The Prognostic Value of a Pathologic Complete Response After Neoadjuvant Therapy for Digestive Cancer: Systematic Review and Meta-Analysis of 21 Studies.
Neoadjuvant therapy (NAT) before radical excision has become the preferred initial option for locally advanced digestive cancers such as esophageal cancer (EC), esophagogastric junction adenocarcinoma (EGJAC), gastric adenocarcinoma (GAC), rectal cancer (RC), and pancreatic cancer (PC). Although some patients reportedly achieve a pathologic complete response (pCR) after neoadjuvant therapy, the published data are inconsistent regarding whether pCR yields a survival benefit. The current meta-analysis was performed to assess the potential prognostic value of pCR after preoperative therapy for patients with digestive cancers. An extensive electronic search in PubMed, Web of Science, and the Cochrane Library was performed for relevant articles, from which data relative to independent correlations of pCR with overall survival (OS) and disease-free survival (DFS) were extracted for analysis. A random-effects model was used to calculate the pooled hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs). The study identified 6780 patients who met the inclusion and exclusion criteria. The results showed that pCR was significantly correlated with better OS (HR, 0.50; 95% CI, 0.43-0.58; P < 0.001) and DFS (HR, 0.49; 95% CI, 0.40-0.60; P < 0.001) for the digestive cancer patients who achieved pCR than for those who did not achieve pCR. Subgroup analysis showed that the correlation of pCR with OS was significant in EC (HR, 0.57; 95% CI, 0.47-0.69; P < 0.001), EGJAC/GAC (HR, 0.38; 95% CI, 0.17-0.86; P = 0.02), RC (HR, 0.48; 95% CI, 0.28-0.81; P = 0.006), and PC (HR, 0.41; 95% CI, 0.17-0.97; P = 0.04). In addition, the survival benefit for pCR patients was of similar magnitude, irrespective of the type of study, type of NAT, or ethnicity. A pCR is correlated with favorable survival outcomes compared with a non-pCR for digestive cancer patients after NAT.


Experts use base rates in real-world sequential decisions.
Human behavior is often assumed to be irrational, full of errors, and affected by cognitive biases. One of these biases is base-rate neglect, which happens when the base rates of a specific category are not considered when making decisions. We argue here that while naïve subjects demonstrate base-rate neglect in laboratory conditions, experts tested in the real world do use base rates. Our explanation is that lab studies use single questions, whereas, in the real world, most decisions are sequential in nature, leading to a more realistic test of base-rate use. One decision that lends itself to testing base-rate use in real life occurs in beach volleyball-specifically, deciding to whom to serve to win the game. Analyzing the sequential choices in expert athletes in more than 1,300 games revealed that they were sensitive to base rates and adapted their decision strategies to the performance of the opponent. Our data describes a threshold at which players change their strategy and use base rates. We conclude that the debate over whether decision makers use base rates should be shifted to real-world tests, and the focus should be on when and how base rates are used.


A 50-year experience of male breast cancer: is outcome changing?
During the period 1933-1983, 124 men (median age 62.5 years, range 33-86 years) were treated for breast carcinoma. Median length of follow-up was 6.7 years and was complete for 93% of patients. Presenting complaints were most frequently a mass (95%) or pain (31%) while physical examination revealed the tumour to be central in 95% of patients with nipple or skin retraction in 36% and associated gynaecomastia in 12%. Twenty-seven per cent of the patients had a positive family history of breast cancer, 6% noted previous breast trauma and 7% had prior chest wall irradiation. Mean tumour size was 2.5 cm, and the pathological stage was 0 in 3%, I in 17%, II in 22%, III in 35%, IV in 11%, and unknown in 12%. Ninety-four per cent were ductal carcinoma. Histological grading of tumours was 2% grade 1, 10% grade 2, 33% grade 3 and 48% grade 4. Ninety-two per cent of patients underwent mastectomy (41% radical, 39% modified radical and 12% simple), while adjuvant irradiation was used in 44% and chemotherapy in 9%. Median disease-free patient survival was 5 years (36% of patients developed tumour recurrence). Median overall patient survival was 6.3 years (57% at 5 years and 31% at 10 years). Tumour size (P < 0.05), pathological stage (P < 0.04), and tumour grade (P = 0.007) were adverse factors for recurrence, while pathological stage (P < 0.02), tumour size (P < 0.03), pain (P < 0.05) and age (P < 0.02) were associated with a decreased survival.(ABSTRACT TRUNCATED AT 250 WORDS)


Precision weighting of cortical unsigned prediction error signals benefits learning, is mediated by dopamine, and is impaired in psychosis.
Recent theories of cortical function construe the brain as performing hierarchical Bayesian inference. According to these theories, the precision of prediction errors plays a key role in learning and decision-making, is controlled by dopamine and contributes to the pathogenesis of psychosis. To test these hypotheses, we studied learning with variable outcome-precision in healthy individuals after dopaminergic modulation with a placebo, a dopamine receptor agonist bromocriptine or a dopamine receptor antagonist sulpiride (dopamine study n = 59) and in patients with early psychosis (psychosis study n = 74: 20 participants with first-episode psychosis, 30 healthy controls and 24 participants with at-risk mental state attenuated psychotic symptoms). Behavioural computational modelling indicated that precision weighting of prediction errors benefits learning in health and is impaired in psychosis. FMRI revealed coding of unsigned prediction errors, which signal surprise, relative to their precision in superior frontal cortex (replicated across studies, combined n = 133), which was perturbed by dopaminergic modulation, impaired in psychosis and associated with task performance and schizotypy (schizotypy correlation in 86 healthy volunteers). In contrast to our previous work, we did not observe significant precision-weighting of signed prediction errors, which signal valence, in the midbrain and ventral striatum in the healthy controls (or patients) in the psychosis study. We conclude that healthy people, but not patients with first-episode psychosis, take into account the precision of the environment when updating beliefs. Precision weighting of cortical prediction error signals is a key mechanism through which dopamine modulates inference and contributes to the pathogenesis of psychosis.


Differential action of thyroid hormones and chemically related compounds on the activity of UDP-glucuronosyltransferases and cytochrome P-450 isozymes in rat liver.
The effect of thyroid hormones and chemically related compounds, on the activity of UDP-glucuronosyltransferases (EC 188.8.131.52) and cytochrome P-450-dependent monooxygenases in rat liver microsomes was investigated. The animals were thyroidectomized and treated with different doses of the drugs for 3 weeks. Opposite effects were observed depending on the isoenzyme of UDP-glucuronosyltransferase considered. While 3,3',5-triiodo-L-thyronine, 3,3',5-triiodothyroacetic acid, 3,3',5-triiodothyropropionic acid, isopropyldiiodothyronine and L- and D-thyroxine strongly increased 4-nitrophenol glucuronidation in a dose-dependent fashion, they decreased markedly bilirubin glucuronidation. However, the activity toward nopol, a monoterpenoid alcohol, was not significantly changed regardless of which compound or dose was used. Variation of UDP-glucuronosyltransferase observed with 4-nitrophenol and bilirubin was related to the thyromimetic effect of the drugs estimated from the increase in alpha-glycerophosphate dehydrogenase. Thyronine and 3,5-diiodo-L-tyrosine, which did not enhance this activity, also failed to affect glucuronidation. Variations in UDP-glucuronosyltransferase activity were more likely due to changes in protein expression rather than changes in enzyme latency, since lipid organization of the microsomal membrane, as estimated from the mean anisotropy of 1,6-diphenyl-1,3,5-hexatriene by fluorescence polarization was not significantly modified by the drug administration. Although some of the drugs could significantly decrease the triacylglycerol and cholesterol contents in plasma, all failed to affect lauric acid hydroxylation. The activities of catalase, palmitoyl-CoA dehydrogenase (CN- insensitive) and carnitine acetyltransferase in the fraction enriched in peroxisomes were also not significantly affected by treatment with the thyroid hormone LT3. In contrast, the activity of 7-ethoxycoumarine O-deethylase was increased by large doses of thyronine and by 3,3',5-triiodothyropropionic acid. The concentration of total cytochrome P-450 was decreased in a dose-dependent fashion by all the compounds used, except thyronine. Finally, significant correlations were observed between glucuronidation of bilirubin and 4-nitrophenol and the content in cytochrome P-450. This suggests a possible coordinate regulation of the two processes, which depends on the physicochemical characteristics of the thyroid hormones and related compounds.


Afferent arteriolar reactivity to angiotensin II is enhanced during the early phase of angiotensin II hypertension.
Increased renal microvascular reactivity may contribute to the blunted pressure natriuretic response and increase in blood pressure during the development of angiotensin II hypertension. The current studies were performed to determine renal microvascular reactivity during the early phases of angiotensin II-infused hypertension. Male-Sprague Dawley rats received angiotensin II (60 ng/min) or vehicle via an osmotic minipump. Normotensive and angiotensin II hypertensive rats were studied 1 and 2 weeks after implantation of the minipump. Systolic blood pressure averaged 117 +/- 4 mm Hg (n = 31) before pump implantation. Angiotensin II infusion increased systolic blood pressure to 149 +/- 3 and 187 +/- 5 mm Hg on infusion days 6 and 12, respectively. Renal microvascular responses to angiotensin II and norepinephrine at renal perfusion pressures of 100 and 150 mm Hg were observed using the in vitro juxtamedullary nephron preparation. Afferent arteriolar diameters of 1-week normotensive animals averaged 22 +/- 1 microm and after 2 weeks of vehicle infusion averaged 21 +/- 1 microm at a perfusion pressure of 100 mm Hg. In animals infused with angiotensin II for 1 or 2 weeks, diameters of the afferent arterioles perfused at a pressure of 100 mm Hg were 20% and 9% smaller, respectively. Additionally, 1- and 2-week hypertensive animals had an enhanced responsiveness of the renal microvasculature to angiotensin II. At a perfusion pressure of 100 mm Hg, angiotensin II (10 nmol/L) decreased afferent arteriolar diameter by 26 +/- 5% and 22 +/- 3% in the 1- and 2-week angiotensin II hypertensive rats, respectively. In 1- and 2-week normotensive animals, angiotensin II (10 nmol/L) decreased afferent arteriolar diameter by 18 +/- 2% and 15 +/- 2%, respectively, at a perfusion pressure of 100 mm Hg. In contrast, the afferent arteriolar response to norepinephrine was not altered in angiotensin II hypertensive rats. These data demonstrate an elevated renal microvascular resistance and enhanced vascular reactivity that is selective for angiotensin II in the early phases of hypertension development after infusion of angiotensin II. Thus, an alteration in renal microvascular function contributes to the blunted pressure natriuretic response and progressive development of hypertension.


Evolving trends in the surgical management of renal masses over the past two decades: A contemporary picture from a large prospectively-maintained database.
To investigate the trends in the presentation and surgical management of renal tumors at Singapore General Hospital, Singapore. We accessed our uro-oncological registry to extract the clinicopathological data of patients with renal tumors who underwent nephrectomy from 2000 to 2015. Binary logistic regression was used to identify predictors of nephron-sparing surgery utilization, Clavien-Dindo grade ≥III complications and progression to stage ≥3 chronic kidney disease. Cox regression models were created to evaluate the proportional hazards of the risk factors for overall survival and cancer-specific survival. A total of 1208 cases of nephrectomy were carried out between 2000 and 2015. The proportion of cT1a tumors increased from 2000-2004 to 2010-2015, which was accompanied by the doubling of utilization rates of nephron-sparing surgery and minimally invasive surgery. Charlson Comorbidity Index score <2, asymptomatic presentation, clinical T1a tumors and having an estimated glomerular filtration rate ≥30 mL/min/1.73 m2 were all independent predictors of nephron-sparing surgery utilization. Age, symptomatic presentation and nephron-sparing surgery utilization were all significantly associated with greater odds of having Clavien-Dindo grade ≥III complications, whereas minimally invasive surgery was associated with decreased risk. The utilization of partial nephrectomy and minimally invasive surgery was significantly associated with a decreased risk of developing postoperative stage ≥3 chronic kidney disease. Both overall survival and cancer-specific survival were not significantly affected by whether nephron-sparing surgery was utilized. There has been an increasing proportion of small renal masses diagnosed incidentally with a shift towards nephron-sparing surgery for clinically localized tumors. With the adoption of nephron-sparing surgery, progression to stage 3 chronic kidney disease has decreased, without any compromise in oncological and survival outcomes.


Local synaptic integration enables ON-OFF asymmetric and layer-specific visual information processing in vGluT3 amacrine cell dendrites.
A basic scheme of neuronal organization in the mammalian retina is the segregation of ON and OFF pathways in the inner plexiform layer (IPL), where glutamate is released from ON and OFF bipolar cell terminals in separate inner (ON) and outer (OFF) sublayers in response to light intensity increments and decrements, respectively. However, recent studies have found that vGluT3-expressing glutamatergic amacrine cells (GACs) generate ON-OFF somatic responses and release glutamate onto both ON and OFF ganglion cell types, raising the possibility of crossover excitation in violation of the canonical ON-OFF segregation scheme. To test this possibility, we recorded light-evoked Ca2+ responses from dendrites of individual GACs infected with GCaMP6s in mouse. Under two-photon imaging, a single GAC generated rectified local dendritic responses, showing ON-dominant responses in ON sublayers and OFF-dominant responses in OFF sublayers. This unexpected ON-OFF segregation within a small-field amacrine cell arose from local synaptic processing, mediated predominantly by synaptic inhibition. Multiple forms of synaptic inhibition compartmentalized the GAC dendritic tree and endowed all dendritic varicosities with a small-center, strong-surround receptive field, which varied in receptive field size and degree of ON-OFF asymmetry with IPL depth. The results reveal a form of short-range dendritic autonomy that enables a small-field, dual-transmitter amacrine cell to process diverse dendritic functions in a stratification level- and postsynaptic target-specific manner, while preserving the fundamental ON-OFF segregation scheme for parallel visual processing and high spatial resolution for small object motion and uniformity detection.


Frequency of endometriosis and adenomyosis in patients with leiomyomas, gynecologic premalignant, and malignant neoplasias.
This study investigated the association between gynecological neoplasms, endometriosis, and adenomyosis in women who underwent surgical treatment for gynecological cancer and uterine leiomyoma during reproductive years or after menopause. Information was collected from patient records from the Hospital's database from 1985 to 2007. The study included 502 women, of which 375 were premenopausal and 132 were postmenopausal. A significant association was observed between the occurrence of adenomyosis in cancer in women with four or more pregnancies, and in women aged over 40 years (p < 0.0001). The frequency of adenomyosis was significantly higher than the frequency of endometriosis for cancer in two sites (p = 0.0419) or for leiomyomas (p < 0.0001). Therefore adenomyosis is more frequently found than endometriosis in women with leiomyomas or cancer in two sites in premenopausal women, and clinicians need to be aware of patients with adenomyosis and the risk of cancer.


Offering smoking treatment to primary care patients in two Wisconsin healthcare systems: Who chooses smoking reduction versus cessation?
Smokers unwilling to make a quit attempt can still benefit from smoking intervention. However, it is unclear what proportion of smokers will enter such a Motivation phase intervention, and whether such an intervention attracts different types of smokers than does abstinence oriented treatment. We conducted a study from June 2010 to October 2013 based on a chronic care model of tobacco treatment among study eligible primary care patients (N=1579; 58% women, 89% White) presenting for regular health care visits in southern Wisconsin, U.S. Medical assistants, prompted via the electronic health record (EHR), invited smokers (n=10,242) to learn more about treatment options to help them either reduce their smoking or quit. Of those invited to learn more who were then reached by study staff, 10.2% (n=1046) reported interest in reduction treatment and 24% (n=2465) reported interest in cessation treatment. Patients who selected and ultimately entered reduction (n=492) versus cessation (n=1087) were more likely to report: older age; a history of anxiety; lower motivation to quit; lower primary dependence motives; more close friends or family who smoke; and a greater interval since their last quit attempt. Results suggest that Motivation phase treatment aimed at smoking reduction may increase the proportion and range of smokers inducted into tobacco treatment.


Protective effect of hyaluronic acid on cryopreserved boar sperm.
This study aimed to evaluate the effects of supplementing freezing and thawing media with hyaluronic acid (HA) on the quality parameters of frozen-thawed boar spermatozoa. Boar semen samples were collected from seven mature Yorkshire boars once a week using the gloved hand technique; these samples were frozen-thawed in the extender with added HA. Boar sperm was cryopreserved in the extender with HA added at concentrations of 0 (used as control), 4, 6, 8, 8 and 12mg/L, and their effects on the quality of frozen-thawed boar sperm were evaluated. HA addition to the extender significantly improved sperm motility, sperm membrane integrity, mitochondrial activity, acrosomal integrity, superoxide dismutase and catalase activity, but decreased sperm malondialdehyde level (p<0.05). Therefore, HA could be a promising cryoprotectant for boar sperm.


Racial and Ethnic Disparities in Autism Spectrum Disorder: Implications for Care.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by difficulties with social interaction and communication and the presence of restrictive and repetitive behavior. Individuals with ASD, particularly those from diverse racial and ethnic backgrounds, are at higher risk of certain health conditions and mortality over the lifespan. Disparities in timing of diagnosis, access to services, and quality of care have a significant impact on the trajectory of individuals on the autism spectrum. Health care providers and law enforcement officers often interact with individuals with ASD and need adequate preparation to provide person-centered care to this vulnerable population.


Positive inotropic and lusitropic effects mediated via the low-affinity state of beta1-adrenoceptors in pithed rats.
1 Activation by CGP 12177 and cyanopindolol of the human and rat low-affinity state of beta(1)-adrenoceptors increases frequency and contractile force and hastens relaxation in isolated cardiac tissues, and probably relaxes isolated vessels. In order to identify the positive inotropic, positive lusitropic and vasodilator effects of both agonists also in vivo, we have determined their effects on the left ventricular systolic pressure (LVSP), the rate of intraventricular pressure rise (+dP dt(-1)(max)) and decline (-dP dt(-1)(max)), the diastolic blood pressure (DBP) and the mesenteric blood flow (MBF) in pithed and vagotomized rats. 2 CGP 12177 (0.1-100 nmol kg(-1)) and cyanopindolol (1-1000 nmol kg(-1)) dose-dependently enhanced all cardiac parameters. The nonselective beta-adrenoceptor antagonist bupranolol 10 micromol kg(-1) diminished the CGP 12177 (100 nmol kg(-1))-stimulated increases in LVSP from 26.3+/-8.2 to 13.1+/-1.8 mmHg (P<0.05), +dP dt(-1)(max) from 5287+/-290 to 2439+/-296 mmHg s(-1) (P<0.001) and -dP dt(-1)(max) from -3836+/-301 to -2187+/-443 mmHg s(-1) (P<0.05), respectively. The beta(1)-adrenoceptor antagonist CGP 20712A 10 micromol kg(-1) (known to block the low-affinity state of beta(1)-adrenoceptors at high doses) inhibited increases in +/-dP dt(-1)(max) elicited by the highest dose of CGP 12177. 3 The highest doses of CGP 12177 and cyanopindolol increased DBP by about 10 mmHg and MBF by 1.4+/-0.3 and 0.6+/-0.3 ml min(-1), respectively. The vascular effects of CGP 12177 were not affected by bupranolol and CGP 20712A. 4 In conclusion, activation of the low-affinity state of beta(1)-adrenoceptors by CGP 12177 and cyanopindolol in pithed rats causes a positive inotropic and lusitropic effect. By contrast, the vascular effects of CGP 12177 and cyanopindolol are not mediated by these receptors and have only marginal influence under in vivo conditions.


The multidimensional construct of resilience across the psychosis spectrum: Evidence of alterations in people with early and prolonged psychosis.
Research has demonstrated that resilience impacts functional outcomes and is often reduced among those with prolonged psychosis. However, little work has examined when during the course of psychosis resilience declines and whether resilience impacts symptoms and functioning similarly in different illness phases. This study examined whether overall resilience (a) differed between those with early compared to relatively prolonged psychosis, (b) differed between the psychosis groups and nonclinical controls, and (c) differentially related to symptoms and functioning in the psychosis groups. Participants with early (n = 30) and prolonged psychosis (n = 64) and nonclinical controls (n = 58) completed the Resilience Scale. Psychosis participants also completed clinician-rated functioning and symptom measures. Analyses of Variance were used to compare group resilience levels. Pearson's correlations identified relationships between resilience, symptoms, and functioning. Overall resilience levels did not significantly differ between the psychosis groups, but both psychosis groups had lower resilience than nonclinical controls. Higher overall resilience was significantly associated with lower negative symptoms in the early psychosis group and lower mood symptoms in the prolonged psychosis group; greater resilience was significantly associated with higher functioning in both psychosis groups. Resilience may be reduced throughout the course of psychosis but may differentially impact symptom domains in different illness phases. Targeting resilience with psychosocial interventions may be important throughout the course of psychosis and may lead to improvements in functioning as well as negative symptoms and mood symptoms (in early and prolonged psychosis, respectively). (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Detection of an enol intermediate in the hydroperoxide lyase chain cleavage reaction.
Guava (Psidium guajava) hydroperoxide lyase (HPL) preparations were incubated with [1-(14)C](9Z,11E,13S,15Z)-13-hydroperoxy-9,11,15-octadecatrienoic acid for 1 min at 0 degrees C, followed by rapid extraction/trimethylsilylation. Analysis of the trimethylsilylated products by gas chromatography-mass spectrometry and radio-high-performance liquid chromatography revealed a single predominant (14)C-labelled compound, identified by its (1)H-nuclear magnetic resonance, ultraviolet and mass spectra as the trimethylsilyl ether/ester of (9Z,11E)-12-hydroxy-9,11-dodecadienoic acid. Longer time incubations afford smaller yield of this enol due to its partial tautomerization into (9Z)-12-oxo-9-dodecenoic acid. The data obtained demonstrate that formation of (9Z)-12-oxo-9-dodecenoic acid in the HPL reaction is preceded by unstable enol oxylipin, and further suggest that hemiacetals are the true products of HPL catalysis.


Characterization of the nucleation process of lysozyme at physiological pH: primary but not sole process.
We report on a kinetic study of the heat-induced aggregation process of lysozyme at physiological pH. The time evolution of the aggregation extent and the conformational changes of the protein were followed by dynamic light scattering (DLS) and FTIR spectroscopy, respectively, whereas the morphology of the aggregates was observed by Atomic Force Microscopy (AFM). The conformational changes of the secondary and tertiary structures were simultaneous and distinct in time with respect to the formation of aggregates. Oligomer formation occurred through at least two different aggregation processes: a nucleation process and a homogeneous non-nucleative diffusion-controlled process. FTIR measurements showed that supramolecular aggregation proceeded without the formation of β-aggregated structures and AFM images revealed the presence of oligomers and amorphous aggregates; no fibrillar structures were observed.


Is Peritonitis Risk Increased in Elderly Patients on Peritoneal Dialysis? Report from the French Language Peritoneal Dialysis Registry (RDPLF).
♦ This study was carried out to examine whether or not elderly patients on peritoneal dialysis (PD) had an increased risk of peritonitis. ♦ This was a retrospective cohort study based on data from the French Language Peritoneal Dialysis Registry. We analyzed 8,396 incident patients starting PD between January 2003 and December 2010. The end of the observation period was 31 December 2012. Patients were separated into 2 age groups: up to 75 and over of 75 years old. ♦ Among 8,396 patients starting dialysis there were 3,173 patients older than 75. When using a Cox model, no association was found between age greater than 75 years and increased risk of peritonitis (hazard ratio [HR]: 0.97 [0.88 - 1.07]). Diabetes (HR: 1.14 [1.01 - 1.28] and continuous ambulatory PD (HR: 1.13 [1.04 - 1.23]) were significantly associated with a higher risk of peritoneal infection whereas nurse-assisted PD was associated with a lower risk of peritonitis (HR: 0.85 [0.78 - 0.94]. In the analysis restricted to the 3,840 self-care PD patients, there was no association between age older than 75 years and risk of peritonitis. ♦ The risk of peritonitis is not increased in elderly patients on PD in a country where assisted PD is available.


Regulation of liver metabolism by the hepatic nerves.
In the isolated rat liver perfused as usual via the portal vein, joint electrical stimulation of the nerve fibers around the artery and the portal vein in the liver hilus increased glucose output, shifted lactate uptake to output, decreased urea and glutamine formation as well as ammonia uptake, reduced ketone body production, lowered oxygen uptake and reduced perfusion flow simultaneously changing the intrahepatic flow distribution; it was accompanied by an overflow of noradrenaline into the hepatic vein. All effects were mediated predominantly via alpha-receptors; they were dependent on extracellular calcium. In livers perfused both via the artery and the portal vein, separate stimulation of the plexus at the common hepatic artery or at the portal vein caused similar effects on glucose and lactate balance and on perfusion flow. Arterial stimulation caused the higher metabolic responses and alterations not only in arterial but also 'transhepaticly' in portal flow, and conversely, portal flow elicited the smaller metabolic responses and alterations in both portal and 'transhepaticly' arterial flow. If sympathetic nerve actions were blocked using alpha- and beta-antagonists, the resulting parasympathetic stimulation increased glucose uptake in the presence of insulin and antagonized the glucagon stimulated glucose release, both alone and more strongly in the presence of insulin. The sympathetic nerves may act directly at the parenchymal cells or indirectly via an overflow of neurotransmitter from the vasculature into the sinusoids or via hemodynamic changes. Experiments with the smooth muscle relaxant sodium nitroprusside and with retrograde flow indicate that neither hemodynamic changes nor noradrenaline overflow from the vasculature can play a major role in the mechanism of action of sympathetic liver nerves on glucose and lactate metabolism. Comparative studies with perfused livers of rats, guinea pigs and tupaias are in line with the view that in the rat the sympathetic nerves act via contacts with only a few periportal hepatocytes, from where the signal is propagated through gap junctions, while in guinea pig and tupaia the nerves act via contacts with almost all parenchymal cells. Sympathetic nerve stimulation of the perfused rat liver caused an increase in the activity of glycogen phosphorylase and a decrease of glycogen synthase, but left the activity of pyruvate kinase unaltered; fructose 2,6-bisphosphate and cAMP were only slightly enhanced.(ABSTRACT TRUNCATED AT 400 WORDS)


The transcription factor Foxp1 regulates aerobic glycolysis in adipocytes and myocytes.
In recent years, lactate has been recognized as an important circulating energy substrate rather than only a dead-end metabolic waste product generated during glucose oxidation at low levels of oxygen. The term "aerobic glycolysis" has been coined to denote increased glucose uptake and lactate production despite normal oxygen levels and functional mitochondria. Hence, in "aerobic glycolysis," lactate production is a metabolic choice, whereas in "anaerobic glycolysis," it is a metabolic necessity based on inadequate levels of oxygen. Interestingly, lactate can be taken up by cells and oxidized to pyruvate and thus constitutes a source of pyruvate that is independent of insulin. Here, we show that the transcription factor Foxp1 regulates glucose uptake and lactate production in adipocytes and myocytes. Overexpression of Foxp1 leads to increased glucose uptake and lactate production. In addition, protein levels of several enzymes in the glycolytic pathway are upregulated, such as hexokinase 2, phosphofructokinase, aldolase, and lactate dehydrogenase. Using chromatin immunoprecipitation and real-time quantitative PCR assays, we demonstrate that Foxp1 directly interacts with promoter consensus cis-elements that regulate expression of several of these target genes. Conversely, knockdown of Foxp1 suppresses these enzyme levels and lowers glucose uptake and lactate production. Moreover, mice with a targeted deletion of Foxp1 in muscle display systemic glucose intolerance with decreased muscle glucose uptake. In primary human adipocytes with induced expression of Foxp1, we find increased glycolysis and glycolytic capacity. Our results indicate Foxp1 may play an important role as a regulator of aerobic glycolysis in adipose tissue and muscle.


Intention to quit smoking and concerns about household environmental risks: findings from the Health in Common Study in low-income housing.
To assess the association between intention to quit smoking and perceptions of household environmental risks among racially/ethnically diverse residents of low-income housing. Baseline data were collected from 2007 to 2009 for the Health in Common Study, which assessed social and physical determinants of cancer risk-related behaviors among residents of 20 low-income housing developments in the Greater Boston metropolitan area. Participants were surveyed about their tobacco use and concerns about household exposures. Household environmental inspections were also conducted to identify conditions associated with increased risk of exposure to indoor environmental agents, including pesticides, mold, and cleaning products. Intention to quit smoking was associated with a greater degree of concern about exposures in the home, yet not with the actual presence of household hazards, as identified by home inspections and survey findings. An ecological approach targeting multiple levels of influence may help to highlight the importance of both quitting tobacco and reducing potential household environmental exposures as part of comprehensive efforts to promote individual and household health.


A general route to strong, conductive and antibacterial curdlan-based purely natural eutectohydrogels with self-assembled layer-by-layer network structure.
To promote the application extension of curdlan from food industry- dominant to advanced flexible biomaterials, a novel group of purely natural curdlan gels with noticeable performance was developed through a simple heating-cooling approach, i.e., heating the dispersion of pristine curdlan in mixed acidic natural deep eutectic solvents (NADESs) and water at 60-90 °C, and cooling at ambient temperature. The NADESs employed are composed of choline chloride and natural organic acids (lactic acid as the representative). The as-developed gels (called eutectohydrogels) are not only compressible and stretchable but conductive, which traditional curdlan hydrogels are not attainable. The compressive stress at 90 % strain exceeds 2.00 ± 0.03 MPa, the tensile strength and fracture elongation reach 0.131 ± 0.002 MPa and 300 ± 9 % respectively, attributed to the distinctive, reciprocally linked self-assembled layer-by-layer network structure formed during gelation. An electric conductivity up to 2.22 ± 0.04 S‧m-1 is achieved. The excellent mechanics and conductivity confer them good strain-sensing behavior. Additionally, the eutectohydrogels display high antibacterial activity against S. aureus (a model Gram-positive bacterium) and E. coli (a model Gram-negative bacterium). The outstanding comprehensive performance together with the purely natural attribute makes them broad application prospects in biomedical fields like flexible bioelectronics.


Identification of two phytotoxins, blumenol A and grasshopper ketone, in the allelopathic Japanese rice variety Awaakamai.
Aqueous methanol extracts of the traditional rice (Oryza sativa) variety Awaakamai, which is known to have the greatest allelopathic activity among Japanese traditional rice varieties, inhibited the growth of roots and shoots of cress (Lepidium sativum), lettuce (Lactuca sativa), timothy (Phleum pratense), Digitaria sanguinalis, Lolium multiflorum and Echinochloa crus-galli. Increasing the extract concentration increased the inhibition, suggesting that the extract of Awaakamai contains growth inhibitory substances. The extract of Awaakamai was purified and two main growth inhibitory substances were isolated and determined by spectral data as blumenol A and grasshopper ketone. Blumenol A and grasshopper ketone, respectively, inhibited the growth of cress shoots and roots at concentrations greater than 10 and 30 μmol/L. The concentrations required for 50% growth inhibition on cress roots and shoots were 84 and 27 μmol/L, respectively, for blumenol A, and 185 and 76 μmol/L, respectively, for grasshopper ketone. These results suggest that blumenol A and grasshopper ketone may contribute to the growth inhibitory effect of Awaakamai and may play an important role in the allelopathy of Awaakamai.


Boosting brackish water treatment via integration of mesoporous γ-Al2O3NPs with thin-film nanofiltration membranes.
In this study, a simple method based on non-ionic surfactant polysorbates-80 was used to create mesoporous γ-Al2O3NPs. The properties of the prepared mesoporous alumina nanoparticles (Al2O3NPs) were verified using ATR-FTIR, XRD, SEM, TEM, DLS, and BET surface area analysis. Then, thin-film nanocomposite (TFN) nanofiltration membranes were fabricated by interfacial polymerization of embedded polyamide layers with varied contents (0.01 to 0.15 wt.%) of mesoporous γ-Al2O3NPs. The surface roughness, porosity, pore size, and contact angle parameters of all the prepared membranes were also determined. The performance of the fabricated membranes was investigated under various mesoporous γ-Al2O3NPs loads, time, and pressure conditions. Mesoporous γ-Al2O3NPs revealed an important role in raising both the membrane hydrophilicity and the surface negativity. The addition of 0.03 wt.% mesoporous γ-Al2O3NPs to the TFN membrane increased water flux threefold compared to the TF control (TFC) membrane, with maximum water flux reaching 96.5, 98, 60, and 52 L/(m2.h) for MgSO4, MgCl2, Na2SO4, and NaCl influent solutions, respectively, with the highest salt rejection of 96.5%, 92.2%, 98.4%. The TFN-Al2O3 membrane was also able to soften water and remove polyvalent cations such as Mg2+ with a highly permeable flux. The TFN-Al2O3 membrane successfully removed the hardness of the applied water samples below the WHO limit compared to using merely the TFC membrane. Furthermore, the TFN-Al2O3 nanofiltration membrane unit proved to be a promising candidate for the desalination of real brine like that collected from the Safaga area, Egypt.


Carcinoma of penis treated with neodymium YAG laser.
Sixteen men with squamous cell carcinoma of the penis were treated primarily with the Neodymium Yttrium Aluminum Garnet (Nd:YAG) laser. Five patients had TIS, 9 had T1 tumors, and 2 had T2 carcinoma. All patients had refused traditional therapy of partial penectomy and gave informed consent as to the investigational nature of the Nd:YAG laser photoradiation therapy. Circumcisions and deep tissue biopsies were performed on all patients prior to tumoricidal neodymium photoradiation treatment. The patients were followed from twelve to thirty-six months. At follow-up, 5 patients with TIS had no evidence of recurrent cancer. Of the 9 patients with T1 squamous cell carcinoma of the penis, 6 (67%) were tumor-free at a mean follow-up of twenty-six months. The 2 men with T2 carcinoma of the penis had reduction of the tumor mass but were not cured. The obvious advantage of the Nd:YAG laser in treating carcinoma of the penis is preservation of the penis eliminating disfiguring amputation.


Current update on combined hepatocellular-cholangiocarcinoma.
Combined hepatocellular-cholangiocarcinoma is a rare but unique primary hepatic tumor with characteristic histology and tumor biology. Recent development in genetics and molecular biology support the fact that combined hepatocellular-cholangiocarcinoma is closely linked with cholangiocarcinoma, rather than hepatocellular carcinoma. Combined hepatocellular cholangiocarcinoma tends to present with an more aggressive behavior and a poorer prognosis than either hepatocellular carcinoma or cholangiocarcinoma. An accurate preoperative diagnosis and aggressive treatment planning can play crucial roles in appropriate patient management.


Panel provides 1978 update on hospital social work.
In a roundtable discussion, three hospital social workers explain some of the special problems and issues confronting them in their individual and interdisciplinary roles in health care settings.


Effect of different angiotensin-converting-enzyme inhibitors on mortality among elderly patients with congestive heart failure.
Existing clinical trial data do not address whether all angiotensin-converting-enzyme (ACE) inhibitors are similarly beneficial in improving survival and reducing the rate of readmission among patients with congestive heart failure. We sought to answer this question using administrative databases from Canada's 3 most populous provinces. Using linked hospital discharge and prescription claims databases in Quebec, Ontario and British Columbia, we identified all patients 65 years or older who were admitted to hospital because of congestive heart failure between Jan. 1, 1998, and Mar. 31, 2002, and who had not been admitted for the same reason in the 3 years preceding the study period. We analyzed the association between the type of ACE inhibitor prescribed within 30 days after discharge and subsequent mortality using Cox proportional hazards models. We then adjusted for demographic, clinical, physician and hospital-related variables, with additional time-dependent variables representing current drug use and dosage. We chose ramipril as the reference category for comparison with the other ACE inhibitors because it has increasingly been prescribed to patients with congestive heart failure. A total of 43 316 patients with congestive heart failure filled prescriptions for ACE inhibitors within 30 days after discharge from hospital. Demographic, clinical and prescription-related characteristics were similar among users of each type of ACE inhibitor. In the time-dependent model, the mortality associated with 5 ACE inhibitors was similar to that with ramipril: adjusted hazard ratios (and 95% confidence intervals [CIs]) were 0.95 (0.89-1.02) for lisinopril, 0.92 (0.85-1.00) for fosinopril, 0.99 (0.88-1.11) for quinapril, 0.90 (0.77-1.06) for perindopril and 1.00 (0.80-1.24) for cilazapril. However, use of enalapril or captopril was associated with higher mortality compared with ramipril: adjusted hazard ratios (and 95% CIs) were 1.10 (1.04-1.16) for enalapril and 1.13 (1.01-1.26) for captopril. When prescribing ACE inhibitors to patients, physicians should consider a possible 10%-15% increase in mortality with captopril and enalapril compared with ramipril among patients with congestive heart failure.


Methodology, results and complications in 2000 extracorporeal shock wave lithotripsy procedures.
Since the installation of an extracorporeal shock wave lithotriptor (ESWL) unit 12 months ago, 2000 lithotripsy procedures have been performed. Overall, 68.4% of patients were stone-free by the end of the first month. Residual lithiasis (fragments less than 0.5 cm) was seen in 19.7% of patients and significant lithiasis (fragments greater than 0.5 cm) was observed in 10.1%. Complications were obstruction, infection, headache due to the epidural anaesthesia, anuria, renal failure, perirenal haematoma and cardiac arrest. A number of patients required additional operative treatment; this was always endoscopic and no open procedures were performed. Hospitalisation averaged 1 day.


Changes in the secondary structure of apolipoprotein B-100 after Cu2+-catalysed oxidation of human low-density lipoproteins monitored by Fourier transform infrared spectroscopy.
Fourier transform infrared (FTIR) spectra have been obtained of human low-density lipoproteins (LDL) in H2O and 2H2O buffers. The absorption bands are assigned to vibrations of the lipid and apolipoprotein B-100 components. The analysis of second-derivative spectra allowed an assignment of individual protein bands to alpha-helical, random, coil or beta-structure and beta-turn conformations. Changes in the FTIR spectra after Cu2+-catalysed oxidation of the LDL particles indicate that the structure of apolipoprotein B-100 becomes less ordered, with some alterations of alpha-helical and beta-turn conformation. The main beta-structure absorption at 1620 cm-1 is unaffected by oxidation. Taking into account the resistance to oxidation and the slow H-2H exchange it is suggested that the beta-structure is hidden from external factors whereas other structures are mostly present on the surface of the LDL particle. Oxidation affects mainly the surface region of apolipoprotein B-100 and leads to a structural rearrangement which consequently changes the receptor specificity of the LDL.


Sandwich-type ELISA for free and bound secretory component in human biological fluids.
Three sandwich-type enzyme-linked immunosorbent assays (ELISA) are described for the measurement of free secretory component (SC) and SC bound to IgA (S-IgA) or IgM (S-IgM). These assays do not require preliminary fractionation of the biological fluids to be tested. The specificity of the assays is achieved with monoclonal antibodies specific for free SC (855 SC) and for SC bound to IgA or IgM (8545 SA). The amount of the three SC molecules in various biological fluids is reported. We demonstrate the presence of low levels of free SC in most of these fluids, including normal serum. Moreover our results suggest that S-IgM in serum may result from a non-covalent association between serum IgM and free SC.


Special Issue "Stem Cell Biology & Regenerative Medicine".
More than 50% of pre-clinical studies fail despite a long and expensive journey of drug discovery using animal models [...].


Planning for aging in the twenty-first century.
The population of Rhode Island is aging more rapidly than that of most states and, therefore, can be used to illustrate the effects of aging on health systems, effects that may occur somewhat later or less extensively in most other states. Rhode Island population projections indicate a lull in aging between 1990 and 2010, followed by a 50 percent increase in the elderly cohort as the post-World War II "baby boom" population becomes 65 years of age and older between 2010 and 2030. Current (constant) Rhode Island rates of physician visits and hospital and nursing home use were applied to the projected population and translated into physician and hospital bed requirements and health expenditures, demonstrating that the resource costs of aging will be very large between 2010 and 2030 unless health service needs are reduced substantially and/or alternatives to hospital and nursing home services are developed. During the next 30 years, there will exist a unique and critical opportunity to restructure the medical care system. By developing alternatives to hospital inpatient care and nursing home care and by investing in primary, secondary, and tertiary prevention efforts, the baby boom population may remain healthier longer and, therefore, may require less medical care than elders today.


Perioperative complications of abdominal surgery in smokers.
This study examined the association between smoking and perioperative complications of laparoscopic abdominal surgery and whether these complications were reduced with ≥ 4 weeks of preoperative smoking cessation. A total of 555 patients who underwent gastric and colorectal cancer surgeries under general anesthesia were divided into the following groups retrospectively: 290 individuals without smoking history (NS group), 144 previous smokers (stopped smoking more than 8 weeks before surgery, PS group), and 121 current smokers (CS group) divided to two groups according to preoperative smoking cessation for < 4 (CS1, n = 76) and 4-8 weeks (CS2, n = 45). When compared with the NS group, postoperative hospitalization duration was significantly longer in the CS1 group (p < 0.01), whereas differences between the CS2 or PS groups and NS group were not significant. The total number of postoperative complications was higher in all groups of smoking than in NS group, independent on preoperative smoking cessation; however, suture failure was significantly more frequent only in CS1 group. Although pack-years did not significantly affect complication rates in smokers, duration of smoking cessation time in PS group was a negative predictor of postoperative complications. Providing more than 4 weeks of smoking cessation before gastrointestinal surgery can reduce the duration of hospitalization and rate of suture failure.


Bladder necrosis presenting with hematuria in a patient with sickle-cell disease.
We present an interesting case of bladder necrosis in an 11-year-old boy with sickle-cell disease. The patient initially presented with sudden onset of abdominal pain and went on to have gross hematuria with clots and severe dysuria. Cysto-urethroscopy revealed global hemorrhagic cystitis and a suprapubic catheter was inserted percutaneously during cystoscopy. The symptoms spontaneously resolved over several weeks and the child voids normally at last follow-up. Multiple bladder biopsies were taken and all were completely necrotic.


Efficacy, Safety, and Subject Satisfaction After AbobotulinumtoxinA Treatment of Upper Facial Lines.
Botulinum toxins are the treatment of choice for wrinkles in the upper third of the face. The purpose of this study was to evaluate the efficacy, safety, and subject satisfaction of abobotulinumtoxinA (ABO) for treatment of upper facial lines. Subjects aged 35 to 50 years with moderate-to-severe upper facial lines were included in this study. Subjects received a maximum of 125 s.U. ABO in at least 2 indications with optional touch-up after 2 weeks. Assessments included wrinkle severity, global aesthetic improvement, subject satisfaction, and adverse events (AEs) 1, 3, and 6 months after treatment. At Month 1, 100, 94, and 93% of subjects were responders in dynamic glabellar, lateral canthal, and forehead lines, respectively. All subjects were improved 1 month after treatment, and the majority of the subjects were still improved after 6 months. After treatment, most subjects were satisfied with the appearance of their face, felt better about themselves, and agreed that the treatment made them look the way they feel. Seven subjects (22%) had 8 ABO-related AEs (mild-moderate); headache was most commonly reported (9%). AbobotulinumtoxinA effectively treated upper facial lines, with high patient satisfaction. Treatment was generally well-tolerated.


MicroRNAs expression in peripheral blood mononuclear cells of patients with multiple sclerosis propose.
MicroRNAs (miRs) are involved in the autoimmune and neurological diseases, including multiple sclerosis (MS), through modulating post-transcriptional gene regulation. Accumulating evidence indicates that miR-10, miR-24a, miR-124, and miR-21 play an imperative role in MS pathogenesis. Therefore, the current research aimed to analyze the expression of the selected miRNAs for MS in Iranian population. Blood sample of 75 relapsing-remitting MS (RRMS) patients and 75 healthy individuals suffering no neurodegenerative illness was collected. Subsequently, the isolation of peripheral blood mononuclear cells (PBMCs) was performed by employing Ficoll-Hypaque density gradient method. Afterward, total RNA was extracted and subjected to qRT-PCR analysis. The obtained results evidenced that the relative expression of miR-10 (P = 0.0002), miR-21 (P = 0.0014), and miR-124 (P = 0.0091) significantly decreased in RRMS patients compared to healthy participants. On the contrary, no notable change was observed between the studies groups regarding miR-24a expression levels (P = 0.107). ROC curve analysis estimated an area under the curve (AUC) value equal to 0.75 with P = 0.0006 for miR-10, while it was decreased for miR-21 (AUC = 0.67 and P = 0.0054) and miR-124 (AUC = 0.66 and P = 0.012). The change in miR-10, miR-124, and miR-21 expression patterns was implied to participate in MS development. Further large scale observational studies are recommended.


Abnormal peripheral blood cell counts in neurofibromatosis type 1.
Neurofibromatosis type 1 (NF1), also known as von Recklinghausen disease, is an autosomal dominant disease characterized by neurofibromas with infiltration of mast cells. Neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR) and basophil-to-lymphocyte ratio (BLR) are examined as markers for various diseases. However, these parameters have not yet been assessed for NF1. This study therefore examined these parameters in NF1 patients. We recruited 153 NF patients (78 males, 75 females) and 51 control patients (31 males, 20 females). Complete blood counts were performed, then NLR, LMR, PLR and BLR were calculated. Neutrophil count was significantly higher in male NF1 patients than in male controls. Lymphocyte count was significantly lower in NF1 patients than in controls for both sexes. Monocyte count was significantly higher in male NF1 patients than in male controls. Basophil count was significantly higher in male NF1 patients than in male controls. NLR, PLR and BLR were significantly higher in NF1 patients than in controls for both sexes. LMR was significantly lower in NF1 patients than in controls for both sexes. NF1 shows high NLR, PLR and BLR and low lymphocyte count and LMR.


Economic losses from an episode of zinc toxicosis on a California veal calf operation using a zinc sulfate-supplemented milk replacer.
An episode of zinc toxicosis in 95 veal calves caused $29,602 in losses to the producer ($315/affected calf), most of them direct, out-of-pocket losses. Increased calf mortality and increased veterinary service costs accounted for a majority (70%) of the losses. Reduction of losses may have been accomplished by removing the source and increasing the roughage content in the diet, or by shipping the animals for immediate slaughter. Given the magnitude of the financial loss, especially those associated with calf mortality, it was concluded that producers should refrain from using large amounts of mineral supplements unless a deficiency has been diagnosed.


Urgent-care antibiotic prescribing: An exploratory analysis to evaluate health inequities.
Healthcare disparities and inequities exist in a variety of environments and manifest in diagnostic and therapeutic measures. In this commentary, we highlight our experience examining our organization's urgent care respiratory encounter antibiotic prescribing practices. We identified differences in prescribing based on several individual characteristics including patient age, race, ethnicity, preferred language, and patient and/or clinician gender. Our approach can serve as an electronic health record (EHR)-based methodology for disparity and inequity audits in other systems and for other conditions.


Caring for older people with dementia in the emergency department.
Admission to an emergency department (ED) may expose the older person with dementia to a range of negative consequences, including a deterioration in their behavioural symptoms. The authors conducted a review of primary research relating to the experiences of older people with dementia, their carers and ED nurses, to understand how these experiences might inform nursing practice. Integrative review with a search of the electronic databases of Medline, CINAHL and PSYCHINFO using specified inclusion and exclusion criteria. Three themes were identified: carers and older people with dementia-waiting and worrying; nurses juggling priorities; and strategies for improvement-taking a partnership approach. Older people with dementia may be exposed to disparities in treatment in the ED. A practice partnership between carers and ED nurses may help to prevent this. ED nurses need support to blend technical- and relationship-centred care. Participatory research exploring the experiences of older people with dementia, their carers and ED nurses is needed.


[Autologous 131J-tagged human fibrinogen for early detection of venous thrombosis (preparation, biological and in vivo properties) (author's transl)].
A method for preparation of autologous 131J-tagged human fibrinogen is demonstrated. In vitro the preparation is characterized by content of fibrinogen, protein, plasminogen, clottability and molecular weight. Total plasma radioactivity, specific radioactivity, non-protein-bound radioactivity, biologic half-life and the local activity at the thrombus define the properties in vivo. With the above criteria autologous 131-J-tagged human fibrinogen was shown to be useful for early diagnosis of venous thrombosis.


Functional characterization of porcine nucleophosmin (NPM1) gene in promoting the replication of Japanese encephalitis virus and induction of inflammatory cytokines.
Nucleophosmin (NPM1) is a multifunctional nucleolar protein that plays a role in cell cycle control, tumorigenesis, induction of the inflammatory cytokine, virus replication, as well as the cellular responses to a variety of stress stimuli. However, its physiological functions in pigs have not been well understood. Here, we cloned the porcine NPM1 (porNPM1) gene and analyzed the functions of the porNPM1 protein in pigs. The full-length porNPM1 gene encoded a 294-amino acid protein with 94.5%-99.3% sequence identity to its orthologues in mammals and was extensively expressed in various pig tissues at the mRNA level. The porNPM1 primarily localizes in the nucleus of ST cells, while it translocates from the nucleus to nucleoplasm upon UV irradiation or H2O2 treatment. Notably, JEV infection blocked the translocation of porNPM1 from the nucleolus to the nucleoplasm. Furthermore, porNPM1 interacted with the JEV C protein and facilitated JEV replication in ST cells. The overexpression and knockdown of porNPM1 respectively enhanced or impaired JEV replication, suggesting the important role of porNPM1 in JEV replication. Additionally, the purified ectodomain of porNPM1 induced the production of inflammatory cytokines (TNF-α, IL-6, and IL-8). Together, these data demonstrated that porNPM1 is involved in cellular stress stimuli, JEV replication, and induction of inflammatory cytokines.


Disulfide relays and phosphorylative cascades: partners in redox-mediated signaling pathways.
Modifications of specific amino-acid residues of proteins are fundamental in order to modulate different signaling processes among which the cascade of phosphorylation represents the most effective example. Recently, also, the modification of the redox state of cysteine residues of certain proteins, which is a widespread mechanism in the regulation of protein function, has been proposed to be involved in signaling pathways. Growing evidence shows that some transcription factors could be modulated by both oxidation and phosphorylation. In particular, the pathways regulated by the mitogen activated protein (MAP) kinases represent well-established examples of the cross talk between redox-mediated signaling and phosphorylative cascades. This review will compare the two modes of signal transduction and propose an evolutionary model of a partnership of the two mechanisms in the eukaryotic cell, with redox-mediated signals being more specific and ancestral and phosphorylative signals being more diffuse but predominant in signal propagation.


Ten-minute chat.
Amanda Melvin is senior product manager at MSD Animal Health, which is supporting the Afya Serengeti rabies prevention project.


Do you want to perform endovascular therapy? Perspectives from neurology trainees across Europe.
Endovascular therapy (EVT) has become standard care for acute ischaemic stroke caused by large-vessel occlusion in the anterior circulation. However, access to this treatment in Europe remains poor. The lack of operators is a contributing factor and there is on-going discussion as to whether other specialists, including neurologists, could contribute to the EVT workforce. The question remains whether the next generation of neurologists want to become 'interventional neurologists'. The aim of this study was to address this question. We conducted a short survey within the National Representatives Network (a division of the Resident and Research Fellow Section, European Academy of Neurology) in order to determine the interest of future neurologists in performing EVT. A total of 1218 responses from 27 European countries were received, with some variation in the number of respondents and results among individual countries. In total, 568 neurology trainees (47%) stated that they would want to be an 'interventional neurologist'. Our findings suggest that neurologists could make a significant contribution to the workforce performing EVT and have important implications for the development and uptake of training programmes in Europe.


Accurate occlusion-driven maxillary reconstruction with deep circumflex iliac artery flap using computer-assisted techniques and intraoral anastomosis: a case series.
The aim of this study was to evaluate the feasibility and accuracy of occlusion-driven maxillary reconstruction with the deep circumflex iliac artery (DCIA) flap, using computer-assisted design and manufacturing (CAD/CAM) technology and intraoral anastomosis. The data of 11 patients who underwent occlusion-driven maxillary reconstruction with this method between December 2018 and December 2020 in the Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology were reviewed retrospectively. Postoperative complications and functional and aesthetic outcomes were recorded. The accuracy of the postoperative restoration was assessed using Geomagic Control 2014. Reconstruction was successful in nine patients; all were satisfied with their aesthetic and functional outcomes. One patient underwent extraoral anastomosis after failure of intraoral anastomosis. In another patient, the DCIA flap had to be removed after the operation because of flap failure. Among the 10 patients with DCIA flap success, colour map analysis showed a mean deviation of 0.40 ± 0.08 mm between the preoperative and postoperative craniomaxillary models. Thus, occlusion-driven maxillary reconstruction with the DCIA flap, using CAD/CAM technology and intraoral anastomosis, appears to be a feasible and accurate method for the repair of maxillary defects.


19-Hydroxy-prostaglandin E and infertility in human males.
We measured the content of 19-hydroxy-prostaglandin E (19-OH-PGE) and prostaglandin E (PGE) in the semen of 10 infertile males by alkaline dehydration, thin layer chromatographic separation and ultraviolet spectrophotometry. 7 fertile males were also studied. In both groups the content of seminal 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) also was measured by thin layer chromatographic separation and highly specific radioimmunoassay. The amounts of 19-OH-PGE and PGE were significantly lower (p < .02, p < .05) in the infertile group than the fertile group. Differences in mean seminal 6-keto-F1 alpha were not significant. The uterine stimulatory actions of 19-OH-PGE demonstrable in the monkey may apply to fertility in man.


Track-Density Imaging of the Human Brainstem for Anatomic Localization of Fiber Tracts and Nerve Nuclei in Vivo: Initial Experience with 3-T Magnetic Resonance Imaging.
The brainstem comprises a large variety of fiber tracts and nerve nuclei and is unarguably one of the most crucial parts of the brain. Reliable noninvasive visualization of its anatomy may help relate normal and pathological anatomic variations to neurologic/psychiatric disorders. In this study, we explored the potential of direction-encoded track-density imaging (TDI) for depicting the intricate anatomy of the brainstem. A total of 18 healthy volunteers (10 females, 8 males; median age, 34.5 years; interquartile range, 31-44.5 years) were examined on a 3-T MRI system. Diffusion tensor imaging data were processed using MRtrix to generate TDI images. These images were then compared with anatomic atlases to identify nerve nuclei and fiber tracts. The ability of TDI to delineate anatomic structures in the mesencephalon, pons, and medulla oblongata was evaluated using a 6-point Likert scale (5, excellent; 4, good; 3, moderate; 2, poor; 1, no adequate differentiation; 0, evaluation not possible). All generated TDI images were evaluable without limitations. In the mesencephalon, delineation of the substantia nigra, crus cerebri, and red nucleus was rated as excellent, that of the medial lemniscus was rated as good, and that of the inferior colliculus was rated as poor. Delineation of all anatomic structures in the pons was rated as excellent. In the medulla oblongata, delineation of the pyramid was rated as excellent and that of the medial lemniscus as moderate, whereas delineation of the inferior olive was not possible. TDI images provide optimal delineation of nerve nuclei and fibers in the upper brainstem, but have more difficulty identifying more caudal structures.


Influence of Antagonistic Tensions on Distributed Friction Forces of Multisegment Tendon-Driven Continuum Manipulators With Irregular Geometry.
In this paper, we thoroughly analyze the effect of single-tendon and antagonistic tendons actuation on tension loss of multi-segment tendon-driven continuum manipulators (TD-CMs) with irregular geometry. To this end, we propose a generic analytical modeling approach and iterative algorithm that can solve the unknown correlation between distributed friction force, tendons' tension transmission loss, and planar deformation behavior of TD-CMs during tendons' pulling and releasing phases. The proposed generic model solely relies on known input tendons' tensions and does not require a priori knowledge of the manipulator's shape and/or other experimental conditions. To investigate the influence of actuation type on tension loss and deformation behavior of TD-CMs, we fabricated two different TD-CMs and performed various simulation and experimental studies with single-tendon and antagonistic tensions actuations. The obtained results indicate the importance of considering the effect of distributed friction force and actuation type on tension(s) loss of multi-segment TD-CMs. Moreover, it clearly demonstrates the efficacy and accuracy of the proposed model in providing insights and understanding of tension transmission process in various types of actuations in multi-segment TD-CMs with irregular geometry.


Impact of plasma-protein binding on receptor occupancy: an analytical description.
In this paper we analyse the dynamics of an inhibitor I which can either bind to a receptor R or to a plasma protein P. Assuming typical association and dissociation rates, we find that after an initial dose of inhibitor, there are three time scales: a short one, measured in fractions of seconds, in which the inhibitor concentration and the plasma-protein complex jump to quasi-stationary values, a medium one, measured in seconds in which the receptor complex rises to an equilibrium value and a large one, measured in hours in which the inhibitor-receptor complex slowly drops down to zero. We show that the average receptor occupancy, the pharmacologically relevant quantity, taken over, say, 24h reaches a maximal value for a specific value of the plasma-protein binding constant. Potentially, understanding and exploiting this optimum could be of great interest to those involved in drug discovery and development.


Circulating levels of resistin and risk of type 2 diabetes in men and women: results from two prospective cohorts.
The purpose of this study was to investigate the role of circulating resistin levels in the development of type 2 diabetes using two prospective cohorts of well-characterized men and women. We conducted two prospective case-control studies nested in the Women's Health Study (WHS) and Physicians' Health Study II (PHS II). In the WHS, during a median of 10-years of follow-up, 359 postmenopausal women, who were apparently healthy at baseline and later developed type 2 diabetes, were prospectively matched with 359 healthy control subjects. In the PHS II, with 8 years of total follow-up, 170 men, who were apparently healthy at baseline and later developed type 2 diabetes, were matched with 170 healthy control subjects. Control subjects were matched by age, race, and time of blood draw. Resistin levels at baseline were significantly higher in women than in men (P = 0.003) and in case patients than in control subjects for both women (P < 0.001) and men (P = 0.07). After adjustment for matching factors, physical activity, alcohol intake, smoking, and family history of diabetes, the relative risk of type 2 diabetes comparing the highest to the lowest quartile of resistin in women was 2.22 ([95% CI 1.32-3.73]; Ptrend = 0.002). This association was attenuated after further adjustment for BMI (1.51 [0.86-2.65]; Ptrend = 0.20) or C-reactive protein (1.18 [0.68-2.07]; Ptrend = 0.60). A similar but weaker pattern was observed in men. Elevated levels of circulating resistin were significantly related to increased risk of type 2 diabetes, which appears to be partially accounted for by adiposity and the inflammatory process.


Modeling of cell inactivation and carcinogenesis in the atomic bomb survivors with applications to the mortality from all solid, stomach and liver cancer.
The two-stage clonal expansion (TSCE) model of carcinogenesis has been applied to cancer mortality data from the atomic bomb survivors, to examine the possible influence of radiation-induced cell inactivation on excess relative risk (ERR) and excess absolute risk (EAR) estimates. Cell survival curve forms being either conventional or allowing for low-dose hypersensitivity (LDH) were investigated. Quality-of-fit tests for non-nested models were used in comparisons with the types of empirical risk models applied at the Radiation Effects Research Foundation (RERF) in Hiroshima. In general the TSCE model was found to represent the data more economically (i.e., with fewer parameters for a similarly good description of the data) than the empirical risk model. However, the data are not strong enough to give a clear preference to one of the very different model types used. Central ERR and EAR estimates (at 1 Sv, for age at exposure 30 and age attained 70) from TSCE and empirical models were in good agreement with each other and with previously published estimates. However, the TSCE models including radiation-induced cell inactivation resulted in a lower estimate of the relative risk at young ages at exposure (0-15 years) than the empirical model. Also the TSCE model allowing for radiation-induced cell inactivation with a conventional cell survival curve resulted at 0.2 Sv in significantly lower risk estimates than the model with LDH. These model differences have been used here to suggest risk estimates which include model uncertainty as well as the usual statistical uncertainty. Model uncertainties were small for central estimates and larger for other values of the variables. Applying the proposed method to excess risk for all solid cancer at 1 Sv, age at exposure 10 and age attained 70, results in total uncertainty ranges that are wider than the pure statistical uncertainty range by about 30% for both ERR and EAR.


Temperature-dependent antimutagenic activity of acrolein in Escherichia coli.
The effect of temperature on the antimutagenic activity of acrolein was investigated using UV-irradiated E. coli B. When incubated at lower temperatures (30 degrees C or 37 degrees C), acrolein greatly reduced the mutation frequency in WP2 (wild-type strain), but no such effect was observed with WP2s and ZA159 (excision repair-deficient strains). The antimutagenic activity of acrolein increased when cells were incubated at higher temperatures (40 degrees C or 42 degrees C). Particularly in excision repair-deficient strains, the antimutagenic activity was observed only at higher temperatures. In heat shock response-deficient background, however, the antimutagenic activity was observed at 30 degrees C even in the excision repair-deficient strains.


Identification and characterization of Neospora caninum cyclophilin that elicits gamma interferon production.
Gamma interferon (IFN-gamma) response is essential to the development of a host protective immunity in response to infections by intracellular parasites. Neosporosis, an infection caused by the intracellular protozoan parasite Neospora caninum, is fatal when there is a complete lack of IFN-gamma in the infected host. However, the mechanism by which IFN-gamma is elicited by the invading parasite is unclear. This study has identified a microbial protein in the N. caninum tachyzoite N. caninum cyclophilin (NcCyP) as a major component of the parasite responsible for the induction of IFN-gamma production by bovine peripheral blood mononuclear cells (PBMC) and antigen-specific CD4(+) T cells. NcCyP has high sequence homology (86%) with Toxoplasma gondii 18-kDa CyP with a calculated molecular mass of 19.4 kDa. NcCyP is a secretory protein with a predicted signal peptide of 17 amino acids. Abundant NcCyP was detected in whole-cell N. caninum tachyzoite lysate antigen (NcAg) and N. caninum tachyzoite culture supernatant. In N. caninum tachyzoite culture supernatant, three NcCyP bands of 19, 22, and 24 kDa were identified. NcAg stimulated high levels of IFN-gamma production by PBMC and CD4(+) T cells. The IFN-gamma-inducing effect of NcAg was blocked by cyclosporine, a specific ligand for CyP, in a dose-dependent manner. Furthermore, cyclosporine abolished IFN-gamma production by PBMC from naïve cows as well as PBMC and CD4(+) T cells from infected/immunized cows. These results indicate that the N. caninum tachyzoite naturally produces a potent IFN-gamma-inducing protein, NcCyP, which may be important for parasite survival as well as host protection.


Supraspinal Sensorimotor and Pain-Related Reorganization after a Hemicontusion Rat Cervical Spinal Cord Injury.
Because the presence of pain impedes motor recovery in individuals with spinal cord injury (SCI), it is necessary to understand their supraspinal substrates in translational animal models. Using functional magnetic resonance imaging (fMRI) in a rat model of hemicontusion cervical SCI, supraspinal changes were mapped and correlated with sensorimotor behavioral outcomes. Female adult rats underwent sham or SCI using a 2.5 mm impactor and 150 kdyn force. SCI permanently impaired motor activity in only the ipsilesional forelimb along with thermal hyperalgesia at 5 and 6 weeks. Spinal MRI at 8 weeks after SCI showed ipsilateral T1 and T2 lesions with no discernable lesions across shams. fMRI mapping during electrical forepaw stimulation indicated SCI-induced sensorimotor reorganization with an expansion of the contralesional forelimb representation. Resting state fMRI-based functional connectivity density (FCD), a marker of regional neuronal hubs, increased or decreased across brain regions involved in nociception. FCD increases after SCI were in the primary and secondary somatosensory cortices (S1 and S2), anterior cingulate cortex (ACC), insula, and the pre-frontal cortex (PFC), and decreases were across the hippocampus, thalamus, hypothalamus, and amygdala in SCI. Resting state functional connectivity (RSFC) assessments from the FCD altered regions of interest indicated cortico-cortical RSFC increases and cortico-insular, cortico-thalamic, and cortico-hypothalamic RSFC decreases after SCI. Hippocampus, amygdala, and thalamus showed decreased RSFC with most cortical regions and between themselves except the hippocampus-amygdala network, which showed increased RSFC after SCI. Whereas select nociceptive region's intrinsic activity associated strongly with evoked pain behaviors after SCI (e.g., PFC, ACC, hippocampus, thalamus, hypothalamus, M1, and S1BF) other nociceptive regions had weaker associations (e.g., amygdala, insula, auditory cortex, S1FL, S1HL, S2, and M2), but differed significantly in their intrinsic activities between sham and SCI. The weaker associated nociceptive regions may possibly encode both the evoked and affective components of pain.


Crop production and nitrogen use in European cropland and grassland 1961-2019.
This paper presents EuropeAgriDB v1.0, a dataset of crop production and nitrogen (N) flows in European cropland 1961-2019. The dataset covers 26 present-day countries, detailing the cropland N harvests in 17 crop categories as well as cropland N inputs in synthetic fertilizers, manure, symbiotic fixation, and atmospheric deposition. The study builds on established methods but goes beyond previous research by combining data from FAOSTAT, Eurostat, and a range of national data sources. The result is a detailed, complete, and consistent dataset, intended as a basis for further analyses of past and present agricultural production patterns, as well as construction of scenarios for the future.


The action of human high density lipoprotein on cholesterol crystals. Part 1. Light-microscopic observations.
High density lipoprotein (HDL) was found in vitro to form myelin buds (liposomes) from washed crystals of free cholesterol (commercial or atheroma sources). This activity led to the progressive destruction and solubilization of the crystals. Low density and very low density lipoproteins did not have any effect. Liposome formation and solubilization were accelerated by calcium ions, phospholipase A and polyunsaturated lecithin (Lipostabil). Cholesterol crystals were nearly completely destroyed after 18 h incubation with HDL-Lipostabil.


Why, when and how should immunosuppressive therapy considered in patients with immunoglobulin A nephropathy?
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Lifelong mesangial deposition of IgA1 complexes subsist inflammation and nephron loss, but the complex pathogenesis in detail remains unclear. In regard to the heterogeneous course, classical immunosuppressive and specific therapeutic regimens adapted to the loss of renal function will here be discussed in addition to the essential common renal supportive therapy. Renal supportive therapy alleviates secondary, surrogate effects or sequelae on renal function and proteinuria of high intraglomerular pressure and subsequent nephrosclerosis by inhibition of the renin angiotensin system (RAASB). In patients with physiological (ΔGFR < 1·5 ml/min/year) or mild (ΔGFR 1·5-5 ml/min/year) decrease of renal function and proteinuric forms (> 1 g/day after RAASB), corticosteroids have shown a reduction of proteinuria and might protect further loss of renal function. In patients with progressive loss of renal function (ΔGFR > 3 ml/min within 3 months) or a rapidly progressive course with or without crescents in renal biopsy, cyclophosphamide with high-dose corticosteroids as induction therapy and azathioprine maintenance has proved effective in one randomized controlled study of a homogeneous cohort in loss of renal function (ΔGFR). Mycophenolic acid provided further maintenance in non-randomized trials. Differentiated, precise, larger, randomized, placebo-controlled studies focused on the loss of renal function in the heterogeneous forms of IgAN are still lacking. Prospectively, fewer toxic agents will be necessary in the treatment of IgAN.


Analysis of the contribution of the beta-oxidation auxiliary enzymes in the degradation of the dietary conjugated linoleic acid 9-cis-11-trans-octadecadienoic acid in the peroxisomes of Saccharomyces cerevisiae.
Beta-oxidation of the conjugated linoleic acid 9-cis,11-trans-octadecadienoic acid (rumenic acid) was analyzed in vivo in Saccharomyces cerevisiae by monitoring polyhydroxyalkanoate production in the peroxisome. Polyhydroxyalkanoate is synthesized by the polymerization of the beta-oxidation intermediates 3-hydroxyacyl-CoAs via a bacterial polyhydroxyalkanoate synthase targeted to the peroxisome. The amount of polyhydroxyalkanaote synthesized from the degradation of rumenic acid was found to be similar to the amount synthesized from the degradation of 10-trans,12-cis-octadecadienoic acid, oleic acid or 10-cis-heptadecenoic acid. Furthermore, the degradation of 10-cis-heptadecenoic acid was found to be unaffected by the presence of rumenic acid in the media. Efficient degradation of rumenic acid was found to be independent of the Delta(3,5),Delta(2,4)-dienoyl-CoA isomerase but instead relied on the presence of Delta(3),Delta(2)-enoyl-CoA isomerase activity. The presence of the unsaturated monomer 3-hydroxydodecenoic acid in polyhydroxyalkanoate derived from rumenic acid degradation was found to be dependent on the presence of a Delta(3),Delta(2)-enoyl-CoA isomerase activity. Together, these data indicate that rumenic acid is mainly degraded in vivo in S. cerevisiae through a pathway requiring only the participation of the auxiliary enzymes Delta(3),Delta(2)-enoyl-CoA isomerase, along with the enzyme of the core beta-oxidation cycle.


Involvement of glucagon-like peptide-1 in the glucose-lowering effect of metformin.
Metformin is an oral antihyperglycaemic drug used in the first-line treatment of type 2 diabetes. Metformin's classic and most well-known blood glucose-lowering mechanisms include reduction of hepatic gluconeogenesis and increased peripheral insulin sensitivity. Interestingly, intravenously administered metformin is ineffective and recently, metformin was shown to increase plasma concentrations of the glucose-lowering gut incretin hormone glucagon-like peptide-1 (GLP-1), which may contribute to metformin's glucose-lowering effect in patients with type 2 diabetes. The mechanisms behind metformin-induced increments in GLP-1 levels remain unknown, but it has been hypothesized that metformin stimulates GLP-1 secretion directly and/or indirectly and that metformin prolongs the half-life of GLP-1. Also, it has been suggested that metformin may potentiate the glucose-lowering effects of GLP-1 by increasing target tissue sensitivity to GLP-1. The present article critically reviews the possible mechanisms by which metformin may affect GLP-1 levels and sensitivity and discusses whether such alterations may constitute important and clinically relevant glucose-lowering actions of metformin.


The effects of Medicaid expansion on job loss induced mental distress during the COVID-19 pandemic in the US.
The COVID-19 pandemic led to an unprecedented level of job losses in the U.S., where job loss is also associated with the loss of health insurance. This paper uses data from the 2020 Household Pulse Survey (HPS) and difference-in-difference (DD) regressions to estimate the effect of Medicaid expansion on anxiety and depression associated with job loss. Estimates show that the respondents who live in expansion states are 96.6% more likely to have Medicaid coverage, and 14.2% less likely to have moderate to severe mental distress following their job loss compared to those living in non-expansion states. The corresponding numbers associated with a family member's job loss are 36.3% and 7.6%, respectively. Next, we explore the mechanisms which suggest that the economic security provided by Medicaid is as important (if not more) as the access to or utilization of healthcare. The difference-in-difference-in-difference (DDD) estimates using just above and below the Medicare eligibility age (65) confirm these results.


Large-scale characterization of the murine cardiac proteome.
Cardiomyopathies are diseases of the heart that result in impaired cardiac muscle function. This dysfunction can progress to an inability to supply blood to the body. Cardiovascular diseases play a large role in overall global morbidity. Investigating the protein changes in the heart during disease can uncover pathophysiological mechanisms and potential therapeutic targets. Establishing a global protein expression "footprint" can facilitate more targeted studies of diseases of the heart.In the technical review presented here, we present methods to elucidate the heart's proteome through subfractionation of the cellular compartments to reduce sample complexity and improve detection of lower abundant proteins during multidimensional protein identification technology analysis. Analysis of the cytosolic, microsomal, and mitochondrial subproteomes separately in order to characterize the murine cardiac proteome is advantageous by simplifying complex cardiac protein mixtures. In combination with bioinformatic analysis and genome correlation, large-scale protein changes can be identified at the cellular compartment level in this animal model.


Seeding for sirtuins: microseed matrix seeding to obtain crystals of human Sirt3 and Sirt2 suitable for soaking.
Sirtuins constitute a family of NAD(+)-dependent enzymes that catalyse the cleavage of various acyl groups from the ℇ-amino group of lysines. They regulate a series of cellular processes and their misregulation has been implicated in various diseases, making sirtuins attractive drug targets. To date, only a few sirtuin modulators have been reported that are suitable for cellular research and their development has been hampered by a lack of structural information. In this work, microseed matrix seeding (MMS) was used to obtain crystals of human Sirt3 in its apo form and of human Sirt2 in complex with ADP ribose (ADPR). Crystal formation using MMS was predictable, less error-prone and yielded a higher number of crystals per drop than using conventional crystallization screening methods. The crystals were used to solve the crystal structures of apo Sirt3 and of Sirt2 in complex with ADPR at an improved resolution, as well as the crystal structures of Sirt2 in complex with ADPR and the indoles EX527 and CHIC35. These Sirt2-ADPR-indole complexes unexpectedly contain two indole molecules and provide novel insights into selective Sirt2 inhibition. The MMS approach for Sirt2 and Sirt3 may be used as the basis for structure-based optimization of Sirt2/3 inhibitors in the future.


Glucose biosensors based on a gold nanodendrite modified screen-printed electrode.
In this study, an enzymatic glucose biosensor based on a three-dimensional gold nanodendrite (GND) modified screen-printed electrode was developed. The GNDs were electrochemically synthesized on the working electrode component of a commercially available screen-printed electrode using a solution acquired by dissolving bulk gold in aqua regia as the precursor. The 3D GND electrode greatly enhanced the effective sensing area of the biosensor, which improved the sensitivity of glucose detection. Actual glucose detections demonstrated that the fabricated devices could perform at a sensitivity of 46.76 μA mM⁻¹ cm⁻² with a linear detection range from 28 μM-8.4 mM and detection limit of 7 μM. A fast response time (∼3 s) was also observed. Moreover, only a 20 μl glucose oxidase is required for detection owing to the incorporation of the commercially available screen-printed electrode.


Modular cognitive-behavioral therapy for affective symptoms in young individuals at ultra-high risk of first episode of psychosis: Randomized controlled trial.
Individuals at ultra-high risk of psychosis often present concurrent affective symptoms (depression/anxiety). This study investigated whether modular cognitive-behavioral therapy (CBT) targeting both ultra-high risk and affective symptoms (a) reduced/delayed risk of a first psychotic episode at posttreatment and 14-month follow-up compared with a supportive intervention, (b) was more effective than control condition in producing remission on depression/anxiety. Fifty-eight ultrahigh risk individuals were randomly assigned to CBT or control condition. CBT consisted of 30 sessions, including CBT for psychotic experiences and depression/anxiety. In the CBT group, the cumulative number of participants who developed a first psychotic episode (n = 3, 10.34%) at follow-up was lower than in the control group (n = 8, 27.60%; logrank χ2(1) = 3.68, p = .05). In the CBT group, a higher number of participants achieved remission than in control condition on affective symptoms at posttreatment/follow-up. CBT can prevent psychosis risk and produce better outcomes on depression/anxiety than supportive intervention.


Novel technique to measure horizontal corneal diameter using a Scheimpflug image on the Pentacam.
A new method to measure the horizontal corneal diameter using a Scheimpflug image (SFI) was introduced and compared with the automated iris camera photo (ICP) method on the Pentacam. Each one eye of 88 subjects without significant abnormality in the cornea was included. In SFI, diameters were measured manually using the built-in software tool with the edge-filter option. ICP value read from the overview display. Repeatability was determined from the first two measurements of each eye. The accuracy was assessed using Bland-Altman plot in comparison with caliper measurements. The measurement failure rate of ICP was aggravated by pupil dilation, while that of SFI was unrelated to pupil dilation. Repeatability coefficients of ICP and SFI were 0.1mm and 0.12mm, respectively. The mean difference between ICP values and caliper values was not significant. SFI values were greater than caliper measurements by a mean of 0.13mm. New SFI was reliable and could complement ICP in dilated pupil. The measurement failure rates of Pentacam need to be improved.


Microstructures and mechanical performance of polyelectrolyte/nanocrystalline TiO2 nanolayered composites.
Biological materials with hierarchically laminated structures usually exhibit a good synergy between strength and fracture toughness. Here, we show that a bio-inspired (polyelectrolyte (PE)/TiO2)4 nanolayered composite with a thickness ratio of TiO2 and amorphous PE layers of about 1.1 has been prepared successfully on Si substrates by layer-by-layer self-assembly and chemical bath deposition methods. Microstructures of the nanolayered composite were investigated by scanning electron microscopy, secondary ion mass spectroscopy, and high-resolution transmission microscopy. Mechanical performance of the composite was characterized by instrumented indentation. The composite consisting of 17.9-nm-thick nanocrystalline TiO2 and 16.4-nm-thick amorphous PE layers has a strength of about 245 MPa, which is close to that of shells, while the fracture toughness of the composite, KIC = 1.62 ± 0.30 MPa · m1/2, is evidently higher than that of the bulk TiO2. A possible strategy to build the composite at nanoscale for high mechanical performance was addressed.


Comparison of weight reduction in different designs of solid and hollow obturator prostheses.
Seven types of the partially edentulous maxillectomy arches based on Aramany's classification were designed to evaluate the weight reduction of hollow obturator prostheses. Six obturator prostheses were made for each type of maxillary defect, three of the solid type and three of the hollow type. The weight of each of the 42 obturator prostheses was measured and all of the data were collected and statistically analyzed. The results showed that the hollow obturator prostheses had significantly increased weight reduction, from 6.55% to 33.06% depending on the size of the defect.


Hearing outcomes following cochlear implantation with anatomic or default frequency mapping in postlingual deafness adults.
The aim of this study was to compare the outcomes of different mapping procedures based on anatomic or default frequency distribution in postlingual deafness adults who underwent cochlear implantation (CI). Forty-eight adults with postlingual deafness who underwent CI (MED-EL) from January 2021 to May 2022 in our hospital were prospectively recruited. The participants were randomly assigned to two groups (the anatomic group and the default group). Postoperative computerized tomography (CT) scans were evaluated with Otoplan® to determine the angular insertion depth (AID) and the specific locations of the intracochlear electrodes. Anatomic maps were imported into MAESTRO 9.0 software (MED-EL) for anatomy-based fitting for anatomic group, while default mapping program was set up for the default group. Hearing thresholds, Speech Recognition Scores (SRS), and subjects' auditory and musical abilities were evaluated 1 year after using the CI. Differences were determined in two groups using Stata statistical software, with significance defined as p < 0.05. SRS under noisy conditions was significantly greater for anatomic group than the default group (p = 0.02). Under quiet conditions, however, mean hearing thresholds (0.5, 1, 2, and 4 kHz) and SRS did not differ significantly between the two groups (p = 0.07). Modified questionnaires showed that auditory (p = 0.02) and musical (p = 0.01) quality were significantly better following the anatomic mapping than the default procedure. CI program based on the anatomic distribution may bring better SRS under noise conditions as well as better auditory and musical qualities than based on the default frequency distribution.


PAX3-FOXO1 coordinates enhancer architecture, eRNA transcription, and RNA polymerase pause release at select gene targets.
Transcriptional control is a highly dynamic process that changes rapidly in response to various cellular and extracellular cues, making it difficult to define the mechanism of transcription factor function using slow genetic methods. We used a chemical-genetic approach to rapidly degrade a canonical transcriptional activator, PAX3-FOXO1, to define the mechanism by which it regulates gene expression programs. By coupling rapid protein degradation with the analysis of nascent transcription over short time courses and integrating CUT&RUN, ATAC-seq, and eRNA analysis with deep proteomic analysis, we defined PAX3-FOXO1 function at a small network of direct transcriptional targets. PAX3-FOXO1 degradation impaired RNA polymerase pause release and transcription elongation at most regulated gene targets. Moreover, the activity of PAX3-FOXO1 at enhancers controlling this core network was surprisingly selective, affecting single elements in super-enhancers. This combinatorial analysis indicated that PAX3-FOXO1 was continuously required to maintain chromatin accessibility and enhancer architecture at regulated enhancers.


Recombinant human interferon alpha increases oestrogen receptor expression in human breast cancer cells (ZR-75-1) and sensitizes them to the anti-proliferative effects of tamoxifen.
Exposure of ZR-75-1 human breast cancer cells for 48 h to human recombinant interferon alpha (IFN alpha) resulted in increased expression of oestrogen receptors as measured in a whole cell binding assay. This effect was inversely proportional to dose being significant following treatment with 10-100 IU IFN ml-1 and was only observed at a low initial cell plating density. The extent of the increase in oestrogen receptor levels ranged from 1.2- to 7.2-fold following treatment with 10 IU IFN ml-1. No increase in progesterone receptor expression was observed under the same experimental conditions. Concentrations of IFN which increased oestrogen receptor levels had no effect on cell proliferation. IFN (500 IU ml-1) inhibited cell proliferation and the combination of this treatment with tamoxifen (2 microM) had a greater anti-proliferative effect than either drug alone although there was no evidence of synergism. However, a 5-day pretreatment of cells with IFN (10 IU ml-1) markedly sensitised them to the growth-inhibiting effect of a subsequent 6-day exposure to tamoxifen.


Enhancement of biohydrogen production from brewers' spent grain by calcined-red mud pretreatment.
This paper investigated the utilization of calcined-red mud (CRM) pretreatment to enhance fermentative hydrogen yields from brewers' spent grain (BSG). The BSG samples were treated with different concentrations (0.0-20g/L) of CRM at 55°C for 48h, before the biohydrogen process with heat-treated anaerobic sludge inoculum. The highest specific hydrogen production of 198.62ml/g-VS was obtained from the BSG treated with 10g/L CRM, with the corresponding lag time of 10.60h. Hydrogen yield increments increased by 67.74%, compared to the control tests without CRM. The results demonstrated that the CRM could hydrolyze more cellulose and further provided adequate broth and suitable pH value for efficient fermentative hydrogen. The model-based analysis showed that the modified Gompertz model presented a better fit for the experimental data than the first-order model.


Preparation of diastereomeric urethane derivatives of atropine and l-hyoscyamine using (-)-1-phenylethylisocyanate.
Diastereomeric urethane derivatives of atropine (d,l-hyoscyamine) and l-hyoscyamine were prepared by reacting the alkaloids with (-)-1-phenylethylisocyanate. The derivatives, as the picrate ion-pairs, were characterized by their melting points, optical rotations, elemental analyses, and IR, NMR, and UV-visible spectra.


Colorectal small cell carcinoma in ulcerative colitis with identical rare p53 gene mutation to associated adenocarcinoma and dysplasia.
Colorectal small cell carcinomas (SCCs) are rare tumors and are infrequently associated with ulcerative colitis (UC). We report a case of primary rectal SCC combined with adenocarcinoma arising in left-sided UC. Immunohistochemically, tumor cells were positive for chromogranin A, synaptophysin, and CD56 in the SCC but not in the adenocarcinoma. The patient simultaneously developed multiple lesions of adenocarcinoma and high-grade dysplasia in the sigmoid colon and rectum. To elucidate whether SCC might evolve from multipotential cells in dysplasia and/or adenocarcinoma, we examined the mutational status of TP53 and KRAS. The same clonality of these lesions including SCC was confirmed by the presence of an identical single nucleotide point mutation in TP53. KRAS mutation was not observed in these lesions. Thus, these lesions seem to have developed from the same origin. Long-standing inflammation leading to dysplasia might be responsible for the development of some SCCs in UC particularly when they are combined with dysplasia and/or adenocarcinoma.


[Minimum Wage Companies in the Second Wave of the Corona Crisis].
For a number of reasons, businesses affected by minimum wage may have a particularly hard time during the coronavirus pandemic. We have found that minimum wage establishments were more frequently affected by the Corona pandemic than the rest of the economy at the beginning of 2021 due to the industry composition of these establishments rather than to minimum wage itself. The findings also indicate that minimum-wage establishments use short-time work more often and that the volume of work is reduced more frequently than in other establishments by cutting back on overtime. Finally, salary increases and special payments are also reduced or suspended more frequently.