is limited. Existing studies reflect the heterogeneity in study design, population, and outcome measures. There is a need for further studies on the effects of digital interventions on related health literacy for individuals with chronic conditions.


Quantitative Analysis of B-Cell Subpopulations in Bone Marrow by Flow Cytometry.
Flow cytometry is a technology that rapidly detects and measures physical and chemical characteristics of single cells or particles. It is a powerful tool for many areas of research, in particular, immunology, which allows for simultaneous analysis of different immune cell populations in a tissue. Here we describe the procedures to quantify and/or purify various B fractions in mouse bone marrows by flow cytometry using their signature surface markers. This method is useful to study B-cell development during steady-state or emergency hematopoiesis such as viral infections.


Rapid maturation of the hepatic cell line Huh7 via CDK inhibition for PXR dependent CYP450 metabolism and induction.
CYP3A4, a cytochrome P450 enzyme regulated by the nuclear receptor PXR, is involved in most of the drug metabolizing pathways. Studying the regulation/induction of CYP3A4 and PXR is critical in toxicology and drug-drug interaction (DDI) studies. Primary human hepatocytes constitute the preferred in vitro platform for drug development efforts. However, they are expensive, scarce and heterogeneous. Hepatic cell lines, such as Huh7, could provide a cost-effective alternative, however, they express negligible amounts of CYP450s and PXR. In this study, we show that dinaciclib, a potent cyclin dependent kinase inhibitor, significantly increases the basal CYP3A4 and PXR levels in 24 hours. We also demonstrated that matured Huh7s can be used for drug induction studies, where CYP3A4, CYP1A2, CYP2C9, and CYP2C19 inductions were achieved following rifampicin treatment. More importantly, through a direct demonstration using amiodarone and rifampicin as model drugs, we showed that matured Huh7s present a suitable platform for DDI studies.


[Two 150 years anniversaries: Claude Bernard's internal environment and Addison disease].
In 2005 two 150 years anniversaries, which essentially influenced the development of modern medicine will be celebrated. French physiologist Claude Bernard from College de France published his work "Lectures on Experimental Physiology, applied to medicine" and British medical doctor T. Addison described insufficiency of adrenal cortex, today known as Addison disease.


Relationship between left atrial reservoir strain, volumes, and geometry: Insights from simple theoretical model.
Left atrial (LA) volume is related to LA reservoir strain (LASR ), but the relationship is not fully resolved. We sought to model the relationship between LA end-diastolic and end-systolic volumes (LAEDV and LAESV) and LASR based on a geometrical approach to exploit the relationship between LASR and volume. Modeling the LA as a hemisphere with radius r, LASR was recognized to vary linearly with r and LA volume with r3 . Expanding this cubic relation as a Taylor series resulted in a simple linear equation: LAESV/LAEDV = 1 + 3 × LASR . To validate this, 52 transthoracic echocardiograms were analyzed from 18 patients who underwent transcatheter edge-to-edge repair (TEER) with MitraClip with serial assessment pre-procedure, 1 month post-clip, and 12 months post-TEER. Linear regression was performed to compare the geometric equation to a statistical model created by a line of best fit to relate LAESV/LAEDV to LASR . The statistical and geometric model both resulted in a strong correlation (r = .8, p < .001, respectively). The slope of the line in the statistical model was 3.3, which was statistically indistinguishable from the expected slope of 3 based on the geometric model (Figure 2A). Using the geometric model to compare the measured versus calculated LAESV/LAEDV also resulted in a strong correlation (r = .8, p < .001)(Figure 2B). We describe the relationship between LA volume and strain mathematically by considering the geometry of the LA. This model enhances our understanding of the interaction between atrial strain and volume. Further research is necessary to validate this using 3D atrial volumes in a broader cohort of subjects.


Different carbon sources affect PCB accumulation by marine bivalves.
Pampean creeks were evaluated in the present study as potential land-based sources of PCB marine contamination. Different carbon and nitrogen sources from such creeks were analysed as boosters of PCB bioaccumulation by the filter feeder bivalve Brachidontes rodriguezii and grazer limpet Siphonaria lessoni. Carbon of different source than marine and anthropogenic nitrogen assimilated by organisms were estimated through their C and N isotopic composition. PCB concentration in surface sediments and mollusc samples ranged from 2.68 to 6.46 ng g(-1) (wet weight) and from 1074 to 4583 ng g(-1) lipid, respectively, reflecting a punctual source of PCB contamination related to a landfill area. Thus, despite the low flow of creeks, they should not be underestimated as contamination vectors to the marine environment. On the other hand, mussels PCB bioaccumulation was related with the carbon source uptake which highlights the importance to consider this factor when studying PCB distribution in organisms of coastal systems.


Repair of aortoesophageal fistula with homograft aortic replacement and primary esophageal closure.
The presence of a fistula between the thoracic aorta and the esophagus is a rare and highly fatal condition. This study aimed to evaluate the outcomes of the surgical treatment of an aortoesophageal fistula (AEF). We retrospectively reviewed patients with AEF who underwent surgery at our institution. Between 2007 and 2018, a total of 10 patients who underwent surgery for AEF. The mean age was 63 ± 12 years, and 6 patients were men. Four patients had primary AEFs and 6 patients had secondary AEFs (3 graft replacements and 3 thoracic endovascular aortic repairs). The timing of AEF since graft replacement or thoracic endovascular aortic repairs was 21.6 ± 27 days. We performed aortic replacement with a prosthetic graft (4 patients) or a homograft (5 patients) and extra-anatomical bypass due to a previous aortic graft infection (1 patient). As a treatment of the esophagus, we conducted primary repair in 7 of 10 patients. The median lengths of hospital and intensive care unit stay were 59 days (range, 9-225 days) and 6.3 days (range, 1-87 days), respectively. Seven patients achieved oral feeding after a median 10.3 postoperative days (range, 7-78 postoperative days). Two of the 10 patients died of sepsis at 9 and 74 days postoperatively. The strategy for patients with AEF should be individualized. Our surgical strategy for AEF, which includes simultaneous aortic graft replacement and primary repair of esophagus in the same operative field, is feasible and promising.


Estimation of mechanical properties of Mg-5Zn-0.5Al-xSn alloy based on virtual crystal approximation.
First-principles calculations of multi-component alloys have been studied in detail. Herein, the first-principles calculations of Mg-5Zn-0.5Al-xSn alloys were performed by using the virtual crystal approximation (VCA) method. By calculating the lattice constants and elastic constants of the Mg-5Zn-0.5Al-xSn doping models, it was found that the mechanical properties and micro-hardness were related with the content of Sn. With the increase of Sn content, and the best ductility and the smallest micro-hardness were achieved at Sn = 2 wt.%. To verify the calculation results, the Mg-5Zn-0.5Al-xSn alloys were prepared and micro-hardness and tensile tests were conducted. The experiments demonstrate that the trends in mechanical properties obtained from the experiments are in agreement with the VCA computational results. These findings indicate that the VCA method has guiding significance in industries for rapid screening of high-performance Mg alloys.


Measuring children's retention of skills to resist stranger abduction: use of the simulation technique.
This paper describes an evaluation which builds upon an earlier project to measure actual behavioral change in the form of reduction of vulnerability to abduction and abuse by strangers; change attributable to participation in a primary prevention program. Simulations, life-like scenarios previously described, were used to address three key questions: Did children who had demonstrated mastery of prevention skills acquired six months earlier retain those skills? Would reteaching the prevention program result in mastery for those children who failed to demonstrate required skills after the first presentation of the prevention program? Could the experimental group results of the first project be repeated with the previous control group? Several findings validated the earlier work and enhanced the understanding of what can be accomplished through prevention programing. Thirty of the original 44 children who participated six months earlier were again available to take part in the final simulation. Of those, all of the previous experimental group children who had performed successfully when participating in the simulation upon completion of the first project were again successful six months later in resisting the invitation of a stranger to leave their school. Each of the previous control group children were successful in the final simulation after participation in the program. But reteaching of the prevention program was successful for just two of the four children who had earlier failed following participation in the program. These findings document the immediate and continued benefits which may accrue from experientially based prevention programing and suggest an important research agenda to facilitate the further evolution of prevention programing and evaluation.


Axial chirality control of tropos BIPHEP-Rh complexes by chiral dienes: synergy effect in catalytic asymmetric hydrogenation.
Diastereopure tropos Rh complexes bearing not only BIPHEP but also chiral dienes can be employed as highly enantioselective hydrogenation catalysts for an olefinic substrate.


Diabetes mellitus in transfemoral transcatheter aortic valve implantation: a propensity matched analysis.
Diabetes Mellitus (DM) affects a third of patients with symptomatic severe aortic valve stenosis undergoing transcatheter aortic valve implantation (TAVI). DM is a well-known risk factor for cardiac surgery, but its prognostic impact in TAVI patients remains controversial. This study aimed to evaluate outcomes in diabetic patients undergoing TAVI. This multicentre registry includes data of > 12,000 patients undergoing transfemoral TAVI. We assessed baseline patient characteristics and clinical outcomes in patients with DM and without DM. Clinical outcomes were defined by the second valve academic research consortium. Propensity score matching was applied to minimize potential confounding. Of the 11,440 patients included, 31% (n = 3550) had DM and 69% (n = 7890) did not have DM. Diabetic patients were younger but had an overall worse cardiovascular risk profile than non-diabetic patients. All-cause mortality rates were comparable at 30 days (4.5% vs. 4.9%, RR 0.9, 95%CI 0.8-1.1, p = 0.43) and at one year (17.5% vs. 17.4%, RR 1.0, 95%CI 0.9-1.1, p = 0.86) in the unmatched population. Propensity score matching obtained 3281 patient-pairs. Also in the matched population, mortality rates were comparable at 30 days (4.7% vs. 4.3%, RR 1.1, 95%CI 0.9-1.4, p = 0.38) and one year (17.3% vs. 16.2%, RR 1.1, 95%CI 0.9-1.2, p = 0.37). Other clinical outcomes including stroke, major bleeding, myocardial infarction and permanent pacemaker implantation, were comparable between patients with DM and without DM. Insulin treated diabetics (n = 314) showed a trend to higher mortality compared with non-insulin treated diabetics (n = 701, Hazard Ratio 1.5, 95%CI 0.9-2.3, p = 0.08). EuroSCORE II was the most accurate risk score and underestimated 30-day mortality with an observed-expected ratio of 1.15 in DM patients, STS-PROM overestimated actual mortality with a ratio of 0.77 and Logistic EuroSCORE with 0.35. DM was not associated with mortality during the first year after TAVI. DM patients undergoing TAVI had low rates of mortality and other adverse clinical outcomes, comparable to non-DM TAVI patients. Our results underscore the safety of TAVI treatment in DM patients. The study is registered at clinicaltrials.gov (NCT03588247).


Predictors of outcome events and 6-year mortality after carotid endarterectomy and carotid stenting in patients with carotid artery stenosis.
The aim of our study was to evaluate the results of CEA and CAS in patients with carotid artery stenosis, and their effect on long-term mortality and morbidity, as well as to identify predictors of long-term mortality in a single-centre observational study. While data on short-term morbidity and mortality after carotid endarterectomy (CEA) and carotid stenting (CAS) is robust, there is only a limited amount of literature on long-term mortality and its predictors five years-plus post these procedures. Consecutive patients with symptomatic and asymptomatic internal carotid artery stenosis treated with CEA or CAS in a single centre in eastern Slovakia between 2012 and 2014 were included. We recorded basic sociodemographic data, the presence of co-morbidities and periprocedural complications. Clinical and sonographic follow-up was performed three and 12 months after the procedures. Patient survival data and any stroke data was obtained at the end of a six-year follow-up. We included 259 patients after CEA (mean age 67.4 ± 8.5, 64.5% men) and 321 after CAS (mean age 66.9 ± 8.4, 73.5% men). We did not identify a statistically significant difference in short-term or long-term mortality, survival times, or the presence of short-term or long-term complications between the CEA and CAS groups. Predictors of long-term mortality included age and diabetes mellitus in both cohorts. Repeated interventions were related to increased mortality only in the CAS cohort. The results of our study show that long-term mortality does not differ between CEA and CAS.


Mapping aboveground woody biomass using forest inventory, remote sensing and geostatistical techniques.
Mapping forest biomass is fundamental for estimating CO₂ emissions, and planning and monitoring of forests and ecosystem productivity. The present study attempted to map aboveground woody biomass (AGWB) integrating forest inventory, remote sensing and geostatistical techniques, viz., direct radiometric relationships (DRR), k-nearest neighbours (k-NN) and cokriging (CoK) and to evaluate their accuracy. A part of the Timli Forest Range of Kalsi Soil and Water Conservation Division, Uttarakhand, India was selected for the present study. Stratified random sampling was used to collect biophysical data from 36 sample plots of 0.1 ha (31.62 m × 31.62 m) size. Species-specific volumetric equations were used for calculating volume and multiplied by specific gravity to get biomass. Three forest-type density classes, viz. 10-40, 40-70 and >70% of Shorea robusta forest and four non-forest classes were delineated using on-screen visual interpretation of IRS P6 LISS-III data of December 2012. The volume in different strata of forest-type density ranged from 189.84 to 484.36 m(3) ha(-1). The total growing stock of the forest was found to be 2,024,652.88 m(3). The AGWB ranged from 143 to 421 Mgha(-1). Spectral bands and vegetation indices were used as independent variables and biomass as dependent variable for DRR, k-NN and CoK. After validation and comparison, k-NN method of Mahalanobis distance (root mean square error (RMSE) = 42.25 Mgha(-1)) was found to be the best method followed by fuzzy distance and Euclidean distance with RMSE of 44.23 and 45.13 Mgha(-1) respectively. DRR was found to be the least accurate method with RMSE of 67.17 Mgha(-1). The study highlighted the potential of integrating of forest inventory, remote sensing and geostatistical techniques for forest biomass mapping.


Longitudinal predictive ability of mapping models: examining post-intervention EQ-5D utilities derived from baseline MHAQ data in rheumatoid arthritis patients.
The purpose of this methodological study was to to provide insight into the under-addressed issue of the longitudinal predictive ability of mapping models. Post-intervention predicted and reported utilities were compared, and the effect of disease severity on the observed differences was examined. A cohort of 120 rheumatoid arthritis (RA) patients (60.0% female, mean age 59.0) embarking on therapy with biological agents completed the Modified Health Assessment Questionnaire (MHAQ) and the EQ-5D at baseline, and at 3, 6 and 12 months post-intervention. OLS regression produced a mapping equation to estimate post-intervention EQ-5D utilities from baseline MHAQ data. Predicted and reported utilities were compared with t test, and the prediction error was modeled, using fixed effects, in terms of covariates such as age, gender, time, disease duration, treatment, RF, DAS28 score, predicted and reported EQ-5D. The OLS model (RMSE = 0.207, R(2) = 45.2%) consistently underestimated future utilities, with a mean prediction error of 6.5%. Mean absolute differences between reported and predicted EQ-5D utilities at 3, 6 and 12 months exceeded the typically reported MID of the EQ-5D (0.03). According to the fixed-effects model, time, lower predicted EQ-5D and higher DAS28 scores had a significant impact on prediction errors, which appeared increasingly negative for lower reported EQ-5D scores, i.e., predicted utilities tended to be lower than reported ones in more severe health states. This study builds upon existing research having demonstrated the potential usefulness of mapping disease-specific instruments onto utility measures. The specific issue of longitudinal validity is addressed, as mapping models derived from baseline patients need to be validated on post-therapy samples. The underestimation of post-treatment utilities in the present study, at least in more severe patients, warrants further research before it is prudent to conduct cost-utility analyses in the context of RA by means of the MHAQ alone.


Copper excess promotes propagation and induces proteomic change in root cultures of Hyoscyamus albus L.
Hyoscyamus albus L. seedlings respond positively to copper (Cu) excess. In the present study, to understand how roots cope with Cu excess, propagation and proteome composition in the presence of Cu were examined using a root culture system. When H. albus roots were cultured in a medium without Cu, root growth deteriorated. However, in the presence of Cu, root growth increased in a concentration-dependent manner, and vigorous lateral root development was observed at 200 μM Cu. Cu accumulation in the roots increased with the Cu supply. Subcellular fractionation revealed that the highest amount of Cu was present in the cell wall-containing fraction, followed by the soluble fraction. However, the highest specific incorporation of Cu, in terms of fresh weight, was in the mitochondria-rich fraction. High Cu levels enhanced respiration activity. Comparative proteomic analysis revealed that proteins involved in carbohydrate metabolism, de novo protein synthesis, cell division, and ATP synthesis increased in abundance, whereas the proteasome decreased. These results indicate that Cu promotes propagation of H. albus roots through the activation of the energy supply and anabolism. Newly propagated root tissues and newly generated proteins that bind to Cu may provide space and reservoirs for deposition of additional Cu.


Removal of hexavalent chromium from water by Z-scheme photocatalysis using TiO2 (rutile) nanorods loaded with Au core-Cu2O shell particles.
All-solid-state Z-scheme photocatalysts, containing Cu2O, TiO2 (rutile), and Au as the electron mediator, were prepared and applied to the reduction of Cr(VI) in aqueous solutions. The Cu2O-Au-TiO2 composites were prepared by loading Au core-Cu2O shell hemisphere particles on TiO2 (rutile) nanorods using a two-step photocatalytic deposition process. Under ultraviolet-visible (UV-vis) light illumination, the Cu2O-Au-TiO2 composites exhibited higher photocatalytic Cr(VI) reduction activities than those exhibited by single TiO2 (rutile) and Cu2O. In this reaction, a precipitate containing Cr, which was considered to be Cr(OH)3, was deposited site-selectively on the Au core-Cu2O shell particles of the composites, indicating that the reduction site of the composite was Cu2O, and the reaction proceeded according to the Z-scheme. The Cu2O-Au-TiO2 composites also exhibited photocatalytic activity under visible light illumination. The oxidation state of Cu in the Cu2O-Au-TiO2 composite gradually changed from Cu(I) to Cu(II) during the photocatalytic Cr(VI) reduction. However the composite maintained its high photocatalytic performance even after oxidation. The role of Au in the Cu2O-Au-TiO2 composite was examined by comparing the properties of the Cu2O-Au-TiO2 composite with those of the Cu2O-TiO2 composite prepared via direct Cu2O deposition on TiO2.


Unilateral optic nerve transection decreases 2-[125I]-iodomelatonin binding in retinorecipient areas and visual pathways of chick brain.
In chick brain, specific 2-[125I]-iodomelatonin-binding was localized primarily in the visual system, i.e., retinorecipient and relay nuclei and fiber tracts of the tectofugal, thalamofugal, circadian and accessory visual pathways. Unilateral transection of the optic nerve (ONX) significantly reduced the binding of 2-[125I]-iodomelatonin (75 pM) in many, but not all, primary retinal targets and visual pathways at 7 and 14 days, but not 1 day, postlesion. As measured using quantitative autoradiography, 2-[125I]-iodomelatonin binding was decreased by 90% in both the central portion of the lesioned optic tract and one of its targets, the nucleus of the basal optic root (nBOR). Other retinorecipient areas exhibiting substantial decreases (60%) in 2-[125I]-iodomelatonin-binding included the optic tectum, lateroventral and dorsolateral geniculate nuclei and tectal gray area contralateral to the lesion. These findings are consistent with the hypothesis that melatonin receptors are located presynaptically on incoming optic nerve terminals in many retinorecipient areas. This localization may account for most of the binding sites in nBOR. In other primary visual areas, however, melatonin receptors also appear to be located on postsynaptic cells and/or non-retinal afferents. ONX had no significant effect on 2-[125I] -iodomelatonin binding in two retinorecipient areas, the visual suprachiasmatic nucleus and the dorsolateral anterior thalamus, which are part of the circadian/oculomotor and thalamofugal pathways, respectively. An unexpected consequence of ONX was that 2-[125I]- iodomelatonin binding was decreased in certain secondary (nucleus rotundus, isthmi nuclei) and tertiary level (ectostriatum) nuclei along the prominent tectofugal visual pathway. Binding in the tectorecipient nucleus triangularis was not significantly altered, however. Analysis of secondary level relay nuclei in the oculomotor pathway revealed that binding after ONX was decreased in the ipsilateral Edinger-Westphal nucleus but not in the oculomotor nuclei. Selective transsynaptic changes in 2-[125I]-iodomelatonin binding after lesion of the visual input most likely reflect activity-dependent regulation and functional plasticity of central melatonin receptors.


The intestinal bacterial community over seasons and its relationship with physiological status of Yesso scallop Patinopecten yessoensis.
Emerging evidence indicates that the intestinal bacterial communities associated with eukaryotes play critical roles in the physiological activities and health of their hosts. Yesso scallop Patinopecten yessoensis, one of the cold-water aquaculture species in the North Yellow Sea of China, has suffered from massive mortality in recent years. In the present study, P. yessoensis were collected from Zhangzi Island, Dalian from March 2021 to January 2022 to investigate the intestinal bacterial community and physiological indices. 16S rRNA gene sequencing data revealed that the diversity of intestinal bacteria changed significantly over seasons, with the highest Chao1 (237.42) and Shannon (6.13) indices detected in January and the lowest Chao1 (115.44) and Shannon (2.73) indices detected in July. Tenericutes, Proteobacteria and Firmicutes were dominant phyla in the intestinal bacteria of P. yessoensis, among which Firmicutes and Proteobacteria significantly enriched in August and January, respectively. Mycoplasma was the most abundant genus during the sampling period, which exhibited the highest abundance in October (75.26%) and lowest abundance in August (13.15%). The functional profiles of intestinal bacteria also exhibited seasonal variation, with the pathways related to pentose phosphate and deoxyribonucleotides biosynthesis enriched in August while the glycogen biosynthesis pathway enriched in October. Redundancy analysis showed that seawater pH, dissolved inorganic nitrogen and silicate were major environmental factors driving the temporal succession of scallop intestinal bacteria. Correlation clustering analysis suggested that the relative abundances of Endozoicomonas and Vibrio in the intestine were positively correlated with superoxide dismutase activity in hepatopancreas while negatively correlated with malondialdehyde content in hepatopancreas and glycogen content in adductor muscle. All the results revealed that the intestine harbored a lower bacterial diversity and a higher abundance of Vibrio in August, compared to January, which were closely related to the oxidative stress status of scallop in summer. These findings will advance our understanding of the relationship between seasonal alteration in the intestinal bacteria and the physiological status of scallops.


[Intrafocal bleomycin injection in florid oral papillomatosis (papillomatosis mucosae carcinoides)].
We report on a case of oral florid papillomatosis treated with intrafocal injections of bleomycine. According to recent clinical experiences in treating oral florid papillomatosis only the administration of cytostatic agents, especially bleomycine, seems to be successful.


Management of necrotizing fasciitis and the use of sealed irrigation system: A case report.
Necrotizing fasciitis [NF] is a deep soft tissue infection with high morbidity and mortality. The diagnosis is mainly clinical, and is confirmed during the surgical exploration, which is also the cornerstone of treatment. We report a case of a 16-year-old female who complained of pain, tenderness, and erythema along her abdomen and back after a minor trauma on her left palm. The patient was treated with systemic antibiotics and daily surgical debridement followed by placement of a bilateral suction drainage system. A split-thickness graft was used to cover the defect on the lower back of the patient. Sealed irrigation technique is an effective method to manage NF. Furthermore, it reduces the hospitalization duration by continuously removing the necrotic and infected material that hinder tissue healing.


Behavioral economics of drug self-administration: an introduction.
Behavioral economics provides a set of concepts for the analysis of factors that control the allocation of behavioral resources among available reinforcers. Terms from micro-economics describe new phenomena previously ignored within the traditional context of behavior analysis. This article reviews these concepts as an introduction to the three papers that follow. The primary dependent measure within the behavioral economic framework is the level of consumption of available commodities as determined by the level and distribution of instrumental responding. The demand curve provides a quantitative metric for analyzing consumption under the constraint of unit price. When the reinforcer is a drug, the demand curve can be a useful tool for analyzing the level of motivation to consume the drug, its abuse liability, and for evaluating interventions, such as alternative reinforcers or medications, to reduce the motivation to consume the drug and instrumental responding to obtain it. Behavioral economics also provides a framework for formulating, testing, and refining drug abuse policy through a series of empirical steps that maximize effectiveness and minimize undesirable social consequences.


Evaluation of modified bleach technique for the detection of acid fast bacilli in lymph node aspirate at the University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia.
Tuberculous Lymphadenitis (TBLN) is the commonest form of extrapulmonary tuberculosis. Definitive diagnosis of TBLN is difficult due to the low efficacy of the routine diagnostic techniques as compared to culture. To determine whether prior bleach concentration can improve the detection of acid-fast bacilli when compared with conventional Ziehl-Neelsen (ZN) staining by using culture as the gold standard. Cross-sectional study was conducted from March 01, 2015 to May 30, 2015. The study subjects were clinically suspected TBLN patients. Fine needle aspiration (FNA) was performed. Two different smears were prepared directly from the first needle pass for cytology and ZN staining. The remaining aspirate was used for the modified bleach concentration. The second needle pass aspirate was transferred into a sterile container containing sterile normal saline. The sediment was inoculated on the Lowenstein Jensen (LJ) medium. Measurement parameters for reliability and validity were used to analyze the results. A total of 93 participants were included in the study. Fifty-six out of the 93 (60.2 %) cases were positive for mycobacterium tuberculosis complex on LJ culture. The detection rates of direct ZN staining and modified bleach method were 20.4 % and 44.1 %, respectively. 73.1 % of the cases showed cytomorphological features consistent with TBLN by cytologic examination. The sensitivities of direct ZN staining and modified bleach method and cytomorphology were 32.0 %, 67.8 %, and 92.8 %, respectively. Implementation of bleach concentration increases the detection rate of AFB over the direct ZN method. The bleach method can also be easily performed and provide a safe working environment by reducing infections.


The importance of rest phase and pollutant removal mechanism of tidal flow constructed wetlands (TFCW) in rural grey water treatment.
This paper explored the effects of the rest phase of tidal flow constructed wetlands (TFCW) on pollutant removal and microbial communities, and further analyzed the mechanism of TFCW removal of pollutants from grey water. The results showed that the removal rate of organic matter was 69.91 ± 2.44% in the control group (NR-TFCW) without the rest phase, 94.95 ± 1.17% in the experimental group (TFCW), and 96.95 ± 2.43% in the control group (P-TFCW) with the ventilation pipe enhanced rest phase. Limiting and enhancing the oxygen supply in the emptying stage of TFCW will enhance the overlap rate of microorganisms in the upper, middle and lower layers of the reactor. Enhancing the rest phase of TFCW leaded to better aerobic removal of organic matter in the microbial community, while limiting the rest phase of TFCW results in the opposite. In addition, the species overlap rate of the top, middle and bottom layers of NR-TFCW (69.98%) and P-TFCW (54.29%) was higher than that of TFCW (11.34%). The removal of organic matter by TFCW mainly relied on the adsorption of biochar in the flood phase, and the microorganisms aerobic degraded the organic matter adsorbed on the biochar in the rest phase. And thus form a continuous cycle of adsorption and biological regeneration. The microbial community in TFCW did not have the ability to nitrify, but had the ability to remove phosphorus. Ammonia nitrogen in the influent was adsorbed by biochar or converted into cytoplasm. While the phosphorus in the influent was adsorbed by the biochar, it was also being biologically removed.


Identification of a key structural feature of cobalt(III)-bleomycins: an exogenous ligand (e.g. hydroperoxide) bound to cobalt.
A series of cobalt(III) complexes of the anticancer antibiotic bleomycin has been prepared. Mass spectrometry and enzymatic analysis show that the green cobalt-bleomycin complex contains a hydroperoxide (-OOH) group bound to cobalt with unusual stability. Under appropriate conditions, cobalt-bleomycins containing other monodentate ligands to cobalt can be formed; fast-atom bombardment mass spectra of such complexes show peaks for cobalt-bleomycin at the expected mass, and also peaks for the intact complexes at the required higher mass.


Integrative genomics and pathway analysis identified prevalent FA-BRCA pathway alterations in arsenic-associated urinary bladder carcinoma: Chronic arsenic accumulation in cancer tissues hampers the FA-BRCA pathway.
Arsenic in drinking water is one of the major etiological factors in urinary bladder carcinoma (BlCa). Here, high-resolution CGH-SNP microarray analysis in arsenic accumulated BlCa tissues showed significant (p < 0.05) association of chromosomal alterations with high arsenic (≥112 ng/g) accumulation, further corroborated by high γH2AX nuclear expression. Cytobands 5q11-35, 9p24.3-21.5, 18q11.1-25, etc. showed deletion, whereas 12q was amplified in high arsenic samples (AsH). Consecutively, IPA® found FA-BRCA pathway to be exclusively altered in AsH group. Validation of several key regulatory genes (RAD50, BRIP1, UIMC1, FANCD2, BRCA2 and BRCA1) of the pathway, were performed in independent BlCa cases (n = 81). UIMC1, RAD50 and BRIP1 were differentially deleted and associated with poor survival of AsH samples. Moreover, reduced nuclear expression with diffused cytoplasmic expression of FANCD2 was higher in AsH samples. Collectively, frequent deregulation of RAD50, UIMC1 and BRIP1 may result in reduced nuclear translocation of FANCD2, which may cause more chromosomal aberrations among AsH samples.


Noninvasive prediction of hyaline membrane disease: an optimized classification of sonographic placental maturation.
Accurate prediction of fetal pulmonary maturity by means of a less invasive procedure than amniocentesis would be desirable. Sonographic diagnosis of a Grade III placenta has been reported to be an excellent predictor of fetal lung maturity. The standard classification of placental grading assigns grade according to the most advanced portion of the placenta. Using this classification, we studied 230 patients. In 80 pregnancies with Grade III placenta, three of the neonates developed respiratory distress syndrome. With reclassification of the placentas as immature, (no Grade III areas), intermediate, (only a portion of the placenta being Grade III), or mature, (Grade III placenta throughout), it was found that no neonatal hyaline membrane disease occurred in the 41 pregnancies with mature placentas, whereas 12% of the neonates in the immature group and 8% in the intermediate group developed hyaline membrane disease. These findings suggest that when sonographic examination of the placenta shows both Grade III and non-Grade III sections, there is still a risk for an immature amniotic fluid lecithin/sphingomyelin ratio and neonatal hyaline membrane disease. The placentas should be considered mature only when Grade III changes are present in all sections examined by ultrasound.


Procyanidin B2 has anti- and pro-oxidant effects on metal-mediated DNA damage.
Procyanidin B2 (epicatechin-(4beta-8)-epicatechin), which is present in grape seeds, apples, and cacao beans, has antioxidant properties. We investigated the mechanism of preventive action of procyanidin B2 against oxidative DNA damage in human cultured cells and isolated DNA. Procyanidin B2 inhibited the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in the human leukemia cell line HL-60 treated with an H2O2-generating system. In contrast, a high concentration of procyanidin B2 increased the formation of 8-oxodG in HL-60 cells. Experiments with calf thymus DNA also revealed that procyanidin B2 decreased 8-oxodG formation by Fe(II)/H2O2, whereas procyanidin B2 induced DNA damage in the presence of Cu(II), and H2O2 extensively enhanced it. An electron spin resonance spin trapping study utilizing 3,3,5,5-tetramethyl-1-pyrroline-N-oxide (M4PO) demonstrated that procyanidin B2 decreased the signal of M4PO-OH from H2O2 and Fe(II), whereas procyanidin B2 enhanced the signal from H2O2 and Cu(II). As an antioxidant mechanism, UV-visible spectroscopy showed that procyanidin B2 chelated Fe(II) at equivalent concentrations. As a pro-oxidant property, we examined DNA damage induced by procyanidin B2, using 32P-labeled DNA fragments obtained from genes relevant to human cancer. Our results raise the possibility that procyanidin B2 exerts both antioxidant and pro-oxidant properties by interacting with H2O2 and metal ions.


A system of counteracting feedback loops regulates Cdc42p activity during spontaneous cell polarization.
Cellular polarization is often a response to distinct extracellular or intracellular cues, such as nutrient gradients or cortical landmarks. However, in the absence of such cues, some cells can still select a polarization axis at random. Positive feedback loops promoting localized activation of the GTPase Cdc42p are central to this process in budding yeast. Here, we explore spontaneous polarization during bud site selection in mutant yeast cells that lack functional landmarks. We find that these cells do not select a single random polarization axis, but continuously change this axis during the G1 phase of the cell cycle. This is reflected in traveling waves of activated Cdc42p which randomly explore the cell periphery. Our integrated computational and in vivo analyses of these waves reveal a negative feedback loop that competes with the aforementioned positive feedback loops to regulate Cdc42p activity and confer dynamic responsiveness on the robust initiation of cell polarization.


Assessment of the risk of obstructive sleep apnoea among patients with type 2 diabetes and its associated factors using the STOP-BANG questionnaire: A cross-sectional study.
To assess the risk of obstructive sleep apnoea (OSA) and its associated risk factors among patients with type 2 diabetes in southern KSA. This was a cross-sectional study conducted at the Armed Forces Hospital in Jazan. The prevalence of OSA was assessed using a validated Arabic translation of the STOP-BANG screening questionnaire. The odds of a higher OSA risk were calculated via regression analysis, according to the measured clinical and demographic variables. The total number of participants was 306, of which 213 (69.6%) were over the age of 50, 247 (80.7%) were married, and 161 (52.6%) were female. The overall median score of the OSA risk level assessed by the STOP-BANG items was three on a scale of 0-8, of which 193 (63.1%) of the participants in the sample were classified as being at high risk of developing OSA. Several statistically significant associations were identified, where odds ratios (ORs) with a higher OSA risk level were detected according to age, sex, marital status, waist and neck circumference, haemoglobin A1c (HbA1c) and body mass index levels, duration of diabetes, and comorbidity with hypertension (p < 0.05). The higher risk of OSA identified in our sample of diabetic patients can be related to a high prevalence of obesity, larger neck circumferences, hypertension, and other factors linked to the duration and treatment of diabetes. Additionally, the association between waist circumference, HbA1c, and duration since the diagnosis of diabetes suggests an interaction effect that requires further investigation.


Retinal granular cell tumor: a case report.
To report a rare case of granular cell tumor invading the retina. A 56-year-old female complained of blurred vision for 2 weeks in her left eye. An irregular-shaped retinal mass in the inferonasal and extending to the optic disc accompanied by dense exudation and extensive serous retinal detachment was observed. Several intravitreal bevacizumab injections were ineffective for stabilizing retinal exudation and intraocular pressure (IOP). Vitrectomy was performed to re-attach the retina and obtain a tumor biopsy specimen. Histopathological analysis revealed that the intraocular mass was a granular cell tumor. Immunohistochemical studies demonstrated that the tumor was positive for S100 and CD68, focal positive for neurofilaments, but negative for ERG and HMB-45. Local recurrence and distant metastasis were not found, but visual acuity had worsened to no light perception at the last visit due to uncontrolled intraocular pressure and retinal exudation after the surgery. Granular cell tumor is a rare benign neoplasm, but it can lead to devastating visual loss if it invades the retina adjacent to the optic nerve head.


Effect of cis-9,trans-11 and trans-10,cis-12 isomers of conjugated linoleic acid on the integrity and functionality of cryopreserved bovine spermatozoa.
Plasma membranes of sperm subjected to low temperatures undergo changes in their structure and permeability. The addition of fatty acids in semen cryopreservation media may influence the sperm motility after thawing, possibly by maintaining the membrane fluidity due to their incorporation in lipid bilayers. In this work, different concentrations of the isomers cis-9,trans-11 and trans-10,cis-12 of conjugated linoleic acid (CLA) were added in the cryopreservation medium of bovine sperm. Four Jersey bulls were used, and the ejaculates were processed as a pool. The Tris-based extender (Dilutris®) was supplemented with 20% egg yolk (MB). The treatments with CLA (Luta-CLA®), which had oily presentation, were prepared from MB with addition of 1% sodium lauryl sulfate, and denominated MBL. The concentrations of CLA tested were 50, 100, and 150 μM. The motility characteristics of the post-thaw semen were analyzed by computerized analysis system (CASA), and plasma membrane integrity and acrosomal and mitochondrial function assessed by the association of the fluorescent probes propidium iodide, fluorescein isothiocyanate-conjugated Pisum sativum agglutinin (FITC-PSA), JC-1 and Hoechst 33342. No significant differences were observed among treatments, excepting for a decreased mitochondrial potential of cells treated with 150 μM CLA. The addition of CLA, at the concentrations used, showed no advantages on the integrity and functionality of bovine sperm submitted to cryopreservation.


Surface Plasmon Resonance (SPR) Analysis of Binding Interactions of Inner-Ear Proteins.
Surface plasmon resonance is an optical technique that is utilized for detecting molecular interactions. Binding of a mobile molecule (analyte) to a molecule immobilized on a thin metal film (ligand) changes the refractive index of the film. The angle of extinction of light that is completely reflected after polarized light impinges upon the film, is altered, and monitored as a change in detector position for a dip in reflected intensity (the surface plasmon resonance phenomenon). Because the method strictly detects mass, there is no need to label the interacting components, thus eliminating possible changes of their molecular properties. We have utilized surface plasmon resonance to study interaction of proteins of inner-ear sensory epithelia.


The accumulation of circulating histones on heparan sulphate in the capillary glycocalyx of the lungs.
Recent findings on the role of circulating histone proteins in mediating acute lung injury prompted us to investigate whether there is a specific mechanism for accumulation of histones in the lungs. Binding sites for polycations are already known in the vasculature of the lungs, and we postulated that these could also be involved in histone accumulation, since histones have a high content of positively charged amino acids. Using a histone-coated colloid of a radiolabelled nanocomposite to track histone biodistribution with imaging techniques, it was found that histones bind avidly in the lungs of rabbits after intravenous injection. Blocking experiments with competing polycations in vivo characterised histone lung binding as dependent on a charge interaction with microvessel polyanions. Pretreatment of rabbits with a specific heparinase confirmed that the lung binding sites consist of heparan sulphate in the endothelial glycocalyx. A range of heparan sulphate analogues was accordingly shown to prevent histone accumulation in the lungs by neutralising histones in blood. These findings provide a rational basis for the design of polyanions that can prevent accumulation of cytotoxic histones in the lungs and thereby intervene at an early key step in the development of acute lung injury.


An elderly man with mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) without neuropsychiatric sequelae.
Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) is less common in the elderly, and most have some sequelae. However, even in the elderly, MERS may have a good prognosis, and a specific treatment is not always required.


Effect of indomethacin on estrogen-induced luteolysis in the ewe.
Three groups of 6 ewes were laparotomized on day 9 of an estrous cycle (estrus = day 0) and the corporà lutea (CL) were marked with India ink. Indwelling cannulae were inserted into the uterine horn adjacent to the CL in groups 2 and 3. Group 1 was injected intramuscularly (i.m.) with corn oil twice daily on day 9. Group 2 received 750 microng 17beta-estradiol (E2) i.m. twice daily on day 9 plus intrauterine injections of indomethacin (INDO) vehicle on days 9 through 13. Group 3 received in the same estrogen treatment plus the injection of 20 mg INDO twice daily on days 9 through 13. Jugular venous samples were taken once daily on days 9 through 14 for progesterone analysis. At re-laparotmy on day 14, the ovaries were examined for new ovulations, and the ovary bearing the marked CL was removed. Results showed that E2 induced premature luteal regression as indicated by decreased CL weights and plasma progesterone levels. INDO when given in conjunction with E2 effectively blocked the luteolytic action of E2. These results suggest that the luteolytic action of E2 is mediated via increased prostaglandin secretion and release from the uterus.


Is three-point fixation needed to mechanically stabilize zygomaticomaxillary complex fractures?
Fixation is critical in zygomaticomaxillary complex (ZMC) fractures to avoid malunion; however, controversy exists as to how much hardware is required to achieve adequate stability. Current fixation regimens may not represent the minimum stabilization needed for uneventful healing. Craniomaxillofacial (CMF) computational models have shown limited load transmission through the infraorbital rim (IOR), and a previous experimental study of ZMC fractures has suggested that IOR plating does not alter CMF bone strain patterns. This study aimed to measure the impact of stabilization on fracture site displacement under muscle loading, testing the hypothesis that three-point fixation is not critical for ZMC fracture stability. Four ZMC complex fractures were simulated on two cadaveric samples and stabilized with three-point plating. Displacements simulating mouth openings of 20 mm and 30 mm were applied to the mandible using a custom apparatus. Fracture gap displacement under load was measured at multiple points along each fracture line, and bone strain was captured using a combination of uniaxial and rosette gauges. Data capture was repeated with the IOR plate removed (two-point fixation) and with the zygomaticomaxillary plate removed (one-point fixation). Fracture displacement under muscle loading was consistent, with gaps of less than 1 mm in 95% of cases (range 0.05-1.44 mm), reflecting clinical stability. Large variabilities were observed in the strain measurements, which may reflect the complexity of CMFS load patterns and the sensitivity of strain values to gauge placement. This study supports the concept of hardware reduction, suggesting that two-point (or even one-point) fixation may provide sufficient stability for a ZMC fracture under applied muscle loading.


The sustainability of changes in agricultural technology: The carbon, economic and labour implications of mechanisation and synthetic fertiliser use.
New agricultural technologies bring multiple impacts which are hard to predict. Two changes taking place in Indian agriculture are a transition from bullocks to tractors and an associated replacement of manure with synthetic fertilisers. This paper uses primary data to model social, environmental and economic impacts of these transitions in South India. It compares ploughing by bullocks or tractors and the provision of nitrogen from manure or synthetic urea for irrigated rice from the greenhouse gas (GHG), economic and labour perspective. Tractors plough nine times faster than bullocks, use substantially less labour, with no significant difference in GHG emissions. Tractors are twice as costly as bullocks yet remain more popular to hire. The GHG emissions from manure-N paddy are 30 % higher than for urea-N, largely due to the organic matter in manure driving methane emissions. Labour use is significantly higher for manure, and the gender balance is more equal. Manure is substantially more expensive as a source of nutrients compared to synthetic nutrients, yet remains popular when available. This paper demonstrates the need to take a broad approach to analysing the sustainability impacts of new technologies, as trade-offs between different metrics are common.


Prognostic role of resection margin in open oncologic laryngeal surgery: survival analysis of a cohort of 139 patients affected by squamous cell carcinoma.
The treatment of laryngeal squamous cell carcinoma needs accurate risk stratification, in order to choose the most suitable therapy. The prognostic significance of resection margin is still highly debated, considering the contradictory results obtained in several studies regarding the survival rate of patients with a positive resection margin. To evaluate the prognostic role of resection margin in terms of survival and risk of recurrence of primary tumour through survival analysis. Between 2007 and 2014, 139 patients affected by laryngeal squamous cell carcinoma underwent partial or total laryngectomy and were followed for mean of 59.44±28.65 months. Resection margin status and other variables such as sex, age, tumour grading, pT, pN, surgical technique adopted, and post-operative radio- and/or chemotherapy were investigated as prognostic factors. 45.32% of patients underwent total laryngectomy, while the remaining subjects in the cohort underwent partial laryngectomy. Resection margins in 73.39% of samples were free of disease, while in 21 patients (15.1%) anatomo-pathological evaluation found one of the margins to be close; in 16 subjects (11.51%) an involved resection margin was found. Only 6 patients (4.31%) had a recurrence, which occurred in 83.33% of these patients within the first year of follow-up. Disease specific survival was 99.24% after 1 year, 92.4% after 3 years, and 85.91% at 5 years. The multivariate analysis of all covariates showed an increased mortality rate only with regard to pN (HR=5.043; p=0.015) and recurrence (HR=11.586; p=0.012). Resection margin did not result an independent predictor (HR=0.757; p=0.653). Our study did not recognize resection margin as an independent prognostic factor; most previously published papers lack unanimous, methodological choices, and the cohorts of patients analyzed are not easy to compare. To reach a unanimous agreement regarding the prognostic value of resection margins, it would be necessary to carry out meta-analyses on studies sharing definition of resection margin, methodology and post-operative therapeutic choices.


Halofuginone inhibits multiple myeloma growth in vitro and in vivo and enhances cytotoxicity of conventional and novel agents.
Multiple Myeloma (MM), a malignancy of plasma cells, remains incurable despite the use of conventional and novel therapies. Halofuginone (HF), a synthetic derivative of quinazolinone alkaloid, has recently been shown to have anti-cancer activity in various preclinical settings. This study demonstrated the anti-tumour activity of HF against a panel of human MM cell lines and primary patient-derived MM cells, regardless of their sensitivity to conventional therapy or novel agents. HF showed anti-MM activity in vivo using a myeloma xenograft mouse model. HF suppressed proliferation of myeloma cells alone and when co-cultured with bone marrow stromal cells. Similarly, HF induced apoptosis in MM cells even in the presence of insulin-like growth factor 1 or interleukin 6. Importantly, HF, even at high doses, did not induce cytotoxicity against CD40 activated peripheral blood mononuclear cells from normal donors. HF treatment induced accumulation of cells in the G(0) /G(1) cell cycle and induction of apoptotic cell death associated with depletion of mitochondrial membrane potential; cleavage of poly (ADP-ribose) polymerase and caspases-3, 8 and 9 as well as down-regulation of anti-apoptotic proteins including Mcl-1 and X-IAP. Multiplex analysis of phosphorylation of diverse components of signalling cascades revealed that HF induced changes in P38MAPK activation; increased phosphorylation of c-jun, c-jun NH(2)-terminal kinase (JNK), p53 and Hsp-27. Importantly, HF triggered synergistic cytotoxicity in combination with lenalidomide, melphalan, dexamethasone, and doxorubicin. Taken together, these preclinical studies provide the preclinical framework for future clinical studies of HF in MM.


Diets of healthy Swedish children 4-24 months old. II. Energy intake.
In a semi-longitudinal investigation comprising a total of 81 infants studied at one or more of the ages 4, 9, 15 and 24 months, the food intake was recorded on three consecutive days at 4 months and on seven consecutive days at 9, 15 and 24 months (40, 40, 38 and 40 infants, respectively in the four age groups). The median energy intake was lower than the Recommend Dietary Allowances in all age groups. The energy intake derived from fat was low among some of the 9-month-old infants. The contribution of sucrose to energy was as high as 10% at 24 months.


Efficacy and safety of infliximab as continuous or intermittent therapy in patients with moderate-to-severe plaque psoriasis: results of a randomized, long-term extension trial (RESTORE2).
Continuous maintenance therapy with infliximab 5 mg kg(-1) every 8 weeks is effective for moderate-to-severe plaque-type psoriasis. To evaluate the efficacy and safety of continuous vs. intermittent infliximab maintenance therapy. RESTORE2 was a long-term extension of RESTORE1. At baseline of RESTORE2, eligible patients who had received infliximab for 26 weeks and achieved Psoriasis Area and Severity Index (PASI) 75 in RESTORE1 were rerandomized 1 : 1 to continuous therapy (infliximab 5 mg kg(-1) every 8 weeks) or intermittent therapy (no infliximab until > 50% loss of PASI improvement). Safety and efficacy assessments occurred throughout the study. In total, 222 patients were randomized to receive continuous therapy, and 219 to intermittent therapy. More serious infusion-related reactions occurred with intermittent therapy (8/219 patients, 4%) than with continuous therapy (1/222 patients, < 1%), leading the sponsor to terminate the study. The mean duration of exposure to infliximab was 40·12 weeks (SD 27·55) with a mean of 5·8 infusions (range 0-16) for continuous therapy and 22·78 weeks (SD 22·98) with a mean of 3·4 infusions (range 0-16) for intermittent therapy. Although no formal efficacy analyses were conducted, continuous therapy led to greater PASI 75 at week 52 in the continuous group (81/101, 80%) than in the intermittent group (39/83, 47%); several other efficacy measures demonstrated similar patterns. For patients with moderate-to-severe plaque-type psoriasis, continuous therapy with infliximab may be more effective than intermittent therapy. The incidence of serious infusion-related reactions in the intermittent group suggests that clinicians should avoid intermittent therapy in this population.


Diagnostic dilemma: rare case of recurrent d-lactic acidosis leading to recurrent acute cardiac failure.
d-Lactic acidosis is a rare form of anion gap acidosis and requires a high index of suspicion for appropriate diagnosis and treatment. We report a rare case of short bowel syndrome with recurrent episodes of antibiotic-induced d-lactic acidosis with the presentation of transient severe left ventricular failure. The patient's cardiac function returned to normal with the resolution of acidosis under conservative management and a low carbohydrate diet. d-Lactic acidosis has been known to be associated with only neurological symptoms, and cardiac failure has not been previously reported.


Thrombospondin-1 enhances human thyroid carcinoma cell invasion through urokinase activity.
Previous studies reported that modification in the expression of the matricellular multidomain glycoprotein thrombospondin-1 (TSP-1) could play a critical role in the control of tumor progression and metastasis development. The function of this multimodular protein in cancers appears highly dependent on the cellular context and thus remains to date very difficult to accurately characterize. Controversial results indeed exist reporting either pro- or anti-invasive properties of TSP-1. Since it appeared that TSP-1 could be of prognostic value for certain specific types of cancers, we examined in this study the prospective function of TSP-1 in the control of human follicular thyroid carcinoma (FTC) cell invasiveness. First, we established that the aggressive behavior of human thyroid malignant cells is closely correlated to the TSP-1 amount. We demonstrated that exogenously added TSP-1 stimulates by two-fold the capacity of FTC cells to invade Matrigel-coated wells. The use of specific anti-TSP-1 blocking antibodies led to a drastic inhibition of the basal FTC cell invasion. Zymography experiments revealed that the uPA-dependent proteolytic activity is directly controlled by TSP-1, MMPs activity is not. The TSP-1-mediated stimulation of uPA appears to occur at post-transcriptional level. Finally, we established that the TSP-1-stimulated FTC cell invasion is wholly abolished under anti-uPA blocking antibodies or aprotinin treatments whereas MMP inhibitors have no effect. All together, we evidenced in the present study that TSP-1 promotes human follicular thyroid carcinoma cell invasion mainly through up-regulation of the urokinase-dependent activity.