Magnetic resonance imaging of the coronary vessel wall at 3 T using an obliquely oriented reinversion slab with adiabatic pulses.
Three-dimensional methods offer volumetric coverage in coronary vessel wall imaging, in addition to high signal-to-noise ratios (SNR). To increase SNR further, it is desirable to implement such 3D methods at 3 T. At this field strength, the pulse sequence must be robust to main field and RF inhomogeneities. To achieve this, the double inversion-recovery (DIR) preparation was adapted to use adiabatic pulses, with a slab-selective reinversion replacing the previously used 2D pencil-beam. The slab was oriented obliquely, in order to avoid upstream blood (e.g., left ventricle) or the navigator beam. Phantom experiments suggest that at 3 T, this approach improves both the net profile of the DIR pulse pair and the restoration of magnetization in the navigator region. Using this method, the feasibility of 3D coronary vessel wall imaging was demonstrated at 3 T. Fourteen healthy subjects were scanned using a segmented gradient-echo sequence with prospective navigator gating. Good-quality images of left and right coronary arteries were obtained, with SNR values of 29.7 +/- 7.5 (vessel wall); 10.5 +/- 4.4 (blood); 14.3 +/- 5.2 (fat); and 45.6 +/- 18.0 (myocardium). No problems occurred with ECG-gating or power deposition (SAR) limits.


Pharmacokinetics of cyproterone acetate and ethinylestradiol in 15 women who received a combination oral contraceptive during three treatment cycles.
The pharmacokinetics of cyproterone acetate (CPA) and ethinylestradiol (EE2) were determined in 15 healthy women (age 19 to 34 years), following single dose administration of a combination oral contraceptive, containing 2.0 mg CPA together with 0.035 mg EE2 (Diane-35R). After a wash-out period of one week, the same preparation was administered during a treatment period of three months. After single dose administration, maximum concentrations of CPA in the serum were 15.2 +/- 6.6 ng/ml. Post maximum drug levels declined biphasically with half-lives of 0.8 +/- 0.4 h and 54.0 +/- 26.0 h, respectively. The apparent clearance was calculated to be 3.6 +/- 0.9 ml x min-1 x kg-1 and the volume of distribution (Vz) was 986 +/- 4371. The free fraction of CPA was 3.5 +/- 1.9% and the fractions bound to heat labile proteins and albumin were 4.6 +/- 2.2% and 92.0 +/- 3.5%, respectively. Trough levels of CPA in the serum increased during a treatment cycle, reaching a steady-state around day 16. An about two-fold accumulation of CPA was observed, which was less than expected theoretically. SHBG concentrations in the serum increased by a factor of three during a cycle, without having any effect on the protein binding of CPA. At the end of treatment cycle three, the terminal half-life of CPA had increased to a mean value of 78.6 +/- 16.0 h and the volume of distribution to a value of 1304 +/- 427 1. The apparent clearance showed a small, although significant decrease to a value of 3.0 +/- 0.4 ml x min-1 x kg-1. The observed changes Vz and t 1/2 during the treatment period were attributed to the distribution of CPA into a deep compartment and the slow release of the drug from this compartment. The AUC(0-4h) values of EE2 following single dose administration of the combination oral contraceptive were found to be 187.5 +/- 79.7 pg x ml-1 x h. On the last day of cycles one and three, the AUC(0-4h) values were 311.2 +/- 109.3 and 304.8 +/- 121.5 pg x ml-1 x h, respectively, which corresponds to an about 60% increase as compared to single dose administration. Total and free testosterone concentrations decreased during treatment cycles one and three by about 39% and 62%, respectively, compared with the corresponding values measured prior to treatment.


Molecular imaging of paper cross sections by FT-IR spectroscopy and principal component analysis.
The molecular imaging of paper cross sections containing the wet-strength additive poly(amidoamine)-epichlorohydrin (PAE) was effected by Fourier transform infrared (FT-IR) spectroscopic imaging. Thin cross sections of laboratory sheet samples were prepared and transferred onto CaF2 substrates. A laboratory sheet sample without PAE acted as a reference. Principal component analysis (PCA) was applied to identify and to reveal the distribution of PAE across the section. Differences in the loading plots of the fourth and fifth principal components for the sheets with and without PAE were found in the region of the amide I, amide II, and amine bands within a variance of 0.4-0.8%. The score images of the PCA reveal inhomogeneous distribution of PAE. Small areas of higher concentration of PAE occur across the cross section. The aim of this study was to demonstrate that FT-IR spectroscopic imaging provides spatially resolved quantitative information about the chemical composition of paper, which was successfully achieved.


Knowledge and compliance towards alendronate therapy among postmenopausal women with osteoporosis in Palestine.
Postmenopausal women compliance to alendronate therapy is suboptimal due to the complex dosing requirements. The poor compliance may increase their potential of fractures and the prevalence of side effects. In this study, the compliance of osteoporotic women on bisphosphonate therapy to the complex dosing instructions and their knowledge of alendronate-interactions were assessed. This is a cross-sectional study, using self-administered questionnaire involving 224 osteoporotic women on alendronate therapy, who visited the orthopedic clinics and community pharmacies in the West Bank. Data was collected using a validated questionnaire consisting of 4 sections and analyzed by descriptive statistics. Moreover, associations between patient's socio-demographic characteristics and the extent of compliance and knowledge of alendronate interactions are established in this study. A total of 300 questionnaires were distributed and 224 were completed. The median compliance score to alendronate dosing instructions was 5 out of a possible maximum 7, and the median knowledge score about alendronate interactions was 7 out of a possible maximum 14. Factors found to affect either or both the knowledge and compliance to alendronate dosing instructions were, residency, and the source of instructions. This study identified the importance of compliance and knowledge gaps among postmenopausal women treated with alendronate. Therefore, appropriate knowledge about the importance of proper compliance to dosing instructions and avoidance of interactions is of a great benefit for maximizing clinical effectiveness, lowering fracture risk and prevention of adverse effects of alendronate among patients treated with alendronate in Palestine.


Building the lipid droplet assembly complex.
In this issue, Choudhary et al. (2020. J. Cell Biol.https://doi.org/10.1083/jcb.201910177) address the nature of the ER subdomain from which lipid droplets emanate and how several assembly proteins interact. Their data indicate that seipin/Nem1 marks these sites and provide a detailed working model for assembling the protein complex.


Effects of selenium on agronomical characters of winter wheat exposed to enhanced ultraviolet-B.
Enhanced ultraviolet-B (UV-B) is one of the most important abiotic stress factors that can influence almost every aspect of plant. Selenium (Se) can increase the tolerance of plants to stressful environment. The paper mainly reported the effects of enhanced UV-B, Se supply and their combination on agronomical characters of winter wheat under field conditions. Enhanced UV-B caused a marked decrease in chlorophyll content, plant height, spike length, weight per spike, grain yield and protein content, grain nitrogen (N) and iron (Fe) concentration, and increased hydrogen peroxide (H2O2), malondialdehyde (MDA) and proline content, and grain zinc (Zn) and manganese (Mn) concentration under without supplemental Se supply. However, it also decreased plant height, spike length, weight per spike, grain yield and Fe concentration, and increased H2O2 content, grain potassium (K), Zn and Mn concentration under supplemental Se supply. On the other hand, Se supply induced an evident increase in chlorophyll content, spike length, weight per spike, grain yield, grain protein content, grain N, Fe, copper (Cu), and Se concentration under both UV-B levels. Moreover, significant UV-B×Se interaction was found on plant height, chlorophyll, MDA, H2O2 and proline content, and grain protein, N, K, Cu and Mn concentrations in wheat. The obtained results supported the hypothesis that Se supply increased the yield and improved the quality of winter wheat exposed to enhanced UV-B to some extent.


Vapor detection enabled by self-assembled colloidal photonic crystals.
Here we report the sensitive and reversible detection of vapors by using self-assembled colloidal photonic crystals. The condensation of various vapors in the interstitials of silica colloidal photonic crystals leads to red-shift and amplitude reduction of optical stop bands. A linear relationship between wavelength shift and vapor partial pressure has been observed for a variety of vapors including ethanol, water, and toluene. Importantly, the sensitivity of colloidal photonic crystal-based vapor detectors can be improved by nearly two orders of magnitude by using a new full-peak analysis technique that takes advantage of the manifest amplitude reduction of optical stop bands during vapor condensation. Optical simulation based on a scalar-wave approximation model shows that the predicted optical responses during vapor condensation in colloidal photonic crystals agree well with experimental results. The condensation of vapors between submicrometer-scale microspheres, a topic that has received little examination, has also been investigated by both experiments and theoretical calculations. Predictions based on a modified Kelvin equation match with the experiments for a wide range of vapor partial pressures.


Intestinal B-cell isotype response in relation to local bacterial load: evidence for immunoglobulin A subclass adaptation.
In experimental animals, the indigenous microbiota modulates mucosal immunity. In humans, such direct evidence is scarce. The aim of this study was to examine the effect of intestinal bacteria on the local immunoglobulin (Ig) response. The numbers of IgA-, IgM-, and IgG-producing immunocytes per defined mucosal length unit were determined, and the local IgA subclass response was studied using immunohistochemistry in jejunal segments from adults with bacterial overgrowth and in sterile ileal urinary conduits from children. The ileal bladder mucosa showed atrophy, but the number of immunocytes only tended to be decreased. The jejunal segments with bacterial overgrowth showed minor histological changes; the numbers of IgA and IgG immunocytes were fairly normal, whereas the number of IgM immunocytes was significantly reduced (P < 0.05) (12 cells/U) compared with control mucosa (24 cells/U). The number of IgA2 immunocytes was significantly decreased (P < 0.01) in ileal conduits (7 cells/U or 30% of total IgA) but increased (P < 0.05) in jejunal segments with bacterial overgrowth (42 cells/U or 43% of total IgA) compared with normal ileum (15 cells/U or 40% of total IgA) and jejunum (24 cells/U or 23% of total IgA). An association exists between bacterial load and IgA subclass production. An increase in IgA2 may enhance mucosal protection and probably reflects immunomodulation caused by lipopolysaccharides.


Cry analysis in infants with severe malnutrition.
Sound spectrographic investigations of the cries of 5 infants, age 7 m to 2 y, with severe malnutrition (one with kwashiorkor and four with marasmus) were compared with the cries of 15 healthy children of corresponding age. The cry of the child with kwashiorkor resembled those of the normal infants. The cries of the marasmic children showed a significant increase in the minimum and maximum pitch, and the occurrence of biphonation and flat melody types. These features have also been found in the cries of children with brain damage. We therefore believe that cry and analysis can be an additional means of investigating to what degree the brain is affected in children with malnutrition.


Anti-platelet effects of nimesulide in isoproterenol-induced myocardial ischaemia and infarction in rabbits.
The present study was designed to determine the effects of cyclooxygenase-2 (COX-2) inhibitor-nimesulide on platelet activating factor (PAF) and arachidonic acid (AA)-induced platelet aggregation during myocardial infarction (Ml) and ischaemia in rabbits. Rabbits were divided into three groups; group I served as control and contains normal rabbits that received saline, group II rabbits received saline before induction of Ml, and group Ill rabbits received nimesulide (25 mg/kg) before Ml induction. Myocardial infarction was induced by isoproterenol (ISP) (65 mg/kg) and confirmed by biochemical, electrophysiological and histopathological methods. Platelet aggregation was induced with arachidonic acid (AA) and platelet activating factor (PAF), and monitored by using light transmission aggregometery. When platelets were challenged with two different aggregating agents, nimesulide-treated infarcted rabbits showed resistance to platelet aggregation while non-treated infarcted rabbits were found prone to aggregation with both aggregating agents (P < 0.05). These results suggest platelet inhibitory effects of nimesulide during experimental ischaemia and infarction in rabbits.


Adsorption of polyethyleneimine and polymethacrylic acid onto synthesized hematite.
An influence of different functional groups of polymer, its molecular weight, polydispersity ratio (M(w)/M(n)) and presence of impurities on its adsorption in different pH values (3, 6 and 9) onto synthesized hematite (Fe(2)O(3)) was measured. A structure of adsorbed macromolecules of PMA and PEI was obtained according to S-F theory. Two polymers were used: polymethacrylic acid (PMA) of 6500 and 75,100 molecular weight as well as polyethyleneimine (PEI) 25,000 commercial and fractionated. Electrokinetic properties of the interface oxide-polymer solution (surface charge density and zeta potential) were also measured as well as adsorption layer thicknesses (with use of viscosimetric measurements). Obtained data show, that all above-mentioned factors do influence not only the adsorption process itself but also a surface charge, zeta potential and structure of adsorbed polymer layers on polymer/hematite interface.


Eye movement abnormalities in rod monochromatism and blue-cone monochromatism.
Eye movements were recorded with electro-oculography in seven patients with rod monochromatism (RM) and five with blue-cone monochromatism (BCM). The continuous horizontal nystagmus was similar in both groups. However, three patients with BCM demonstrated an intermittent, high-frequency nystagmus, in addition to the continuous nystagmus. The most striking differences between the groups were present during monocular smooth pursuit and optokinetic tracking. Patients with RM demonstrated better tracking when targets moved in the temporal-to-nasal (T-N) direction in the visual field of the viewing eye, than when targets moved in the nasal-to-temporal (N-T) direction. The velocity of optokinetic nystagmus (OKN) increased gradually over several seconds during T-N target movement. Patients with BCM did not show a directional asymmetry or a slow build-up of OKN during monocular tracking. Differences in eye movement abnormalities can be useful in differentiating these two forms of congenital color blindness from other forms of congenital nystagmus and from each other.


Protein fishing from single live cells.
Intracellular protein and proteomic studies using mass spectrometry, imaging microscopy, flow cytometry, or western blotting techniques require genetic manipulation, cell permeabilization, and/or cell lysis. We present a biophysical method that employs a nanoaspirator to 'fish' native cytoplasmic or nuclear proteins from single mammalian cells, without compromising cell viability, followed by ex cellulo quantitative detection. Our work paves the way for spatiotemporally-controlled, quantitative, live, single-cell proteomics.


The nuclear receptor COUP-TFI represses differentiation of Cajal-Retzius cells.
The cellular diversity of neurons located in the marginal zone (MZ) of the cortex has a crucial role in cortical development. However, little is known about the molecular mechanisms involved in how these different neuronal cell types are specified. Here, we show that in the MZ, the nuclear receptor COUP-TFI is localized in calbindin-positive cells and not in reelin-positive cells. High expression of COUP-TFI has been detected in preplate (PP) and subplate (SP) cells, suggesting that this nuclear receptor is down-regulated during preplate differentiation towards the Cajal-Retzius (CR) cell lineage. By maintaining high ectopic expression of COUP-TFI in preplate cells, we show that COUP-TFI represses the CR cell markers reelin and calretinin, and with lower efficiency the transcription factor Tbr1. Furthermore, general differentiation is not affected, strongly suggesting that COUP-TFI represses differentiation of CR cells.


Comparative Study of Ex Vivo Antiplatelet Activity of Aspirin and Cilostazol in Patients with Diabetes and High Risk of Cardiovascular Disease.
The role of aspirin in primary cardiovascular disease prevention in patients with diabetes remains controversial. However, some studies have suggested beneficial effects of cilostazol on cardiovascular disease in patients with diabetes. We prospectively investigated the antiplatelet effects of cilostazol compared with aspirin in patients with diabetes and cardiovascular risk factors. We randomly assigned 116 patients with type 2 diabetes and cardiovascular risk factors but no evident cardiovascular disease to receive aspirin at a dose of 100 mg or cilostazol at a dose of 200 mg daily for 14 days. The primary efficacy outcome was antiplatelet effects of aspirin and cilostazol assessed with the VerifyNow system (aspirin response units [ARU]) and PFA-100 (closure time [CT]). Secondary outcomes were changes of clinical laboratory data (ClinicalTrials.gov Identifier: NCT02933788). After 14 days, there was greater decrease in ARU in aspirin (-28.9%±9.9%) compared cilostazol (-0.4%±7.1%, P<0.001) and was greater increase in CT in aspirin (99.6%±63.5%) compared cilostazol (25.7%±54.1%, P<0.001). The prevalence of aspirin resistance was 7.5% according to VerifyNow (defined by ARU ≥550) and 18.9% according to PFA-100 (CT <192 seconds). Compared with aspirin, cilostazol treatment was associated with increased high density lipoprotein cholesterol (7.1%±12.7% vs. 4.2%±18.0%, P=0.006) and decreased triglycerides (-9.4%±33.7% vs. 4.4%±17.57%, P=0.016). However, there were no significant changes in total and low density lipoprotein cholesterol, C-reactive protein level, and cluster of differentiation 40 ligand between cilostazol and aspirin groups. Aspirin showed better antiplatelet effects assessed with VerifyNow and PFA-100 compared with cilostazol. However, there were favorable changes in atherogenic dyslipidemia only in the cilostazol.


Angiotensin II receptor antagonist reduces subsequent uterine arterial dysfunction in pregnant offspring of protein-restricted rat dams.
A low-protein diet (LPD) during pregnancy induces vascular dysfunction and hypertension in the offspring, prevented by administration of an angiotensin II type 1 (AT(1)) receptor antagonist in early life to the offspring. Whether such protection extends to subsequent pregnancy is unknown; we therefore hypothesized that administration of a specific AT(1) receptor antagonist (losartan) in early life to offspring of LPD dams would improve vascular dysfunction in their uterine arteries when they, in turn, were pregnant. Pregnant rats were randomly divided into two dietary groups fed a control (C) or protein-restricted (R) diet throughout pregnancy. Between two and 10 weeks postnatally, female offspring (F(1)) were randomly assigned to drink either pure tap water (CO, RO) or water with losartan (CL, RL). Offspring were mated and killed on gestational day 19 or 20 in order to investigate uterine artery function. In pregnant offspring, vasoconstriction of the uterine arteries to phenylephrine (PE) and the thromboxane A2 mimetic U46619 was greater in RO than CO (F(1)). Responses to both antagonists were suppressed in RL (F(1)). Relaxation to sodium nitroprusside was increased in RO versus CO and suppressed in RL versus RO (F(1)). Administration of an AT(1) receptor antagonist to offspring during the suckling and juvenile period improves the uterine vascular dysfunction in pregnancy induced by prior maternal LPD during their development. Such treatment may contribute to decreasing the transmitted risks of maternal malnutrition from offspring to the subsequent generation.


Stimulus selection and tracking during urination: autoshaping directed behavior with toilet targets.
A simple procedure is described for investigating stimuli selected as targets during urination in the commode. Ten normal males preferred a floating target that could be tracked to a series of stationary targets. This technique was used to bring misdirected urinations in a severely retarded male under rapid stimulus control of a floating target in the commode. The float stimulus was also evaluated with nine institionalized, moderately retarded males and results indicated rapid autoshaping of directed urination without the use of verbal instructions or conventional toilet training. The technique can be applied in training children to control misdirected urinations in institution for the retarded, in psychiatric wards with regressed populations, and in certain male school dormitories.


Limits of myocardial protection with potassium cardioplegia.
Preservation of left ventricular function with various potassium-based cardioplegic solutions has been considered to be effective for at least 60 minutes during occlusion of the ascending aorta. The purpose of this study was to define the limits of protection offered by potassium alone. A single bolus of 150 ml of potassium (24 mEq per liter) in normal saline solution at 30 degrees C was injected in the aortic roots of foxhounds at the initiation of periods of 45 minutes, 60 minutes, and 75 minutes of aortic occlusion at a core temperature of 30 degrees C. Data derived from postischemic recovery phase ventricular function curves and force-velocity relations demonstrated excellent protection during 45 minutes of ischemia, inconsistent protection at 60 minutes, and poor protection at 75 minutes.


Possible applications of digital analysis of ultrasonic images of the placenta.
Analysis of the digitised ultrasonic images of in vivo placentae at 15-18 weeks gestation has revealed various textural differences. These have been correlated with smoking, visual appearance and the subsequent development of hypertension. The total number of patients included in this study was 98, of which 70 had images suitable for analysis. There were no significant textural differences between the images of the placentae of smokers and non-smokers nor did the spatially dependent co-occurrence matrices correlate with visual appearance. Textural differences were however detected when the placentae of the normotensive group were compared to those of patients who subsequently developed hypertension (latent hypertension) in the third trimester of pregnancy (p less than 0.05 Mann Whitney 'U' test).


Construction, characterization and immunogenicity of a glycoprotein E negative bovine herpesvirus-1.1 Egyptian strain "Abu-Hammad".
A full glycoprotein E (gE) deletion was generated in genome of the Egyptian BoHV-1.1 Abu-Hammad strain. Integrity of the gE negative (gE(-)) mutant virus was proved by successful specific PCR amplifications of gB, gC, tk, gD, gI and gE genes along with definite immune reaction to polyclonal anti-BoHV-1 antibody in infected cell culture. BoHV-1 gE(-) mutant exhibited growth kinetics inferior to those of the parental virus manifested as lower virus titers with delayed and poorer cytopathic effect in infected cells. Adjuvanted vaccines were made of the gE(-) mutant, live and killed; besides a conventional killed vaccine made of the parental virus and were used to immunize separate groups of calves. After i.m. vaccinations, no virus shedding could be detected in nasal swabs collected from all vaccinates and all calves remained apparently healthy. They all seroconverted to BoHV-1 as was revealed by virus neutralization test and a gB enzyme-linked immunosorbent assay (ELISA). Calves vaccinated with live and killed gE(-) vaccines did not elicit any detectable anti-gE antibody as shown by a blocking gE-ELISA. In conclusion, the constructed BoHV-1.1 gE(-) mutant was proved as safe and immunogenic as a reliable candidate for inclusion in a local marker vaccine.


Stress induces rapid changes in central catecholaminergic activity in Anolis carolinensis: restraint and forced physical activity.
Immobilization stress and physical activity separately influence monoaminergic function. In addition, it appears that stress and locomotion reciprocally modulate neuroendocrine responses, with forced exercise ameliorating stress-induced serotonergic activity in lizards. To investigate the interaction of forced physical activity and restraint stress on central dopamine (DA), norepinephrine (NE), and epinephrine (Epi), we measured these catecholamines and their metabolites in select brain regions of stressed and exercised male Anolis carolinensis lizards. Animals were handled briefly to elicit restraint stress, with some lizards additionally forced to run on a track until exhaustion, or half that time (50% of average time to exhaustion), compared to a control group that experienced no restraint or exercise. Norepinephrine concentrations in the hippocampus and locus ceruleus decreased with restraint stress, but returned to control levels following forced exhaustion. Levels of NE in the raphé nuclei and area postrema, and epinephrine in raphé became elevated following restraint stress, and returned to control levels following forced physical activity to 50% or 100% exhaustion. Striatal DA increased as animals were exercised to 50% of exhaustion, and returned to baseline with exhaustion. At exhaustion, striatal Epi levels were diminished, compared with controls. In the area postrema, exhaustion reversed a decline in epinephrine levels that followed forced physical activity. These results suggest that stress stimulates a rapid influence on central catecholamines. In addition, forced exercise, and even exhaustion, may alleviate the effects of restraint stress on central monoamines.


Home Biofeedback Versus Physical Therapy for Stress Urinary Incontinence: A Randomized Trial.
The aim of the study was to assess whether home biofeedback is noninferior to supervised pelvic floor physical therapy (PFPT) for the treatment of stress urinary incontinence (SUI) in women. The study used a randomized controlled noninferiority trial to compare a home biofeedback device with PFPT. Women older than 18 years with SUI and no history of a prior incontinence surgery or PFPT were eligible. Forty-two participants were required to determine noninferiority for the primary outcome, improvement in quality of life as measured by the International Consultation on Incontinence Questionnaire Short Form. The noninferiority margin was 4 points. Secondary outcomes included sexual function, overactive bladder symptoms, and patient impression of improvement. From June 2018 to October 2019, 54 women with SUI were recruited (27 biofeedback, 27 PFPT) and 43 (21 biofeedback, 22 PFPT) completed follow-up. The groups had comparable baseline characteristics. For the primary outcome of change in mean International Consultation on Incontinence Questionnaire-Short Form scores (where lower scores indicate less incontinence), home biofeedback was found to be noninferior to PFPT with a mean decrease from baseline of -3.95 (95% confidence interval [CI] = -2.21 to -5.70) in the home biofeedback group versus -4.73 (95% CI = -3.21 to -6.25) and -3.95 (95% CI = -2.21 to -5.70) in the PFPT group (P = 0.009). The PFPT group showed more improvement in overactive bladder symptoms, but not in incontinence severity without difference in sexual function. Home biofeedback was noninferior to PFPT for the primary treatment of SUI in women at 3 months. These results support the use of personal biofeedback devices for the treatment of SUI.Clinical Trial Registration: ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT03443687.


E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer.
Deregulation of E2F1 activity and resistance to TGFbeta are hallmarks of gastric cancer. MicroRNAs (miRNAs) are small noncoding RNAs frequently misregulated in human malignancies. Here we provide evidence that the miR-106b-25 cluster, upregulated in a subset of human gastric tumors, is activated by E2F1 in parallel with its host gene, Mcm7. In turn, miR-106b and miR-93 regulate E2F1 expression, establishing a miRNA-directed negative feedback loop. Furthermore, upregulation of these miRNAs impairs the TGFbeta tumor suppressor pathway, interfering with the expression of CDKN1A (p21(Waf1/Cip1)) and BCL2L11 (Bim). Together, these results suggest that the miR-106b-25 cluster is involved in E2F1 posttranscriptional regulation and may play a key role in the development of TGFbeta resistance in gastric cancer.


Functional interactions between 7TM receptors in the renin-angiotensin system--dimerization or crosstalk?
The Renin-Angiotensin System (RAS) is important for the regulation of cardiovascular physiology, where it controls blood pressure, and salt- and water homeostasis. Dysregulation of RAS can lead to severe diseases including hypertension, diabetic nephropathy, and cardiac arrhythmia, and -failure. The importance of the RAS is clearly emphasised by the widespread use of drugs targeting this system in clinical practice. These include, renin inhibitors, angiotensin II receptor type I blockers, and inhibitors of the angiotensin converting enzyme. Some of the important effectors within the system are 7 transmembrane (7TM) receptors (or G-protein-coupled receptors) such as the angiotensin II Receptors type I and II (AT1R and AT2R) and the MAS-oncogene receptor. Several findings indicate that the 7TM receptors can form both homo- and heterodimers, or higher orders of oligomers. Furthermore, dimerization may be important for receptor function, and in the development of cardiovascular diseases. This is very significant, since "dimers" may provide pharmacologists with novel targets for improved drug therapy. However, we know that 7TM receptors can mediate signals as monomeric units, and so far it has been very difficult to establish if our observations reflect actual well-defined dimerization or merely reflect close proximity between the receptors and/or various types of functional interaction. In this review, we will present and critically discuss the current data on 7TM receptor dimerization with a clear focus on the RAS, and delineate future challenges within the field.


A yeast and a human CCAAT-binding protein have heterologous subunits that are functionally interchangeable.
The S. cerevisiae HAP2 and HAP3 gene products have been shown to recognize CCAAT-containing transcription elements as a HAP2/HAP3 multisubunit heterologous complex, or heteromer. Recently, we have demonstrated that the human sequence-specific DNA-binding protein, CP1, also recognizes CCAAT-containing transcription elements as a heteromer. Mammalian cells contain at least three distinct CCAAT-binding proteins, all of which appear to be multisubunit complexes composed of heterologous subunits. One of these proteins, CP1, has DNA-binding properties that are virtually identical to the yeast HAP2/HAP3 complex. These two proteins bind to the same target sequences, make the same DNA contacts, and are affected in a similar manner by mutations in the CCAAT element. Most surprisingly, the subunits of CP1 and HAP2/HAP3 are functionally interchangeable. That is, the yeast/human hybrid complexes that are formed retain the ability to specifically recognize CCAAT elements.


Acute, single, intravenous doses of cibenzoline: an evaluation of safety, tolerance, and hemodynamic effects.
Cibenzoline is a new antiarrhythmic agent with predominant Vaughan-Williams type 1 properties. The safety, tolerance, and adverse effects of incremental single intravenous doses of this agent were investigated. A total of 28 patients received incremental doses of 0.25 mg/kg (four patients), 0.5 mg/kg (five patients), 0.75 mg/kg (seven patients), 1.0 mg/kg (six patients), or 1.2 mg/kg (six patients) cibenzoline. Another six patients received 2.0 mg/kg disopyramide. Left ventricular function by radionuclide ventriculography and plasma cibenzoline levels were measured at frequent intervals. In the patients who received 1.0 mg/kg and 1.2 mg/kg cibenzoline or patients who received 2.0 mg/kg disopyramide, right and left ventricular filling pressures and cardiac output were measured with a Swan-Ganz catheter. At low-dose cibenzoline (0.25 to 0.75 mg/kg) there was a modest drop in ejection fraction (60% +/- 7% to 53% +/- 7%). With the higher doses of cibenzoline (1.0 or 1.2 mg/kg) there was a more profound fall in ejection fraction (69% +/- 8% to 49% +/- 8%) that persisted for approximately 2 hours. This was associated with a rise in end diastolic volume index (74 +/- 24 to 85 +/- 27 ml/m2) and end systolic volume index (29 +/- 15 to 43 +/- 18 ml/m2) and a fall in cardiac index (2.65 +/- 0.62 to 2.14 +/- 0.24 L/min/m2).(ABSTRACT TRUNCATED AT 250 WORDS)


The effect of long-term oestrogen treatment on the development of osteoarthrosis at the small hand joints.
The effect of long-term oestrogen treatment of at least 5 yr on the development of osteoarthrosis was studied in 48 postmenopausal women. Osteoarthrosis at the hand joints was graded according to Kellgren's criteria, using hand X-rays. Data obtained in a normal population of 155 women served as controls as well as data obtained in 24 postmenopausal women who didnot receive oestrogen replacement therapy. No significant difference in osteoarthrosis between the treated and non-treated groups was found. The development of osteoarthrosis at the hand joints seems to be independent of the hormonal status in postmenopausal women.


Analysis of in-hospital mortality among people with and without diabetes in South Western Sydney public hospitals (2014-2017).
Diabetes is a major public health problem affecting about 1.4 million Australians, especially in South Western Sydney, a hotspot of diabetes with higher than average rates for hospitalisations. The current understanding of the international burden of diabetes and related complications is poor and data on hospital outcomes and/or what common factors influence mortality rate in people with and without diabetes in Australia using a representative sample is lacking. This study determined in-hospital mortality rate and the factors associated among people with and without diabetes. Retrospective data for 554,421 adult inpatients was extracted from the population-based New South Wales (NSW) Admitted Patient Data over 3 financial years (from 1 July 2014-30 June 2015 to 1 July 2016-30 June 2017). The in-hospital mortality per 1000 admitted persons, standardised mortality ratios (SMR) were calculated. Binary logistic regression was performed, adjusting for potential covariates and co-morbidities for people with and without diabetes over three years. Over three years, 8.7% (48,038 people) of admissions involved people with diabetes. This increased from 8.4% in 2014-15 to 8.9% in 2016-17 (p = 0.007). Across all age groups, in-hospital mortality rate was significantly greater in people with diabetes (20.6, 95% Confidence intervals CI 19.3-21.9 per 1000 persons) than those without diabetes (11.8, 95%CI 11.5-12.1) and more in men than women (23.1, 95%CI 21.2-25.0 vs 17.9, 95%CI 16.2-19.8) with diabetes. The SMR for those with and without diabetes were 3.13 (95%CI 1.78-4.48) and 1.79 (95%CI 0.77-2.82), respectively. There were similarities in the factors associated with in hospital mortality in both groups including: older age (> 54 years), male sex, marital status (divorced/widowed), length of stay in hospital (staying longer than 4 days), receiving intensive care in admission and being admitted due to primary respiratory and cardiovascular diagnoses. The odds of death in admission was increased in polymorbid patients without diabetes (28.68, 95%CI 23.49-35.02) but not in those with diabetes. In-patients with diabetes continue to have higher mortality rates than those without diabetes and the Australian population. Overall, similar factors influenced mortality rate in people with and without diabetes, but significantly more people with diabetes had two or more co-morbidities, suggesting that hospital mortality may be driven by those with pre-existing health/comorbidities. Urgent measures in primary care to prevent admissions among people with multiple co-morbidities are needed.


Effect of bile acids on fibroblast proliferation and viability.
To examine the in vitro effects of bile acids and salts on the viability, growth and morphology of human Tenon's capsule fibroblasts. Human Tenon's capsule fibroblasts were grown from explants in culture and used between passages 3 and 5. Fibroblasts (n = 3) were treated in triplicate with deoxycholic acid (DA), sodium deoxycholate (NaD) and cholic acid (CA) at concentrations between 50 microM and 1 mM. Cell viability and growth were assessed with trypan blue staining and haemocytometer counting, and a colorimetric (MTT) assay. Morphology was assessed with light microscopy and cresyl violet staining. A dose-dependent decrease in viability was observed following bile acid treatment (24 and 48 h) where the effects of DA > NaD > CA. The LD50 values at 48 h for DA, NaD and CA were 300 microM, 400 microM and 720 microM respectively. Cell growth following bile acid treatment was reduced compared with controls. Fibroblasts treated with bile acids displayed a loss of normal spindle-shaped morphology and multiple processes, some with varicosities, extended from many cells. These changes were dose-dependent, and at higher concentrations cells became detached and were non-viable (trypan-blue-positive). Extensive cell death was observed in cultures treated with DA 400 microM, NaD 500 microM and CA 800 microM. Lower doses of bile acids and salts reduced in vitro fibroblast growth associated with morphological changes; higher doses induced fibroblast cytotoxicity. These observations suggest that bile acids and salts, in particular DA, may be useful in regulating wound fibrosis following trabeculectomy surgery.


Influence of the sympathetic nervous system in the development of abnormal pain-related behaviours in a rat model of neuropathic pain.
This study evaluated the effect of surgical sympathectomy on pain-related behaviours in a well established model of peripheral mononeuropathy produced by loose ligatures around the common sciatic nerve in the rat. Behavioural abnormalities include spontaneous abnormal position of the hindpaw after the nerve constriction, indicative of "spontaneous pain", and changes in responses to mechanical or thermal stimuli applied to this paw. These changes are usually maximal at week 2 after the surgery, stable until weeks 3-4, and disappear between weeks 8 and 12. To assess the role of the sympathetic nervous system in the development and persistence of these abnormalities, four groups of rats were behaviourally tested: (i) rats receiving a complete sham surgery, (ii) rats with a sciatic nerve constriction produced by loose ligatures around the common nerve trunk plus a sham sympathectomy, (iii) rats receiving a lumbar sympathectomy with a sham nerve ligature, and (iv) rats receiving a simultaneous surgical lumbar sympathectomy and a sciatic nerve constriction. The efficacy of the sympathectomy was assessed by the measure of the noradrenaline level in the sciatic nerve. Sympathectomy reduced selectively or even prevented the abnormal reaction to cold temperature and to heat (45 degrees C) in rats with a peripheral mononeuropathy. In contrast, the abnormal reaction to mechanical pressure was not influenced, and the behavioural abnormalities indicating spontaneous pain were still present. Sympathectomy alone resulted in a reduction of the vocalization threshold to pressure on both hindpaws, but also a short-lasting increased tolerance to cold immersion. This study confirms the selective role of the sympathetic nervous system in affecting the development and maintenance of some abnormal pain-related behaviours to thermal stimuli in rats with a moderate, but persistent, constriction of one sciatic nerve.


Green and facile synthesis of Ag nanoparticles using Crataegus pentagyna fruit extract (CP-AgNPs) for organic pollution dyes degradation and antibacterial application.
In this work, a cost-effective/green/high-efficient/facile process for the preparation of silver nanoparticles using C. pentagyna (CP-AgNPs) fruit extractas as reducing agent and capping agent was reported. The influence of different parameters including temperature, pH, concentration and time were studied to reach optimum conditions. The as-synthesized CP-AgNPs were characterized using UV/Vis, XRD, SEM, TEM, EDS and DLS analysis. Regular, spherical morphology and homogeneous of CP-AgNPs with a mean particles size of 25-45 nm was determined from TEM images. The CP-AgNPs in presence of sunlight catalyzed the degradation of the organic contaminant dyes, rhodmine b (RhB), eosin (EY) and methylene blue (MB) with percent degradation of 85% and 70% and 78%, respectively. In addition, CP-AgNPs exhibit antibacterial activities against seven ATCC strains of bacteria and eight strains of drug-resistant bacteria. Due to the results, CP-AgNPs enhanced antimicrobial potential against S. aureus, E. faecalis, P. aeruginosa, A. baumannii and E. coli with MIC and MBC of (0.11, 7.1 µg/ml), (0.11, 1.7 µg/ml), (0.11, 0.22 µg/ml), (0.11, 0.22) and (0.11, 0.44 µg/ml), respectively. Generally, CP-AgNPs have excellent potential application for the photocatalytic degradation of organic pollutant and in the development of antibacterial materials.


Value of Endoscopic Visualization During the Sling-Transposition Technique for Microvascular Decompression of the Facial Nerve in a Case with Hemifacial Spasm.
Endoscopic visualization during microvascular decompression for hemifacial spasm enables better identification of compression areas along the facial nerve, which is especially important in cases with complex compression and enlarged vessels obscuring the compression site. A 40-year-old man presented with a 10-year history of left hemifacial spasm. Magnetic resonance imaging showed a deep compression site with multiple vessels. Within the narrow space, the compression area was clearly visualized using an angled endoscope. Arterial transposition was performed using a polytetrafluoroethylene (Teflon) sling, which was fixed to the nearby dura using an aneurysm clip. Decompression was visually confirmed using the angled endoscope. The patient was free of spasms directly after surgery with no further complications and no recurrence of spasm during 6-month follow-up (Video 1).


Efficacy, Safety, and Immunogenicity of Biosimilar Insulin Aspart Premix SAR341402 Mix 70/30 Compared with Originator Insulin Aspart Mix 70/30 in Adults with Diabetes (GEMELLI M): A Subgroup Analysis by Prior Type of Premix Insulin.
We compared the efficacy, safety, and immunogenicity of biosimilar insulin aspart premix SAR341402 Mix 70/30 (70% intermediate SAR341402 protamine and 30% rapid SAR341402 solution) (SARAsp-Mix) with its originator NovoMix 30 insulin aspart mix (NN-Mix) in adults with type 1 or type 2 diabetes switching from different premix insulin analogs. This phase 3, randomized, open-label, multinational, 26-week trial (GEMELLI M) enrolled 402 participants with type 1 or type 2 diabetes. At randomization, participants switched from their prestudy premix insulin NovoMix 30 (n = 341) or Humalog Mix 25/Liprolog Mix 25 (n = 61) to equivalent (1:1) doses of either SARAsp-Mix or NN-Mix at least twice daily (1:1 randomization). In this subgroup analysis, efficacy measures [change in hemoglobin A1c (HbA1c), daily insulin dose], and safety outcomes [hypoglycemia incidence, adverse events (including hypersensitivity and injection site reactions), anti-insulin aspart antibodies] of SARAsp-Mix were compared with those of NN-Mix separately according to the participants' prestudy premix insulin. At week 26, change from baseline in HbA1c (primary efficacy endpoint) was similar between SARAsp-Mix and NN-Mix in those participants pretreated with NovoMix 30 [least squares (LS) mean difference 0.05%, 95% confidence interval (CI) -0.195% to 0.289%] or Humalog Mix 25/Liprolog Mix 25 (LS mean difference 0.28%, 95% CI -0.279% to 0.830%) (P value for treatment-by-subgroup interaction = 0.46). In both subgroups, safety outcomes, including immunogenicity, and changes in daily insulin doses were similar between treatments over 26 weeks. Efficacy, safety, and immunogenicity profiles of SARAsp-Mix are similar to NN-Mix over 26 weeks in adults with diabetes irrespective of prior type of premix insulin. EudraCT number 2017-000092-84.


Pathophysiology of hypopituitarism in the setting of brain injury.
The complex pathophysiology of traumatic brain injury (TBI) involves not only the primary mechanical event but also secondary insults such as hypotension, hypoxia, raised intracranial pressure and changes in cerebral blood flow and metabolism. It is increasingly evident that these initial insults as well as transient events and treatments during the early injury phase can impact hypothalamic-pituitary function both acutely and chronically after injury. In turn, untreated pituitary hormonal dysfunction itself can further hinder recovery from brain injury. Secondary adrenal insufficiency, although typically reversible, occurs in up to 50% of intubated TBI victims and is associated with lower systemic blood pressure. Chronic anterior hypopituitarism, although reversible in some patients, persists in 25-40% of moderate and severe TBI survivors and likely contributes to long-term neurobehavioral and quality of life impairment. While the rates and risk factors of acute and chronic pituitary dysfunction have been documented for moderate and severe TBI victims in numerous recent studies, the pathophysiology remains ill-defined. Herein we discuss the hypotheses and available data concerning hypothalamic-pituitary vulnerability in the setting of head injury. Four possible pathophysiological mechanisms are considered: (1) the primary brain injury event, (2) secondary brain insults, (3) the stress of critical illness and (4) medication effects. Although each of these factors appears to be important in determining which hormonal axes are affected, the severity of dysfunction, their time course and possible reversibility, this process remains incompletely understood.


Surgical margin status of open versus laparoscopic radical prostatectomy specimens.
To compare the surgical margin (SM) status between open and laparoscopic radical prostatectomy (RRP and LRP, respectively) specimens. Surgical specimens from 137 patients undergoing LRP and 220 patients undergoing RRP for clinically localized prostate cancer were included in the analysis. SM status in each resected specimen, including the number of positive SM as well as their location, was examined. The incidence of positive SM in the LRP group was significantly greater than that in the RRP group. Despite the lack of significant difference in the proportion of solitary positive SM between these two groups, the proportion of multiple positive SM in the LRP group was significantly greater than that in the RRP group. There was no significant difference in the incidence of anterior positive SM between the two groups, while the incidences of positive SM at the apex, posterior site and bladder neck in the LRP group were significantly greater than those in the RRP group. Furthermore, there were no significant preoperative parameters predicting positive SM in the LRP group. On the other hand, the biopsy Gleason score and clinical T stage were identified as significant predictors of positive SM in the RRP group, of which the biopsy Gleason score was independently related to the presence of positive SM. Clinical T stage and Gleason score could be useful predictors of SM status following RRP, while positive SM in LRP specimens were detected irrespective of preoperative parameters, suggesting the need for an effort for further refining the LRP procedure.


Dimensions of human ejaculated spermatozoa in Papanicolaou-stained seminal and swim-up smears obtained from the Integrated Semen Analysis System (ISAS(®)).
Objective measurements are required for computer-aided sperm morphometric analysis (CASMA) machines to distinguish normal from abnormal sperm heads. The morphometric characteristics of spermatozoa in 72 samples of semen and of spermatozoa from 72 other semen samples after swim-up were quantified by the semi-automated Integrated Sperm Analysis System (ISAS) computer-aided system, which measured the sperm head parameters length (L), width (W), area (A), perimeter (P), acrosomal area (Ac), and the derived values L/W and P/A. For each man a homogeneous population of distributions characterized seminal spermatozoa (7 942 cells: median values L 4.4 μm, W 2.8 μm, A 9.8 μm(2), P 12.5 μm, Ac 47.5%, L/W 1.57, P/A 1.27), and there was no significant difference in within- and among-individual variation. Different men could have spermatozoa of significantly different dimensions. Head dimensions for swim-up spermatozoa from different men (4 812 cells) were similar to those in semen, differing only by 2%-5%. The values of L, W and L/W fell within the limits given by the World Health Organization (WHO). Although these samples were not biologically matched, linear mixed-effects statistical analyses permitted valid comparison of the groups. A subpopulation of 404 spermatozoa considered to fit the stringent criteria of WHO 'normal' seminal spermatozoa from both semen and swim-up were characterized by median values (and 95% confidence intervals) of L, 4.3 μm (3.8-4.9), W, 2.9 μm (2.6-3.3), A, 10.2 μm(2) (8.5-12.2), P, 12.4 μm (11.3-13.9), Ac, 49% (36-60), L/W, 1.49 (1.32-1.67) and P/A, 1.22 (1.11-1.35). These median values fall within the 95th centile confidence limits given by WHO, but the confidence intervals for L and W were larger. Although these differences in head dimensions among men and after swim-up could be detected by CASMA, the small differences make it unlikely that technicians would be able to distinguish them. The values could be used as default sperm head values for the CASMA machine used here.


Hyperemic response of intracoronary contrast agents during two-dimensional echographic delineation of regional myocardium.
Several intracoronary echo contrast agents that provided satisfactory regional myocardial delineation with two-dimensional echocardiography were compared in 15 dogs and their effects on coronary blood flow were examined. Reproducible delineation of myocardium subserved from the intracoronary echo contrast injection site was achieved with hand-agitated agents containing greater than or equal to 30% Renografin, greater than or equal to 30% glucose, greater than or equal to 30% sucrose or 6% dextran. After a 2 cc injection of the echo contrast agent, peak hyperemic augmentation of coronary flow was 56.7 +/- 54.4% for 6% dextran, 116.0 +/- 71.1% for 30% Renografin, 119.3 +/- 47.8% for 30% sucrose, 173.8 +/- 38.3% for 30% glucose. Although, 6% dextran resulted in the lowest and shortest hyperemic response of the four agents, computer-derived echo contrast appearance-disappearance analysis indicated a prolonged myocardial contrast decay half-life (21.0 seconds). On the other hand, 30% Renografin had a more rapid myocardial echo contrast washout (T 1/2 = 15.5 seconds), but a significantly greater hyperemic effect was observed. It is concluded that development of echo contrast agents for myocardial contrast two-dimensional echocardiographic assessment of myocardial perfusion will require consideration of alterations in coronary flow due to contrast-induced hyperemia.


Anaphylactic shock induced by polyethylene glycol after bowel preparation for the colorectal cancer surgery: A case report.
Polyethylene glycol (PEG) is widely used as an additive because of its hydrophilic and chemically inert properties. However, there are been increasing reports of PEG allergies, including anaphylaxis, although they are still rare. This case report aims to raise awareness, that the commonly used bowel cleansing agent containing PEG can cause serious allergic reactions. Prior to surgery for sigmoid colon cancer, a 63-year-old man was prescribed a bowel cleansing agent containing PEG. Within 30 min of ingestion, he developed symptoms of anaphylactic shock and did not respond to initial intramuscular epinephrine injection. Under diagnosis of anaphylaxis to PEG, he was stabilized with fluid hydration and continuous norepinephrine infusion. While allergic reactions to PEG are rare, they can be life-threatening. Therefore, it is crucial for clinicians to be aware of this possibility and to diagnose and resuscitate patients immediately.


The neuronal basis of the anesthetic state: a comparative physiological approach. II. The influence of anesthetics on various reactions in flies.
The sensitivity of specific neuronal pathways to Halothane and N2O has been investigated in flies. The effects were tested by monitoring the responses of photoreceptors and their second order neurons, as well as two behavioral responses--a leg reflex induced by light flashes and head movements induced by moving optical patterns--chosen because their neuronal substrates are fairly well known. Sensitivity to both agents rises with the length of dendrites and the number of input synapses of the neurons involved. The findings confirms the hypothesis, formulated in Part I of this paper, that neurons with long dendrites and/or axonal endings and large numbers of input synapses are the elements in the central nervous system with the highest sensitivity to anesthetic action. Under physiological conditions this kind of neuron is capable of "gain-control": the relationship between input and output is modified according to functional requirements. Possible molecular mechanisms leading to functional impairment under anesthesia are discussed.


Effect of an enterally administered glutamine-rich protein on the catabolic response to a zymosan challenge in rats.
Glutamine is considered to be a conditionally essential amino acid during critical illness and has, therefore, been advocated to be included in nutritional support supplied in these situations. We investigated whether a diet containing a protein source rich in glutamine can restore depleted glutamine pools (plasma and muscle) and counteract muscle wasting, in a rat model of critical illness (intraperitoneal injection of zymosan). A glutamine-rich protein source was obtained by mixing a wheat protein hydrolysate (25% glutamine) with a whey protein isolate (to prevent essential amino acid deficiency). Feeding healthy control rats for 2 weeks with an adequate diet containing this protein source increased the two main glutamine pools (plasma and muscle). However, no effect was observed on the following zymosan-induced changes: 1) decreased glutamine and arginine concentrations (plasma and muscle), 2) wasting of muscle protein, and 3) decreased mitochondrial content in skeletal muscle. We conclude that a diet containing a glutamine-rich protein source can be used to increase plasma and muscle glutamine concentrations in healthy rats, but is of limited value to counteract wasting of skeletal muscle in zymosan-treated rats.


Analysis of predictors of adherent perinephric fat and its impact on perioperative outcomes in laparoscopic partial nephrectomy: a retrospective case-control study.
Adherent perinephric fat (APF), characterized by inflammatory fat surrounding the kidney, can limit the isolation of renal tumors and increase the operative difficulty in laparoscopic partial nephrectomy (LPN). The aim of this study was to investigate the predictors of APF and its impact on perioperative outcomes during LPN. A total of 215 consecutive patients undergoing LPN for renal cell carcinoma (RCC) from January 2017 to June 2019 at our institute were included. We divided these patients into two groups according to the presence of APF. Radiographic data were retrospectively collected from preoperative cross-sectional imaging. The perioperative clinical parameters were compared between the two groups. Univariate and multivariate analyses were performed to evaluate the predictive factors of APF. APF was identified in 41 patients (19.1%) at the time of LPN. Univariate analysis demonstrated that APF was significantly correlated with the male gender (P = 0.001), higher body mass index (P = 0.002), lower preoperative estimated glomerular filtration rate (P = 0.004), greater posterior perinephric fat thickness (P < 0.001), greater perinephric stranding (P < 0.001), and higher Mayo Adhesive Probability (MAP) score (P < 0.001). The MAP score (P < 0.001) was the only variable that remained an independent predictor for APF in multivariate analysis. We found that patients with APF had longer operative times (P < 0.001), warm ischemia times (P = 0.001), and greater estimated blood loss (P = 0.003) than those without APF. However, there were no significant differences in surgical approach, transfusion rate, length of postoperative stay, complication rate, or surgical margin between the two groups. Several specific clinical and radiographic factors including the MAP score can predict APF. The presence of APF is associated with an increased operative time, warm ischemia time, and greater estimated blood loss but has no impact on other perioperative outcomes in LPN.


Emerging roles of circRNAs in mice kidney with aging.
Circular RNA (circRNA) is a novel type of noncoding RNA expressed in different tissues and species. Up to now, little is known of the function and expression of circRNAs in kidney aging. In this research, we used RNA sequencing to identify 11,929 circRNAs in kidney from 3-, 12-, and 24-month-old mice, of which 12 circRNAs were validated by qPCR. Based on the validated circRNAs and their predicted miRNA-mRNA target pairs, a circRNA-miRNA-mRNA interactions network was conducted. Bioinformatics analysis for all the mRNAs in the ceRNA network showed that the most enriched gene ontology (GO) term and one of the most enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were associated with endoplasmic reticulum (ER). The network also identified circNpas2, which was decreased significantly in mice kidney during aging, as a hub gene. Subsequently, we found that the cell cycle was arrested in G1 phase and the expression of P53 and P16 increased significantly in the circNpas2-knockdown cells. Moreover, knockdown of circNpas2 inhibited expression of ER-related proteins, HSPA5 and ERO1L. Taken together, our findings contribute to a better understanding of the role played by circRNA during kidney aging and provide potential therapeutic targets for the prevention of kidney aging. RESEARCH HIGHLIGHTS: This study is the first to systematically analyze the dysregulated circRNAs and ceRNA network during renal aging. The dysregulated circRNAs during renal aging are most enriched in ER stress-related pathway. CircNpas2 regulates senescence in TCMK-1.


A comprehensive review on Brigatinib - A wonder drug for targeted cancer therapy in non-small cell lung cancer.
The mortality rate in patients suffering from non-small cell lung cancer (NSCLC) is quite high. This type of cancer mainly occurs due to rearrangements in the anaplastic lymphoma kinase (ALK) gene which leads to form an oncogene of fused gene NPM-ALK. Brigatinib is recently approved by FDA in April 2017 as a potent tyrosine kinase inhibitor (TKI) for the NSCLC therapy. In the present scenario, it is no less than a wonder drug because it is indicated for the treatment of advanced stages of metastatic ALK positive NSCLC, a fatal disease to overcome the resistance of various other ALK inhibitors such as crizotinib, ceritinib and alectinib. In addition to ALK, it is also active against multiple types of kinases such as ROS1, Insulin like growth factor-1Receptor and EGFR. It can be synthesized by using N-[2-methoxy-4-[4-(dimethylamino) piperidin-1-yl] aniline] guanidine and 2,4,5-trichloropyrimidine respectively in two different ways. Its structure consists of mainly dimethylphosphine oxide group which is responsible for its pharmacological activity. It is active against various cell lines such as HCC78, H2228, H23, H358, H838, U937, HepG2 and Karpas- 299. Results of ALTA (ALK in Lung Cancer Trial of AP26113) phase ½ trial shows that 90 mg of brigatinib for 7 days and then 180 mg for next days is effective in the treatment of NSCLC. Brigatinib has been shown to have favorable risk benefit profile and is a safer drug than the available cytotoxic chemotherapeutic agents. In comparison to other FDA approved drugs for the same condition, it causes fewer minor adverse reactions which can be easily managed either by changing the dose or by providing good supportive care. This article is intended to provide readers with an overview of chemistry, pharmacokinetic, pharmacodynamic and safety profile of brigatinib, which addresses an unmet medical need.


Comparison of the steady-state pharmacokinetics of nefazodone after administration of 200 mg twice daily or 400 mg once daily in the morning or evening.
1. The steady-state pharmacokinetics of nefazodone, an antidepressant drug with non-linear pharmacokinetics, were determined in a multiple-dose, three-period crossover study in 24 male volunteers to evaluate whether administration of the same total daily dose of nefazodone by different dosing schedules has an effect on systemic exposure to the drug and its metabolites. 2. Three treatments administered were: a 400 mg dose once daily in the a.m. (treatment 1) or in the p.m. (treatment 2) for 5 days or a 200 mg twice daily (every 12 h, a.m. and p.m.) dose daily for 7 days (treatment 3). Prior to the administration of the 400 mg once daily dose, the subjects were administered 200 mg nefazodone once daily (a.m. or p.m.) for 2 days. There was a 7 day washout between treatments. 3. Serial blood samples were collected up to 72 h post dose for treatment 1 and treatment 2 and up to 84 h post a.m. dose for treatment 3 on day 7 for determination of pharmacokinetic parameters. Blood samples for trough (Cmin) plasma concentrations were also obtained on days 5, 6 and 7 of each treatment to assess attainment of steady state. Plasma samples were assayed for nefazodone and its metabolites, hydroxynefazodone, m-chlorophenylpiperazine and triazoledione by a validated h.p.l.c./u.v. assay. 4. The Cmin data indicated that nefazodone and its metabolites reached steady state by study day 5 of each treatment period. 5. Mean steady-state pharmacokinetic parameter values were similar among treatments. Statistical analyses indicated that, as reflected by AUC(0,24 h) and the ratios of individual nefazodone metabolite AUCs to nefazodone AUC over a dosing interval, there were no differences in steady-state exposure to nefazodone and its metabolites among treatments. For NEF, AUC(0,24 h) (point estimate and 90% CI) values were 102% (86%, 119%) for 400 mg a.m. and 91% (76%, 105%) for 400 mg p.m. when compared with the 200 mg twice daily. 6. Although there were some small differences in mean pharmacokinetic parameter values after a.m. and p.m. administration, no consistent diurnal variation was observed in the pharmacokinetics of nefazodone or its metabolites. 7. There were no serious or unexpected adverse events noted in the study. 8. It is concluded that despite the nonlinearity in the pharmacokinetics of nefazodone, the exposure to nefazodone and its metabolites is comparable for the once daily (400 mg) and twice daily (200 mg) treatments.


Cutaneous findings in congenital disorders of glycosylation: the hanging fat sign.
The congenital disorders of glycosylation are a group of rare metabolic disorders with predominantly neurologic findings. Some variants of this disorder also exhibit cutaneous manifestations. We report a patient with a congenital disorder of glycosylation type Ia, the most common form, with emphasis on the cutaneous findings of this type, and summarize the cutaneous findings in the other forms of the disorder.


Delayed appearance of propranolol sensitivity in cultured heart cells.
Examination of the appearance of adrenaline responsiveness and propranolol sensitivity with culture age in myoblasts cultured from neonatal rat hearts shows that propranolol sensitivity lags behind adrenergic responsiveness. Such a finding may illustrate subtle differences in sites for agonist and antagonist at the beta-receptor of these cells.


The relative contributions of termites and microarthropods to fluff grass litter disappearance in the Chihuahuan Desert.
We tested the hypotheses that both subterranean termites and soil microarthropods are important in the disappearance of fluff grass (Erioneuron pulchellum) litter on the soil surface by an experiment designed to separate termite and microarthropod effects. Subterranean termites (Gnathamitermes tubiformans) removed more than 50% of the fluff grass litter in one year.Since there was no difference in mass loss of fluff grass with microarthropods present or excluded, they had no effect on decomposition of fluff grass litter. Microarthropod densities increased during the first 3 months then slowly decreased. The densities of microarthropods in fluff grass litter were too low to have a measurable effect on decomposition even if we assumed that the microarthropods consumed litter equivalent to their body weight each day.


Molecular mechanics parameterization of thionucleoside disulfides for modeling cross-linked duplex DNA.
We describe a solution to a molecular mechanics parameterization problem involving disulfide bonds between thionucleosides. Key torsional and bending parameters developed from ab initio calculations were incorporated into the AMBER* force-field in order to accurately represent the disulfide linkage in DNA cross-linked via this bond.


Concentration-dependent roles for heparin in modifying lipopolysaccharide-induced activation of mononuclear cells in whole blood.
In addition to their anticoagulant activity, unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) have important immunomodulatory properties. However, different studies have reported conflicting pro- and anti-inflammatory effects in association with heparin. Moreover, the molecular basis for these heparin effects on inflammation remains unclear. It was the objective of this study to determine how UFH and LMWH regulate lipopolysaccharide (LPS)-induced activation of human mononuclear cells in whole blood, and define the role of lipopolysaccharide-binding protein (LBP) in mediating this effect. Whole blood was pre-treated with UFH or LMWH (0.1-200 IU/ml), prior to stimulation with LPS (10 ng/ml). After six hours, monocyte pro-inflammatory cytokine (interleukin (IL)-1beta, IL-6, IL-8, and TNF-alpha) secretion was determined by plasma ELISA. Parallel experiments using THP-1 cell line and primary monocytes were performed under serum-free conditions, in the presence or absence of LBP (50-100 nM). Under serum-free conditions, heparin demonstrated dose-dependent anti-inflammatory effects, significantly reducing secretion of pro-inflammatory cytokines (IL-1beta, IL-6, IL-8, and TNF-alpha) in response to LPS-stimulation of THP-1 cells and primary monocytes. In contrast, in the presence of LBP, both UFH and LMWH demonstrated dose-dependent pro-inflammatory effects at all heparin concentrations. In ex-vivo whole blood experiments, pro-inflammatory effects (increased IL-1beta and IL-8 following LPS-stimulation) of heparin were also observed, but only at supra-therapeutic doses (10-200 IU/ml). Our data demonstrate that in the absence of LBP, the direct effect of heparin on LPS-stimulated monocytes is anti-inflammatory. However in whole blood, the immunomodulatory effects of heparin are significantly more complex, with either pro- or anti-inflammatory effects dependent upon heparin concentration.


Solid-state laser refrigeration of a composite semiconductor Yb:YLiF4 optomechanical resonator.
Photothermal heating represents a major constraint that limits the performance of many nanoscale optoelectronic and optomechanical devices including nanolasers, quantum optomechanical resonators, and integrated photonic circuits. Here, we demonstrate the direct laser refrigeration of a semiconductor optomechanical resonator >20 K below room temperature based on the emission of upconverted, anti-Stokes photoluminescence of trivalent ytterbium ions doped within a yttrium-lithium-fluoride (YLF) host crystal. Optically-refrigerating the lattice of a dielectric resonator has the potential to impact several fields including scanning probe microscopy, the sensing of weak forces, the measurement of atomic masses, and the development of radiation-balanced solid-state lasers. In addition, optically refrigerated resonators may be used in the future as a promising starting point to perform motional cooling for exploration of quantum effects at mesoscopic length scales, temperature control within integrated photonic devices, and solid-state laser refrigeration of quantum materials.


Pressor response to microinjection of orexin/hypocretin into rostral ventrolateral medulla of awake rats.
Orexin A (or hypocretin 1)-immunoreactive neurons in the rat lateral hypothalamus project to several areas of the medulla oblongata that are closely associated with cardiovascular regulation. The present study was undertaken to further strengthen the hypothesis that orexin A accelerates cardiovascular response by activating sympathoexcitatory neurons in the rat rostral ventrolateral medulla (RVLM). First, immunohistochemical studies revealed the presence of orexin A-immunoreactive fibers in the RVLM. Double labeling the sections with orexin A- and tyrosine hydroxylase (TH)-antisera further showed that orexin A-immunoreactive fibers are in close proximity with TH-immunoreactive neurons, some of which may be barosensitive, bulbospinal neurons in the RVLM. Second, microinjection of orexin A (6.35, 12.7 and 38.1 microM) into the RVLM, which was verified later by histological examination, caused a significant increase of mean arterial pressure (MAP) and a moderate increase of heart rate (HR) in awake rats. L-glutamate (33.3 mM) injected into the same sites, caused a larger increase in MAP, but a decrease in HR; whereas, saline injection was without significant effect. Results from this study suggest that orexin A, which may be released from the nerve fibers originating from the neurons in the lateral hypothalamus, acting on RVLM neurons in the medulla, increases sympathetic outflow targeted to the heart and blood vessels in awake animals.


A spontaneous mouse deletion in Mctp1 uncovers a long-range cis-regulatory region crucial for NR2F1 function during inner ear development.
Hundreds of thousands of cis-regulatory DNA sequences are predicted in vertebrate genomes, but unlike genes themselves, few have been characterized at the functional level or even unambiguously paired with a target gene. Here we serendipitously identified and started investigating the first reported long-range regulatory region for the Nr2f1 (Coup-TFI) transcription factor gene. NR2F1 is temporally and spatially regulated during development and required for patterning and regionalization in the nervous system, including sensory hair cell organization in the auditory epithelium of the cochlea. Analyzing the deaf wanderer (dwnd) spontaneous mouse mutation, we traced back the cause of its associated circling behavior to a 53 kb deletion removing five exons and adjacent intronic regions of the poorly characterized Mctp1 gene. Interestingly, loss of Mctp1 function cannot account for the hearing loss, inner ear dysmorphology and sensory hair cell disorganization observed in dwnd mutants. Instead, we found that the Mctp1dwnd deletion affects the Nr2f1 gene located 1.4 Mb away, downregulating transcription and protein expression in the embryonic cochlea. Remarkably, the Mctp1dwnd allele failed to complement a targeted inactivation allele of Nr2f1, and transheterozygotes or Mctp1dwnd homozygotes exhibit the same morphological defects observed in inner ears of Nr2f1 mutants without sharing their early life lethality. Defects include improper separation of the utricle and saccule in the vestibule not described previously, which can explain the circling behavior that first brought the spontaneous mutation to attention. By contrast, mice homozygous for a targeted inactivation of Mctp1 have normal hearing and inner ear structures. We conclude that the 53 kb Mctp1dwnd deletion encompasses a long-range cis-regulatory region essential for proper Nr2f1 expression in the embryonic inner ear, providing a first opportunity to investigate Nr2f1 function in postnatal inner ears. This work adds to the short list of long-range regulatory regions characterized as essential to drive expression of key developmental control genes.


Implementing a student practicum within a WIC program.
This article describes the efforts of the Larimer County Health Department's WIC program to expand nutrition services by developing a student practicum experience. Nutrition students from Colorado State University have successfully participated in WIC clinics providing individualized and group counseling sessions.


Hypertension and aldosterone overproduction without renin suppression in Cushing's syndrome from an adrenal adenoma.
Adrenal steroids and compenents of the renin-angiotensin system were measured before and after adrenalectomy in a woman with Cushing's syndrome and hypertension from a functioning adrenocortical adenoma. Aldosterone, deoxycorticosterone and cortisol were produced in excess by the adenoma, and were measured in tumor tissue. High plasma renin substrate concentrations, and normal basal and furosemide-stimulated plasma renin activities and plasma renin concentrations which were present before surgery, decreased after adrenalectomy, and the hypertension diminished. The inappropriately normal levels of renin and potassium in this patient, despite autonomous aldosterone overproduction, suggest an ineffective mineralocorticoid action of aldosterone, possibly from interaction with her other adenoma-produced steroids. The decrease in components of the renin-angiotensin system suggests a partial renin-dependence of her hypertension.


Association between serum lactate levels and mortality in patients with cardiogenic shock receiving mechanical circulatory support: a multicenter retrospective cohort study.
To evaluate the prognostic value of peak serum lactate and lactate clearance at several time points in cardiogenic shock treated with temporary mechanical circulatory support (MCS) using veno-arterial extracorporeal membrane oxygenation (VA-ECMO) or Impella CP®. Serum lactate and clearance were measured before MCS and at 1 h, 6 h, 12 h, and 24 h post-MCS in 43 patients at four tertiary-care centers in Southern Brazil. Prognostic value was assessed by univariable and multivariable analysis and receiver operating characteristic (ROC) curves for 30-day mortality. VA-ECMO was the most common MCS modality (58%). Serum lactate levels at all time points and lactate clearance after 6 h were associated with mortality on unadjusted and adjusted analyses. Lactate levels were higher in non-survivors at 6 h, 12 h, and 24 h after MCS. Serum lactate > 1.55 mmol/L at 24 h was the best single prognostic marker of 30-day mortality [area under the ROC curve = 0.81 (0.67-0.94); positive predictive value = 86%). Failure to improve serum lactate after 24 h was associated with 100% mortality. Serum lactate was an important prognostic biomarker in cardiogenic shock treated with temporary MCS. Serum lactate and lactate clearance at 24 h were the strongest independent predictors of short-term survival.


Pseudomonas paucimobilis empyema after cardiac transplantation.
Empyema caused by P paucimobilis and mouth flora occurred in a 56-year-old man two months after orthotopic cardiac transplantation. Successful treatment was accomplished with chest tube drainage and four weeks of intravenous cefazolin and clindamycin.


Carotidynia: report of eight cases and prospective evaluation of therapy.
The essential clinical features of eight cases of carotidynia are outlined. As little is known about treatment, the effectiveness was evaluated of drugs used in some specific forms of vascular headache with similar pain characteristics. Indomethacin or flurbiprofen were shown to be potent drugs in the treatment of carotidynia.


Clinical characteristics and pregnancy outcomes of infertile patients with endometriosis and endometrial polyps: A retrospective cohort study.
The aim of this study was to discuss the clinical characteristics and the prognosis of surgically diagnosed endometriosis complicated by endometrial polyps and investigate the association between pregnancy outcomes during subsequent pregnancies. From January 2013 to December 2016, 1263 infertile patients were enrolled in the study. We identified 451 patients with endometriosis, and divided them into a polyp group (n = 204) and a non-polyp group (n = 247) based on whether or not they were associated with endometrial polyps. Postoperative clinical pregnant women (n = 82) among the polyp group were then classified into a study group and a control group composed of those undergoing a singleton pregnancy (n = 164) who delivered during the same time period. Clinical statuses and complications during pregnancy and delivery were collected from hospitals and by telephone interviews and surveys through the mail. The prevalence rate of endometriosis infertile group was obviously higher than the non-endometriosis infertile group ([45.23%; 204/451] versus [17.12%; 139/812]). Women suffering from stage 1 to 4 endometriosis had a 42.44% (73/172), 40.69% (59/145), 55.89% (38/68) and 51.52% (34/66) occurrence rate of endometrial polyps, respectively. The frequency of endometrial polyps for stage 3 and 4 patients was obviously higher than that of stage 1 and 2 patients ([53.73%; 72/134] versus [41.64%; 132/317]). Moreover, the occurrence rate of deep infiltrating endometriosis (DIE) was 57.81% (37/64), which was obviously higher than that of ovarian endometriosis (42.42%; 98/231) and peritoneal endometriosis (44.23%; 69/156). Of the 204 women diagnosed with posterior endometrial polyps, 89 became pregnant, 7 pregnancies ended in a spontaneous abortion, and 82 successfully delivered a baby. The clinical pregnancy rate of patients in stages 1 and 2 was wholly higher than that of patients in stages 3 and 4 ([48.70%; 56/115] versus [37.71%; 26/82]). The postsurgical pregnancy status of patients suffering from peritoneal endometriosis was slightly better than those with ovarian or DIE, but differences were not statistically significant (P = 0.626). We also found that the pregnancy rate was statistically elevated in patients whose EFI scores range from 7 to 10. When compared to the control group, women with endometriosis and endometrial polyps had a higher risk of their pregnancy being complicated by placenta previa (13.41%) and cesarean delivery (59.76%). Patients with endometriosis have a higher frequency of endometrial polyps. We found that a combined hysteroscopy and laparoscopy surgical procedure is an effective way to increase pregnancy rates. Different endometriosis stages and types in patients were associated with clinical pregnancy and spontaneous abortion rates. Women affected by both endometriosis and endometrial polyps have an independently elevated risk of placenta previa and cesarean delivery during pregnancy.


N-[2-(4-Bromo-benzo-yl)eth-yl]isopropyl-aminium chloride.
The crystal structure of the title compound, C(12)H(17)BrNO(+)·Cl(-), is stabilized by N-H⋯Cl and C-H⋯O hydrogen bonds, forming a three-dimensional network. The inter-actions framework is completed by C-H⋯π contacts between a methyl-ene group and the benzene ring of a symmetry-related mol-ecule.


Associations of preterm births with child health and development: Japanese population-based study.
To examine associations between the duration of gestation and health and development outcomes at 2.5 years and 5.5 years using a Japanese population-based longitudinal survey (n = 47 015). Hospitalization was used as an indicator of physical health, and responses to questions about age-appropriate behaviors were used as an indicator of behavioral development. We conducted logistic regression analyses controlling for a set of neonatal and family factors. We also estimated population-attributable fractions. We observed a steady increase toward shorter duration of gestation in the risk of hospitalizations at age 2.5 years and 5.5 years and developmental delays at 2.5 years (Plinear trend < .001 for all outcomes). We found associations only between extremely preterm birth and delayed behavioral development at age 5.5 years. There is a linear relationship between shorter duration of gestation and increased risk of later health and developmental problems. In line with Rose's "population paradox," the population-attributable risks for these problems are greater for moderately preterm infants compared with extremely preterm infants.


Using a zebrafish model to understand adherent-invasive Escherichia coli infection.
A zebrafish model was developed to study AIEC colonization, invasion, and inflammation. This model can also be used to study the beneficial effects of a probiotic on AIEC infection of adult zebrafish. Bacteria are grown in vitro and then fish are infected with AIEC by immersion. Subsequently, colonization and inflammation can be assessed. Exposing fish to probiotic at different time points relative to AIEC can determine beneficial effects of probiotics as prophylactics or therapeutics against AIEC. For complete details on the use and execution of this protocol, please refer to Nag et al. (2022).


The membrane depolarization and increase intracellular calcium level produced by silver nanoclusters are responsible for bacterial death.
This work highlights how our silver ultra nanoclusters (ARGIRIUM-SUNc) hand-made synthesized, are very useful as a bactericide and anti-biofilm agent. The Argirium-SUNc effective antibacterial concentrations are very low (< 1 ppm) as compared to the corresponding values reported in the literature. Different bacterial defense mechanisms are observed dependent on ARGIRIUM-SUNc concentrations. Biochemical investigations (volatilome) have been performed to understand the pathways involved in cell death. By using fluorescence techniques and cell viability measurements we show, for the first time, that membrane depolarization and calcium intracellular level are both primary events in bacteria death. The ARGIRIUM-SUNc determined eradication of different biofilm at a concentration as low as 0.6 ppm. This suggests that the effect of the nanoparticles follows a common mechanism in different bacteria. It is highly probable that the chemical constitution of the crosslinks could be a key target in the disrupting mechanism of our nanoparticles. Since the biofilms and their constituents are essential for bacterial survival in contact with humans, the silver nanoparticles represent a logical target for new antibacterial treatments.


Xanthohumol attenuates tumour cell-mediated breaching of the lymphendothelial barrier and prevents intravasation and metastasis.
Health beneficial effects of xanthohumol have been reported, and basic research provided evidence for anti-cancer effects. Furthermore, xanthohumol was shown to inhibit the migration of endothelial cells. Therefore, this study investigated the anti-metastatic potential of xanthohumol. MCF-7 breast cancer spheroids which are placed on lymphendothelial cells (LECs) induce "circular chemorepellent-induced defects" (CCIDs) in the LEC monolayer resembling gates for intravasating tumour bulks at an early step of lymph node colonisation. NF-κB reporter-, EROD-, SELE-, 12(S)-HETE- and adhesion assays were performed to investigate the anti-metastatic properties of xanthohumol. Western blot analyses were used to elucidate the mechanisms inhibiting CCID formation. Xanthohumol inhibited the activity of CYP, SELE and NF-kB and consequently, the formation of CCIDs at low micromolar concentrations. More specifically, xanthohumol affected ICAM-1 expression and adherence of MCF-7 cells to LECs, which is a prerequisite for CCID formation. Furthermore, markers of epithelial-to-mesenchymal transition (EMT) and of cell mobility such as paxillin, MCL2 and S100A4 were suppressed by xanthohumol. Xanthohumol attenuated tumour cell-mediated defects at the lymphendothelial barrier and inhibited EMT-like effects thereby providing a mechanistic explanation for the anti-intravasative/anti-metastatic properties of xanthohumol.


Emerging systems: between vertebrates and arthropods, the Lophotrochozoa.
Novel molecular model organisms for the study of development and regeneration are emerging among the Lophotrochozoa, the third major branch of bilaterian animals. The polychaete Platynereis, the leech Helobdella, the snail Ilyanassa, and several planarians are efficiently accessed for molecular techniques including large-scale whole-mount in situ hybridization screening, RNA interference or morpholino knock-down. Joint efforts include the generation of genomic resources in the form of expressed sequence tag collections and bacterial artificial chromosome libraries. Current research focuses on early pattern formation during cleavage, the emergence and diversification of body segments, and the formation of photoreceptor cells and eyes. Several lophotrochozoan groups (in particular nereid polychaetes) exhibit modes of development, organ design, or body plans that are considered ancestral in many respects. This is also reflected in the level of genes, making these groups ideally suited for developmental comparative studies.


Ocular findings of congenital Zika virus infection with microcephaly.
To describe ocular findings in infants with signs of congenital Zika virus syndrome (CZS) in Paraíba, Brazil, as well as to conduct a literature review and report correlations with published clinical cases. In the Paraíba sample, infants with microcephaly suggestive of CZS were classified as Z (confirmed), PZ (probable), or SZ (suspected) according to serological testing and/or clinical findings of CZS. The patients underwent a clinical eye examination, and the results were correlated with published clinical cases. Ocular findings were present in 24 (42.9%) of 56 patients, consisting of gross retinal pigmentation in 11 (45.8%), macular chorioretinal atrophy in 11 (45.8%), optic nerve hypoplasia in 1 (4.2%), optic nerve pallor in 14 (58.3%), and increased cup-to-disk ratio in 2 (8.3%). The study revealed retina and optic nerve findings consistent with previous reports of ophthalmic involvement in CZS. However, external ocular changes observed in other studies were not detected. Ocular findings similar and consistent with the literature on CZS were observed with considerable frequency and severity, regardless of the patients' serological confirmation or classification. Infants with signs of CZS should undergo ocular examination.


The interplay between food insecurity and family factors in relation to disordered eating in adolescence.
This study examined the association between food insecurity and both binge eating and unhealthy weight-control behaviors (UWCBs) and assessed whether such associations differ by factors within the family environment. Data were collected from a diverse sample of adolescents (Mage = 14.5 years; 54.1% female) and their parents/guardians (N = 2137 dyads) participating in EAT 2010 (Eating and Activity over Time). Food-insecure adolescents were more likely to report binge eating (prevalence ratio [PR] = 1.94; 95% confidence interval [CI]: 1.41-2.69) and UWCBs (PR = 1.34; 95% CI: 1.21-1.49) than food-secure adolescents. Family meal importance (p = .03) and family communication (p < .001) significantly moderated the association between food insecurity and UWCBs, such that the association was weaker at lower levels of these factors. Significant interactions with parental weight talk/concern (p < .001) and weight teasing (p = .04) indicated a weaker association between food insecurity and UWCBs in the presence of these factors. Findings indicate that the association between food insecurity and UWCBs among youth is less salient in the absence of family protective factors and in the presence of family risk factors for UWCBs, indicating the importance of targeting food insecurity itself, regardless of the presence of family risk or protective factors for UWCBs.


Impact of COVID vaccination rollout on the use of computed tomography venography for the assessment of cerebral venous sinus thrombosis.
Cerebral venous sinus thrombosis (CVST) is rare; however, it has been observed in patients with vaccine-induced immune thrombotic thrombocytopaenia syndrome (VITT) following the use of adenovirus vector vaccines against COVID-19. Adverse vaccine effects have been heavily addressed in mainstream media, likely contributing to vaccination anxiety. This study aimed to assess how the vaccine rollout and media coverage has influenced the use of computed tomography venography (CTV) in an acute care setting of a tertiary hospital. Single-centre retrospective cohort study from 30 March 2021 to 13 June 2021. Direct comparison to same calendar dates in the preceding 3 years. In 2021, 57 patients received CTV with headache being the reason in 48 (84%) and 40 (70%) had received ChAdOx1 nCov-19 (AstraZeneca COVID-19 vaccination). Only 20 of these patients received CTV after platelets and D-Dimer had returned, and only three patients met existing guidelines for imaging. Zero cases were positive. The number of CTV studies was 5.2 times than in 2020 and 2.7 times the mean number for the 3 preceding years. The use of CTV in patients with headache has markedly increased at our centre since negatively biased vaccination influence of mainstream media. Headache is a common vaccine-related side effect and VITT is exceptionably rare. With the rates of vaccination increasing in the community, these results highlight the importance of strict adherence to established evidence-based guidelines. Otherwise, critical care capacity, and in particular imaging resources already under pressure will be strained further.


Immunotherapy in Melanoma: Recent Advancements and Future Directions.
Immune checkpoint inhibition has fundamentally altered the treatment paradigm of resectable and unresectable melanoma, resulting in dramatic improvements in patient outcomes. With these advances, the five-year overall survival in patients with newly diagnosed unresectable disease has eclipsed 50%. Ongoing research is focused on improving outcomes further, with a considerable emphasis on preventing de novo and acquired resistance and personalizing therapeutic options. Here, we review the ongoing advancements in the treatment of malignant melanoma, focusing on novel combination strategies that aim to build upon the successes of the last decade.


Simultaneous screening for two different antibodies in ELISA by combining two solid phases: microtiter plate and Falcon assay screening test system lid.
An enzyme-linked immunosorbent assay (ELISA) is described that used a combination of 2 solid phases: a microtiter plate covered with a Falcon assay screening test (F.A.S.T.) system lid. By coating each solid phase with a different antigen, it was possible to simultaneously detect 2 different antibodies. The results of the combined test were compared and found similar to those obtained in separate assays on the same solid phases by the usual ELISA method. Further, the combined test was more economical in time, work and materials than 2 separate tests for the 2 antibodies. This method was used in a serological survey for 2 turkey viral infections: hemorrhagic enteritis and paramyxovirus type 3.


Cardiac magnetic resonance longitudinal strain analysis in acute ST-segment elevation myocardial infarction: A comparison with speckle-tracking echocardiography.
Strain analysis with speckle-tracking echocardiography (STE) is considered superior to ejection fraction for ventricular function assessment in different clinical scenarios. Feature tracking (FT) permits cardiac magnetic resonance (CMR) strain analysis in routinely acquired cine images. This study evaluated the feasibility of CMR-FT and its agreement with STE in patients with acute ST-segment elevation myocardial infarction (STEMI). An echocardiogram and CMR were performed in 128 patients who underwent primary percutaneous revascularisation after a STEMI. Adequate strain analysis was obtained by both techniques in 98 patients and peak systolic longitudinal strain (LS) was assessed with STE and CMR-FT. Of 1568 myocardial segments, 97.2% were correctly tracked with STE and 97.7% with CMR-FT. For global LS, STE showed a mean of -14.8 ± 3.3% and CMR-FT -13.7 ± 3.0%, with good agreement between modalities [intraclass correlation coefficient (ICC) 0.826; bias -1.09%; limits of agreement (LOA) ± 4.2%]. On the other hand, segmental LS agreement was only moderate, with an ICC of 0.678 (bias -1.14%; LOA ± 11.76%) and the ICC ranged from 0.538 at the basal antero-lateral segment to 0.815 at the apical lateral segment. Finally, both STE and CMR-FT showed excellent intra- and inter-observer reproducibility (ICC > 0.9). CMR-FT provides LS with similar feasibility to STE and both techniques showed good agreement for global LS, although agreement at segmental level was only moderate. CMR-FT showed excellent reproducibility, strengthening its robustness and potential for both research and clinical applications.


Reviewing age-structured epidemiological models of cattle diseases tailored to support management decisions: Guidance for the future.
Mechanistic simulation models are being increasingly used as tools to assist with animal health decision-making in the cattle sector. We reviewed scientific literature for studies reporting age-structured cattle management models in application to infectious diseases. Our emphasis was on papers dedicated to support decision making in the field. In this systematic review we considered 1290 manuscripts and identified 76 eligible studies. These are based on 52 individual models from 10 countries addressing 9 different pathogens. We provide an overview of these models and present in detail their theoretical foundations, design paradigms and incorporated processes. We propose a structure of the characteristics of cattle disease models using three main features: [1] biological processes, [2] farming-related processes and [3] pathogen-related processes. It would be of benefit if future cattle disease models were to follow this structure to facilitate science communication and to allow increased model transparency.


[Health-related quality of life after implantation of a keratoprosthesis with biological haptic].
Many studies report comparatively good long-term results among patients with keratoprostheses with biological haptic. However, overall costs are correspondingly high. A clear cost-benefit relationship is therefore desirable. This study investigates health-related quality of life after implantation of a keratoprosthesis with biological haptic. We present a retrospective analysis of medical data of 25 patients treated between 1996 and 2006 at the Department of Ophthalmology, University Hospital Homburg/Saar and the Klinikum Offenburg. Health-related quality of life was assessed by means of a questionnaire based on validated instruments, with particular emphasis on physical symptoms, mental health, functional limitations, and social interactions. At a patient age of 49.8 ± 15.7 years (minimum-maximum: 19-78 years; 6 female, 19 male), the mean duration of corneal blindness was 13.8 ± 13.1 years (minimum-maximum: 1-47 years). Changes in visual acuity and subjective satisfaction were statistically significant (p <0.001). Quality of life (on a scale of 1 to 6: median 2) at the time "before the onset of eye disease" and ≥15 months after surgery were identical. Patients with a postoperative visual acuity ≤0.1 (n =11) also showed a statistically significant (p =0.016) benefit in this context. The expenditures and costs of keratoprosthetics can be justified by an improvement in the health-related quality of life of the persons concerned. Even a postoperative visual acuity of ≤0.1 correlates with a statistically significant improvement in the subjective quality of life of these patients.


Cross-testing of direct-action antivirals, universal vaccines, or search for host-level antivirals: what will sooner lead to a generic capability to combat the emerging viral pandemics?
Mitigation of future viral pandemics is an enormous technical problem, but its solution is essential for preservation of life, economic well-being, and social stability. The author examined host-level, direct action antiviral, and universal vaccine approaches while presenting a specific screening proposal. The author examined the most recent biomedical literature publicly available in the databases and identified the publications supporting the principle of cross-applicability of direct-action antivirals (DAA) within similar viral families and at greater phylogenetic distances. Comparing different approaches, the author showed that the cocktails of DAAs, including parent compounds that passed Phase I trials need to be preemptively tested for all major viral families, approved, and stockpiled (or dual-use production facilities designated). The quick distribution of the pre-approved and pre-positioned antiviral cocktails (even of moderate efficiency) reduces mortality and economic damage many-fold, resulting in the trillion-scale savings in a pandemic context. This pre-positioning approach is only one in the combinatorial toolkit that needs to be included in the plan for all viral families of importance. A dedicated international public-private initiative can achieve savings in these proactive preparedness efforts, as well as to keep the focus of politicians and public on the problem.