Complexes of aluminium with peptide ligands: a Fourier transform IR spectroscopic study.
Aluminium has been recognized to be a neurotoxic agent and a risk factor in Alzheimer's disease and other neuronal dysfunctions. CD spectroscopic studies on two synthetic fragments of the human neurofilament protein midsized subunit (NF-M), and their alanine-for-serine-substituted and/or serine-phosphorylated derivatives showed the formation of stable, citric acid resistant complexes of Al3+ with peptide ligands [M. Hollósi, Z. M. Shen, A. Perczel, and G. D. Fasman (1994) Proc. Natl. Acad. Sci. USA, vol. 9, pp. 4902-4906]. In the case of Ser-phosphorylated fragments, a beta-sheet inducing effect of Ca2+ and Al3+ ions was observed. However, the serine-containing parent peptides, NF-M13 (KSPVPKSPVEEKG) and NF-M17 (EEKGKSPVPKSPVEEKG), failed to show CD spectral changes reflecting beta-sheet formation upon addition of Al3+ ions. On the basis of the amide I region of the Fourier transform ir spectra, in trifluoroethanol, the peptide backbone of NF-M17 and NF-M17 (A6A11) shows marked changes in the presence of Al3+. The most significant spectral differences are seen in the carboxyl region (> 1700 cm-1). The high-frequency component bands above 1760 cm-1 in both spectra belong to the C = O of undissociated CF3COOH. Another strong band at 1710 cm-1 which appears only in the spectrum of NF-M17 (A6A11)(NF-M17 with Ser6 and Ser11 replaced by Ala) can be assigned to the side chain or C-terminal COOH groups. The differential protonation state of the carboxyl groups in the two peptides suggests the formation of Al3+ complexes of different structure and stability.(ABSTRACT TRUNCATED AT 250 WORDS)


Proteasomal degradation of ubiquitinated proteins in oocyte meiosis and fertilization in mammals.
Gametogenesis and fertilization are the key events in sexual reproduction. In the female, meiosis results in a large oocyte that is competent for fertilization and fundamental for the success of early embryonic development. Progression through meiosis is monitored by fine regulatory mechanisms. In this review, we focus on one of the most well-known regulatory elements, the E3 ligase APC/C, which mediates proteolytic degradation of a number of important substrates via the ubiquitin proteasome pathway (UPP). The UPP also indirectly regulates protein synthesis by affecting proteins involved in RNA metabolism, a process that is paramount for the transcriptionally silent oocyte. During the past few years, more evidence has accumulated to suggest that the UPP has an important role in zona pellucida penetration and gamete fusion in mammals. This review focuses on the function of the UPP in regulating oocyte meiotic maturation in mammals, with special attention to its role in chromosome segregation and polar body extrusion, its role in the acquisition of meiotic/developmental competence and recent advances in our understanding of the UPP role in fertilization.


Effects of electrolysis time and electric potential on chlorine generation of electrolyzed deep ocean water.
Electrolyzed water is a sustainable disinfectant, which can comply with food safety regulations and is environmentally friendly. A two-factor central composite design was adopted for studying the effects of electrolysis time and electric potential on the chlorine generation efficiency of electrolyzed deep ocean water (DOW). DOW was electrolyzed in a glass electrolyzing cell equipped with platinum-plated titanium anode and cathode. The results showed that chlorine concentration reached maximal level in the batch process. Prolonged electrolysis reduced chlorine concentration in the electrolyte and was detrimental to electrolysis efficiency, especially under high electric potential conditions. Therefore, the optimal choice of electrolysis time depends on the electrolyzable chloride in DOW and cell potential adopted for electrolysis. The higher the electric potential, the faster the chlorine level reaches its maximum, but the lower the electric efficiency will be.


Fruit composition and patterns of fruit dispersal of two Cornus spp.
Fruiting phenology and pattern of fruit removal of two shrubby dogwoods were examined in relation to fruit composition. It was predicted that fruit of the species bearing high fat fruit would disappear more rapidly and fall to the ground sooner than fruit of the species bearing low fat fruit. Field observation at two sites in central Pennsylvania contradicts these predictions. C. racemosa fruit, containing relatively high concentrations of crude fat, were retained on plants longer and fell into fruit traps later than c. amomum fruit, containing relatively low concentrations of crude fat. A substantial portion of the crops of both species fell under plants and most fallen fruit were secondarily removed. Potential explanations for patterns observed in this study are discussed.


Electronic Medication Management System Introduction and Deprescribing Practice in Post-Acute Care.
To determine the effect of introducing an electronic medication management system (EMMS) on deprescribing practice in a post-acute hospital setting. This study used a before-after study design. This study examined the admission and discharge medications prescribed to patients admitted to an Australian post-acute hospital before and after the introduction of an EMMS. Data were collected over a 1-month period before and after the introduction of an EMMS and included summary measures of drug burden including Potentially Inappropriate Medications and the Drug Burden Index. We calculated and compared admission and discharge medication prescription as well as change in medication use before and after the introduction of an EMMS. Medication prescription data were available for 121 people before and 107 people after EMMS introduction. In both phases, when compared with admission, those discharged were prescribed fewer medications (mean reduction pre-EMMS = 2.9, P < .001, post-EMMS = 2.6, P < .001), fewer Potentially Inappropriate Medications (mean reduction pre-EMMS = 0.4, P < .001, post-EMMS = 0.6, P < .001) and had lower Drug Burden Index (mean reduction pre-EMMS = 0.1, P < .001, post-EMMS = 0.2, P < .001). The degree of reduction in each measure was similar before and after EMMS introduction. The introduction of an EMMS did not affect deprescribing practice in a post-acute hospital setting. Future work is required to explore the potential for clinical decision support within an EMMS to further improve the safety and effectiveness of deprescribing within post-acute care.


The effect of gallamine triethiodide on the activity of gamma motor neurons in the acute spinal cat.
Gallamine triethiodide, a drug commonly used in neurophysiological experiments, causes statistically significant and inconsistent changes in the information-carrying capacity of trains of action potentials generated by members of a population of gamma motor neurons recorded from the same cat under the same conditions during the same time period.


A case-controlled study of cognitive progression in Chinese lacunar stroke patients.
(1) To determine and compare the rates of cognitive change using global and executive psychometric measures between lacunar stroke patients and matched controls and; (2) to identify features associated with cognitive changes in patients. Sixty-one lacunar stroke patients and 35 demographically-matched controls were followed-up for 28.6 months (range 19.4-45.9 months) with psychometric assessments performed at baseline and follow-up. Lacunar stroke patients were more impaired than controls in general and executive functions at both time points. Both groups had similar stability in all psychometric tests. Patients, but not controls, exhibited a trend for improvement in general cognitive functions overtime (interaction term, p=0.084). No patient who was non-demented at baseline became demented during the study period. Two (5.7%) and five (8.2%) incident cerebrovascular events occurred among the controls and patients, respectively. Linear regression analyses performed upon patients failed to identify any predictor for the cognitive change. Similar to controls, cognition in lacunar stroke patients is stable during the first 2-3 years after the stroke. There maybe a spontaneous improvement in general cognition overtime, but this awaits confirmation by future studies.


Extension of Shelf-life of Fresh, Whole Broilers, Using a Potassium Sorbate Dip.
The shelf life of fresh, whole broilers was extended by dipping freshly chilled carcasses into a 5% (w/v) solution of potassium sorbate for 30 sec. One hundred broilers were removed from a processing line immediately following the final chill tank. Fifty carcasses were dipped in water for 30 sec, and 50 were dipped in the sorbate solution for 30 sec. The birds were allowed to drain and then individually bagged and stored at 3 C until spoilage odors were noted. The control birds were stored for 10 days when spoilage was evident, and the sorbate treated birds were stored for 19 days, at which time spoilage was evident.


Tibiocalcaneal kinematics of barefoot versus shod running.
Barefoot running kinematics has been described to vary considerably from shod running. However, previous investigations were typically based on externally mounted shoe and/or skin markers, which have been shown to overestimate skeletal movements. Thus, the purpose of this study was to compare calcaneal and tibial movements of barefoot versus shod running using skeletal markers. Intracortical bone pins with reflective marker triads were inserted under standard local anesthetic into the calcaneus and tibia of five healthy male subjects. The subjects ran barefoot, with a normal shoe, with three shoe soles and two orthotic modifications. The three-dimensional tibiocalcaneal rotations were determined using a joint coordinate system approach. Test variables were defined for eversion and tibial rotation. The results showed that the differences in bone movements between barefoot and shod running were small and unsystematic (mean effects being less than 2 degrees ) compared with the differences between the subjects (up to 10 degrees ). However, differences may occur during midstance when extreme shoe modifications (i.e. posterior orthosis) are used. It is concluded that calcaneal and tibial movement patterns do not differ substantially between barefoot and shod running, and that the effects of these interventions are subject specific. The result of this in vivo study contrasts with previous investigations using skin and shoe mounted markers and suggests that these discrepancies may be the result of the overestimation with externally mounted markers.


Neuroprotective effects of linear ubiquitin E3 ligase against aging-induced DNA damage and amyloid β neurotoxicity in the brain of Drosophila melanogaster.
E3 ubiquitin ligase, HOIL1-interacting protein (HOIP), forms the linear ubiquitin chain assembly complex (LUBAC) with HOIL and SHANK-associated RH domain interactor and catalyzes linear ubiquitination, directly linking the N- and C-termini of ubiquitin. Recently, several studies have implicated linear ubiquitination in aging and Alzheimer disease (AD). However, little is currently known about the roles of HOIP in brain aging and AD pathology. Here, we investigated the role of linear ubiquitin E3 ligase (LUBEL), a Drosophila HOIP ortholog, in brain aging and amyloid β (Aβ) pathology in a Drosophila AD model. DNA double-strand breaks (DSBs) were increased in the aged brains of neuron-specific LUBEL-knockdown flies compared to the age-matched controls. Silencing of LUBEL in the neuron of AD model flies increased the neuronal apoptosis and neurodegeneration, whereas silencing in glial cells had no such effect. Aβ aggregation levels and DSBs were also increased in the LUBEL-silenced AD model fly brains, but autophagy and proteostasis were not affected by LUBEL silencing. Collectively, our results suggest that LUBEL protects neurons from aging-induced DNA damage and Aβ neurotoxicity.


Microaggressions: Black students' experiences - A qualitative study.
Studies in other disciplines have shown that Black college students experience microaggressions on campus. This affects campus learning climates, posing a risk to students' success. The purpose of this secondary analysis is to describe Black nursing students' experiences with microaggression at a predominantly white institution. In this secondary analysis of a descriptive qualitative study, principles of thematic analysis were used to code, categorize, and synthesize interview data from 16 nursing alumni participants specifically to examine microaggression. The thematic analysis of the data revealed microaggressive behaviors experienced by Black nursing students. Three salient themes emerged: microaggressions among peers, from faculty members to students, and in the clinical setting. This study offers critical insights into the microaggressions that Black students experience. These microaggressions interfere with students' learning and highlight the need for academic institutions to take measures to dismantle these behaviors. These findings can illuminate to faculty and students the roles they play in perpetuating racism and subjecting students of color to detrimental psychological distress.


L-glutamate specific [3H]kainic acid binding in the rat neostriatum after degeneration of the cortico-striatal pathway.
Four weeks after lesion of the cortico-striatal pathway, the specific kainic acid binding was reduced by 20% in the neostriatum. It is concluded that the binding sites are most likely not located on cortico-striatal neurons. The displacement of kainic acid by some chemical indicates that the kainic acid binding site is different from the glutamate binding site, as defined iontophoretically.


Novel exosome-targeted T-cell-based vaccine counteracts T-cell anergy and converts CTL exhaustion in chronic infection via CD40L signaling through the mTORC1 pathway.
CD8+ cytotoxic T lymphocyte (CTL) exhaustion is a chief issue for ineffective virus elimination in chronic infectious diseases. We generated novel ovalbumin (OVA)-specific OVA-Texo and HIV-specific Gag-Texo vaccines inducing therapeutic immunity. To assess their therapeutic effect in chronic infection, we developed a new chronic infection model by i.v. infecting C57BL/6 mice with the OVA-expressing adenovirus AdVova. During chronic AdVova infection, mouse CTLs were found to express the inhibitory molecules programmed cell-death protein-1 (PD-1) and lymphocyte-activation gene-3 (LAG-3) and to be functionally exhausted, showing a significant deficiency in T-cell proliferation, IFN-γ production and cytolytic effects. Naive CD8+ T cells upregulated inhibitory PD-ligand 1 (PD-L1), B- and T-lymphocyte attenuator and T-cell anergy-associated molecules (Grail and Itch) while down-regulating the proliferative response upon stimulation in mice with chronic infection. Remarkably, the OVA-Texo vaccine counteracted T-cell anergy and converted CTL exhaustion. The latter was associated with (i) the upregulation of a marker for CTL functionality, diacetylated histone-H3 (diAcH3), (ii) a fourfold increase in CTLs, occurring independent of host DCs or CD4+ T cells, and (iii) the restoration of CTL IFN-γ production and cytotoxicity. In vivo OVA-Texo-stimulated CTLs upregulated the activities of the mTORC1 pathway-related molecules Akt, S6, eIF4E and T-bet, and treatment of the CTLs with an mTORC1 inhibitor, rapamycin, significantly reduced the OVA-Texo-induced increase in CTLs. Interestingly, OVA-Texo-mediated CD40L signaling played a critical role in the observed immunological effects. Importantly, the Gag-Texo vaccine induced Gag-specific therapeutic immunity in chronic infection. Therefore, this study should have a serious impact on the development of new therapeutic vaccines for human immunodeficiency virus (HIV-1) infection.


Development and validation of influenza forecasting for 64 temperate and tropical countries.
Accurate forecasts of influenza incidence can be used to inform medical and public health decision-making and response efforts. However, forecasting systems are uncommon in most countries, with a few notable exceptions. Here we use publicly available data from the World Health Organization to generate retrospective forecasts of influenza peak timing and peak intensity for 64 countries, including 18 tropical and subtropical countries. We find that accurate and well-calibrated forecasts can be generated for countries in temperate regions, with peak timing and intensity accuracy exceeding 50% at four and two weeks prior to the predicted epidemic peak, respectively. Forecasts are significantly less accurate in the tropics and subtropics for both peak timing and intensity. This work indicates that, in temperate regions around the world, forecasts can be generated with sufficient lead time to prepare for upcoming outbreak peak incidence.


Linear porokeratosis of the foot with dermoscopic manifestations: A case report.
Porokeratosis (PK) is a common autosomal dominant chronic progressive dyskeratosis with various clinical manifestations. Based on clinical manifestations, porokeratosis can be classified as porokeratosis of mibelli, disseminated superficial porokeratosis, disseminated superficial actinic porokeratosis, linear porokeratosis (LP), porokeratosis palmaris et plantaris disseminata, porokeratosis punctata, popular PK, hyperkeratosis PK, inflammatory PK, verrucous PK, and mixed types. We report a case of LP in a child and describe its dermoscopic findings. Linear porokeratosis is a rare PK. The patient presented with unilateral keratinizing maculopapular rash of the foot in childhood. The patient underwent skin pathology and dermoscopy, and was treated with liquid nitrogen freezing and topical drugs. From this case we take-away that LP is a rare disease, by the dermoscopic we can identify it.


Cushions and specialist chairs for pressure sore management.
Many patients spend more time sitting out of bed than being cared for in bed. Consequently, the demand for specialist support surfaces for chairs to reduce the risk of pressure damage while the patient is up sitting is rising. This product focus examines a number of seating support surfaces produced by Karomed.


Comparative study of methods for measuring cholesterol in biological fluids.
A method combining enzymatic and electrochemical detection of cholesterol in biological fluids was compared with conventional detection methods: two chromatographic methods--gas chromatography or high performance liquid chromatography--and two enzymatic methods with colorimetric detection either by kinetic measurement or at the end of the reaction. For serum, enzymatic determination is accurate with both colorimetric detection methods; but for bile, colorimetric detection is difficult to perform due to interference from bile pigments. Enzymatic cholesterol determination, combined with electrochemical detection, is simpler and gives results in good agreement with those of chromatographic methods.


Persistent air-leak after transhiatal oesophagectomy: A case report.
Transhiatal oesophagectomy is a widely accepted technique for resection of tumours of the lower oesophagus. We present a life-threatening complication associated with the placement of a corrugated neck drain during this procedure. Our patient underwent a transhiatal oesophagectomy for a lower oesophageal tumour. He developed persistent bilateral pneumothoraces despite chest drain insertions. Following removal of the corrugated neck drain, both lungs were successfully re-inflated. To the authors' knowledge, this serious complication has been described only once before in the medical literature; other surgeons should be made aware of this problem. Alternative drainage systems should be considered to help prevent this injury. Exercise caution if positioning corrugated drains in the neck.


Genetic and molecular regulation of increased photosynthetic cell number contributes to leaf size heterosis in Arabidopsis.
Heterosis is an important genetic phenomenon that has been observed and widely utilized in agriculture. However, the genetic and molecular bases of heterosis are unclear. Through transcriptome-wide association studies (TWAS) and expression quantitative trait locus (eQTL) analysis to integrate genome, transcriptome, and heterotic phenotype of a half-sibling Arabidopsis hybrid population, we report that the genetic and molecular bases of variations in leaf growth heterosis can be explained by the varied expression levels of growth-regulating genes resulting from distinct sets of heterozygous eQTLs carried by the half-sibling hybrids. In F1 versus parent, the degree of up-regulated gene expression in the cell cycle pathway in the shoot apex and the photosynthesis pathway in true leaf positively correlates with true leaf area heterosis level, and this is affected by the accumulation of superior heterozygous eQTLs. This was further corroborated by the major contribution of increased photosynthetic cell number to leaf area heterosis.


Microbial interactions regulated by the dosage of ferroferric oxide in the co-metabolism of organic carbon and sulfate.
Effects of ferroferric oxide (Fe3O4) and organic carbon on co-metabolism of sulfate and organic carbon were investigated. With Fe3O4, the degradation of acetate and sulfate was inhibited when fed with acetate, while the degradation of acetate and propionate produced from ethanol was promoted when fed with ethanol. The dominant sulfate reducing bacteria (SRB) of acetate-fed reactors were Desulfobacteraceae (complete oxidizing SRB, CO-SRB) and Desulfurmonas (incomplete oxidizing SRB, IO-SRB). IO-SRBs of Desulfobulbus and Desulfomicrobium were dominant in ethanol-fed reactors. CO-SRB had higher competitiveness than methanogens to utilize acetate, while IO-SRBs might cooperate with methanogens to produce methane when dosed with ethanol and Fe3O4. The dosage of Fe3O4 changed the dominant methanogen from Methanosarcina to Methanosaeta with acetate as the organic carbon, while increased the relative abundance of Methanosaeta with ethanol as the organic carbon.


Acid-base catalysis in the yeast alcohol dehydrogenase reaction.
The effect of pH on steady state kinetic parameters for the yeast alcohol dehydrogenase-catalyzed reduction of aldehydes and oxidation of alcohols has been studied. The oxidation of p-CH3 benzyl alcohol-1,1-h2 and -1,1-d2 by NAD+ was found to be characterized by large deuterium isotope effects (kH/kD = 4.1 plus or minus 0.1) between pH 7.5 and 9.5, indicating a rate-limiting hydride trahsfer step in this pH range; a plot of kCAT versus pH could be fit to a theoretical titration curve, pK = 8.25, where kCAT increases with increasing pH. The Michaelis constnat for p-CH3 benzyl alcohol was independent of pH. The reduction of p-CH3 benzaldehyde by NADH and reduced nicotinamide adenine dinucleotide with deuterium in the 4-A position (NADD) cound not be studied below pH 8.5 due to substrate inhibition; however, between pH 8.5 and 9.5, kCAT was found to decrease with increasing pH and to be characterized by significant isotope effects (kH/kD = 3.3 plus or minus 0.3). In the case of acetaldehyde reduction by NADH and NADD, isotope effects were found to be small and exxentially invariant (kH/kD = 2.O plus or minus 0.4) between pH 7.2 and 9.5, suggesting a partially rate-limiting hydride transger step for this substrate; a plot of kCAT/K'b (where K'b is the Michaelis constant for acetaldehyde) versus pH could be fit to a titration curve, pK = 8.25. The titration curve for acetaldehyde reduction has the same pK but is opposite in direction to that observed for p-CH3 benzyl alcohol oxidation. The data presented in this paper indicate a dependence on different enzyme forms for aldehyde reduction and alcohol oxidation and are consistent with a single active site side chain, pK = 8.25, which functions in acid-base catalysis of the hydride transfer step.


Thyroid cancer: surgery for the primary tumor.
Surgery is the mainstay of therapy for most patients who present with thyroid cancer. The surgeon must select an appropriate procedure based upon pre operative factors such as tumor histology, extent of primary disease, the presence of regional or distant metastases, associated disease in the contralateral thyroid lobe and the potential for post operative adjuvant therapy. Preservation of the vital structures in the central neck, including the recurrent and superior laryngeal nerves and the parathyroid glands is critical as is the maintenance of absolute hemostasis. In this review article we describe the management of Well Differentiated Thyroid Cancer (WDTC) presenting as a solitary nodule, WDTC in a background of multinodular disease and the management of WDTC presenting as advanced local disease. We go onto discuss the impact that regional and distant metastases have on the choice of surgical approach. The focus of this article is WDTC, however the principles of management of the primary in medullary and anaplastic carcinoma are also discussed.


Tips and tricks to avoid bile duct injury in SILC: an experience of 500 cases.
Conventional laparoscopic cholecystectomy is the gold standard surgical treatment for symptomatic gallstones. Surgeons have attempted to minimize the number of incisions via single-incision laparoscopic cholecystectomy (SILC), which offers benefits including improved cosmesis, possibly less postoperative pain, and improved patient satisfaction. However, studies show that there is an increased risk of operative complications-in particular bile duct injuries. We report 500 consecutive cases of SILC performed without bile duct injury. A retrospective study of 500 continuous cases of SILC performed by the same surgeon at a single institution was conducted. Data on patient demographics, operative details, and postoperative outcomes were collected and evaluated. Detailed analysis of surgical techniques specifically to reduce bile duct injury was performed and described in this study. In total, 500 patients underwent SILC during the study period. Eight patients needed additional ports to complete the surgery, while one was converted to an open surgery. No serious intraoperative complications, such as bile duct injury, were encountered. Our experience shows that with due care and caution during SILC, with particular attention towards achieving the critical view of safety and a standardized technique, bile duct injury in SILC can be avoided.


Can host body size explain the parasite species richness in tropical freshwater fishes?
The variability of monogenean gill ectoparasite species richness in 19 West African cyprinid species was analyzed using the following seven predictor variables: host size, number of drainage basins, number of sympatric cyprinid species, host diversity, association with mainland forest, host ecology, and monogenean biological labelling. The size of the host species accounted for 77% of the variation in the number of parasite species per host, and host ecology an additional 8%. Together the effects of host size and host ecology accounted for 85% of the variation in monogenean species richness. This study shows that the deciding factors for explaining monogenean species richness in West African cyprinid fishes are host species size and host ecology. These results were compared with main factors responsible for parasite species richness in fish communities. Other possible explanations of monogenean community structure in west African cyprinids are discussed.


Evaluation of factors that influence anxiety and satisfaction in patients undergoing bronchofiberoscopy with analgosedation.
Bronchofiberoscopy (BF) is a key tool used in the management of patients with respiratory diseases. Describing factors that contribute to patient anxiety surrounding BF has the potential to influence patient management and willingness to undergo the procedure again in the future if needed. This study sought to understand what factors influence anxiety and satisfaction experienced by patients undergoing BF under conscious sedation. This study had a prospective observational character and evaluated 463 consecutive patients undergoing BF. Participants were divided into two groups, those undergoing BF for the first time and those who had undergone the procedure at least once in the past. Data were collected from three questionnaires prepared by the research team. Patients who had undergone multiple bronchoscopies were more satisfied with their physician's explanation of the procedure (P < 0.0001), had a better understanding of the indications (P < 0.0001) and potential complications (P < 0.0001) of BF and knew what specific procedure was planned (P < 0.001). Patients undergoing BF for the first time experienced anxiety before the procedure more frequently (P < 0.001). No significant difference in satisfaction was observed between patient groups and 89% would agree to BF in the future. Patients who had previously undergone BF were better prepared for their procedure; however, satisfaction levels after the procedure were similar in both groups. Results suggest that medical staff should target patients who have not undergone BF previously to relieve anxiety.


A novel immunoassay of smooth muscle myosin heavy chain in serum.
We have developed a double monoclonal sandwich enzyme immunoassay to measure smooth muscle myosin heavy chain (MHC). Analytical performance of the assay showed reliable detection of smooth muscle MHC in human sera. The mean of the smooth muscle MHC level in normal human sera was 0.9 +/- 0.9 ng/ml. In sera of patients with aortic dissection, the smooth muscle MHC level sharply elevated at the onset and rapidly decreased to normal levels. Immunoassay of smooth muscle MHC in serum is a promising method for biochemical diagnosis of smooth muscle disorders.


Recent advances of oxidative stress in thromboangiitis obliterans: biomolecular mechanisms, biomarkers, sources and clinical applications.
Oxidative stress (OS) has been identified as a key factor in the development of Thromboangiitis Obliterans (TAO). The detection of OS levels in clinical and scientific research practice is mainly based on the measurement of oxidative stress such as reactive oxygen species (ROS), reactive nitrogen species (RNS) and lipid peroxides. These markers are typically assessed through a combination of physical and chemical methods. Smoking is known to the state of OS in TAO, and OS levels are significantly increased in smokers due to inadequate antioxidant protection, which leads to the expression of apoptotic proteins and subsequent cell injury, thrombosis and limb ischemia. There, understanding the role of OS in the pathogenesis of TAO may provide insights into the etiology of TAO and a basis for its prevention and treatment.


Conductive hearing loss induced by experimental middle-ear effusion in a chinchilla model reveals impaired tympanic membrane-coupled ossicular chain movement.
Otitis media with effusion (OME) occurs when fluid collects in the middle-ear space behind the tympanic membrane (TM). As a result of this effusion, sounds can become attenuated by as much as 30-40 dB, causing a conductive hearing loss (CHL). However, the exact mechanical cause of the hearing loss remains unclear. Possible causes can include altered compliance of the TM, inefficient movement of the ossicular chain, decreased compliance of the oval window-stapes footplate complex, or altered input to the oval and round window due to conduction of sound energy through middle-ear fluid. Here, we studied the contribution of TM motion and umbo velocity to a CHL caused by middle-ear effusion. Using the chinchilla as an animal model, umbo velocity (V U) and cochlear microphonic (CM) responses were measured simultaneously using sinusoidal tone pip stimuli (125 Hz-12 kHz) before and after filling the middle ear with different volumes (0.5-2.0 mL) of silicone oil (viscosity, 3.5 Poise). Concurrent increases in CM thresholds and decreases in umbo velocity were noted after the middle ear was filled with 1.0 mL or more of fluid. Across animals, completely filling the middle ear with fluid caused 20-40-dB increases in CM thresholds and 15-35-dB attenuations in umbo velocity. Clinic-standard 226-Hz tympanometry was insensitive to fluid-associated changes in CM thresholds until virtually the entire middle-ear cavity had been filled (approximately >1.5 mL). The changes in umbo velocity, CM thresholds, and tympanometry due to experimentally induced OME suggest CHL arises primarily as a result of impaired TM mobility and TM-coupled umbo motion plus additional mechanisms within the middle ear.


Fractal dimension of dendritic tree of cerebellar Purkinje cell during onto- and phylogenetic development.
The cerebellar Purkinje cell has highly branched dendrites extending in a transverse plane to the cerebellar folium. Branching patterns of the dendrites were subjected to fractal analysis to obtain a quantitative measure of their intricacy. Using a square-covering method, we found that dendrites have a statistical self-similarity so that their fractal dimension can be evaluated. In postnatal mouse, dimensions of Golgi-stained Purkinje cells increased as dendrites developed. The time course of the dimension increase was correlated with development of the width and area of the dendritic fields. After the dimension reached the maximum value at postnatal day 20, the width and area further continued to grow until day 100. In human cerebellum, dimensions of Purkinje cell dendrites increased greatly during pregnancy and reached 97% of the adult value at birth. On the other hand, 41% of the adult dendritic field width and 11% of the adult area had been attained at birth. The physical size of dendrites increased in a more lagged phase than the dimensions, and growth proceeded mainly after birth. These observations indicate that after the maximum complexity and fundamental tree pattern have been attained, the overall tree size further increases. It is observed that phylogenetic development of dendritic trees of Purkinje cells in several species of vertebrates showed a correlation with the increase in dimensions. These studies demonstrated the potency of the fractal analysis in evaluating development of dendritic trees of neurons.


Anti-histone antibodies in dogs with leishmaniasis and glomerulonephritis.
The association between serum anti-histone antibodies and glomerulonephritis was studied in 43 dogs with leishmaniasis (Leishmania infantum). Dogs with increased serum creatinine levels and urine protein-creatinine ratio >1 were considered to have glomerulonephritis. Moderately elevated anti-histone antibodies were found in 38.89% (7/18) of infected dogs without glomerulonephritis, whereas 88% of dogs with glomerulonephritis (22/25) showed moderate or strongly elevated anti-histone antibodies. Prevalence of positive anti-histone antibodies reactions and mean serum concentration was significantly higher (P<0.001; P<0.0001) in infected dogs with glomerulonephritis. Correlation between anti-histone antibodies and urine protein-creatinine ratio was significant when groups were analysed together (P<0.046). Positive predictive value for glomerulonephritis of positive anti-histone antibodies was 88%. In conclusion, high anti-histone antibodies are significantly associated with glomerulonephritis. Although other factors must be involved, dogs with moderate or strong positive anti-histone antibodies reactions may have a higher probability to develop glomerular lesions in canine leishmaniasis.


Isolation, propagation, and titration of human immunodeficiency virus type 1 from peripheral blood of infected individuals.
HIV-1 can be isolated from peripheral blood mononuclear cells and is easily propagated on primary cells in vitro. Here we describe the method for bulk isolation of the HIV-1 quasispecies and a limiting dilution virus isolation protocol by which single coexisting clones can be obtained. In addition, methods for propagation and titration of HIV-1 are provided.


MicroRNA216b mediated downregulation of HSP27/STAT3/AKT signaling is critically involved in lambertianic acid induced apoptosis in human cervical cancers.
Since heat shock protein (HSP27) is a prognostic marker in cervical cancer, in the present study, the apoptotic mechanism of lambertianic acid (LA) was investigated in human cervical cancers in association with HSP27/STAT3/AKT signaling axis. LA exerted significant cytotoxicity, induced sub-G1 population, and increased the cleavage of Poly (ADP-ribose) polymerase (PARP) and cysteine aspartyl-specific protease 3 (caspase3) in HeLa and Caski cancer cells. Consistently, LA downregulated anti-apopotic genes such as B-cell lymphoma 2 (Bcl-2) and inhibitors of apoptosis proteins (c-IAP) in HeLa and Caski cells. Furthermore, LA-inhibited phosphorylation of HSP27, signal transducer, and activator of transcription 3 (STAT3) and Protein kinase B (AKT) through disturbing the binding of HSP27 with STAT3 or AKT in HeLa cells. Notably, LA upregulated the level of miR216b in HeLa and Caski cells. Consistently, miR216b mimic suppressed phosphorylation of HSP27 and reduced the expression of pro-PARP, while miR216b inhibitor reversed the ability of LA to attenuate phosphorylation of AKT, HSP27, and STAT3 and to reduce the expression of pro-PARP in HeLa cells. Overall, our findings suggest that miRNA216b mediated inhibition of HSP27/STAT3/ AKT signaling axis is critically involved in LA-induced apoptosis in cervical cancers.


Regulation of the KCNJ5 gene by SF-1 in the adrenal cortex: Complete genomic organization and promoter function.
Activating mutations in the KCNJ5 gene are responsible for the significant number of aldosterone-producing adenomas. To elucidate the molecular mechanisms underlying KCNJ5 expression, we characterized the entire human KCNJ5 gene. The gene spanned approximately 29.8 kb and contained three exons and two introns. The strongest expression of KCNJ5 mRNA was observed in the adrenal gland. The promoter region contained a putative binding site for SF-1 at -1782 bp. A construct containing -2444 bp of the promoter region exhibited the strongest promoter activity in adrenal H295R cells, and the introduction of a mutation in the SF-1 binding site almost completely abolished promoter activity. Furthermore, deletion mutation, EMSA, and knockdown analyses revealed that SF-1 bound to this element and was functional. Immunochemistry showed that KCNJ5 was predominantly expressed in the zona glomerulosa, while SF-1 was ubiquitously expressed in the adrenal cortex. These results demonstrated that SF-1 mediates the expression of human KCNJ5 in the adrenal cortex.


Toward the synthesis of norzoanthamine: building carbocyclic core by a transannular Michael reaction cascade.
A 12-step synthesis of the ABC carbocyclic core of norzoanthamine is described. It features an organocatalytic asymmetric intramolecular aldolization to set the stereochemistry of the entire molecule, a fragment coupling by selective alkylation of a bis-enolate, and a transannular Michael reaction cascade for rapid and stereoselective synthesis of the polycyclic core.


Insulin receptor protein-tyrosine phosphatases. Leukocyte common antigen-related phosphatase rapidly deactivates the insulin receptor kinase by preferential dephosphorylation of the receptor regulatory domain.
A number of protein-tyrosine phosphatase(s) (PTPases) have been shown to dephosphorylate the insulin receptor in vitro; however, it is not known whether any individual PTPase has specificity for certain phosphotyrosine residues of the receptor that regulate its intrinsic tyrosine kinase activity. We evaluated the deactivation of the insulin receptor kinase by three candidate enzymes that are expressed in insulin-sensitive rat tissues, including the receptor-like PTPases LAR and LRP, and the intracellular enzyme, PTPase1B. Purified insulin receptors were activated by insulin and receptor dephosphorylation, and kinase activity was quantitated after incubation with recombinant PTPases from an Escherichia coli expression system. When related to the level of overall receptor dephosphorylation, LAR deactivated the receptor kinase 3.1 and 2.1 times more rapidly than either PTPase1B or LRP, respectively (p less than 0.03). To assess whether these effects were associated with preferential dephosphorylation of the regulatory (Tyr-1150) domain of the receptor beta-subunit, we performed tryptic mapping of the insulin receptor beta-subunit after dephosphorylation by PTPases. Relative to the rate of initial loss of 32P from receptor C-terminal sites, LAR dephosphorylated the Tris-phosphorylated Tyr-1150 domain 3.5 and 3.7 times more rapidly than either PTPase1B or LRP, respectively (p less than 0.01). The accelerated deactivation of the insulin receptor kinase by LAR and its relative preference for regulatory phosphotyrosine residues further support a potential role for this transmembrane PTPase in the physiological regulation of insulin receptors in intact cells.


Consequences of right siting of endocrinology patients--a financial and caseload simulation.
Right siting has been actively advocated to mitigate rising healthcare costs as well as to free up tertiary resources for the provision of care to more complex patients, research and education. There are, however, concerns that in a block budget setting right siting will reduce patient volumes, thus impacting on subsequent funding allocations and also patient revenues. We sought to determine through modelling and simulation the financial and volume impacts of right siting of endocrinology outpatients in a large tertiary hospital in Singapore. Data were collected prospectively on patient casemix including complexity (complex defined as requiring specialist care), time required for consultations and revenues garnered. The data were used to simulate 2 scenarios: right siting of all simple cases with freed up resources directed to research and teaching (research scenario) and right siting of all simple cases with replacement by complex cases (service scenario). The department sees an estimated 33,000 outpatients per year with a total annual outpatient revenue of $8.6 million. The research scenario would see a decline in patient volume to 11,880 cases per year which would result in a corresponding decrease in revenue of $5 million and freeing up of 2.8 hours/ week for each staff. The service scenario yields a drop in patient volume of 9500 per annum and a drop in revenue of $1.9 million. Right siting reduces tertiary care patient volumes and revenues and may discourage right siting efforts. A viable business model for the tertiary institutions is needed to facilitate support for right siting.


[Hemoglobin-oriented and coagulation factor-based algorithm : Effect on transfusion needs and standardized mortality rate in massively transfused trauma patients].
Bleeding and trauma-induced coagulopathy (TIC) are major contributors to death related to trauma in the first 24 h and the major preventable contributors. Early surgical therapy and aggressive correction of TIC are key steps to prevent death in patients suffering from hemorrhage. Therefore, a standard operating procedure (SOP) using a hemoglobin (Hb)-oriented and coagulation factor-based algorithm for early correction of TIC was introduced in this level 1 trauma center. This SOP uses the correlation of the Hb values measured in the trauma bay and standard coagulation tests as the basis for various aggressive coagulation therapies. The aim was to investigate the effectiveness of the SOP in trauma patients requiring massive transfusions. The main objective was the effect on the transfusion requirements and the standardized mortality ratio (SMR), the ratio of observed deaths to expected/predicted deaths, in the cohort of massively transfused trauma patients after introduction of the SOP compared with a historical cohort. A retrospective, single center study was carried out at a supraregional trauma center between 2005 and 2014. After introduction of the Hb-oriented, coagulation factor-based SOP for correction of TIC in 2011 a before/after comparison of all trauma patients requiring massive transfusions during trauma bay resuscitation and intensive care unit (ICU) admission was carried out. Main outcome parameters were the transfusion requirement and the SMR. The historical cohort of massively transfused trauma patients before introduction of the SOP (group 1) was compared with the cohort after introduction of the SOP (group 2). Furthermore, the two cohorts were compared regarding injury severity, expected death calculated with the revised injury severity classification (RISC), hemostatic results on trauma bay and ICU admission, clotting therapy and outcome. Of the 952 patients investigated 86 (9%) required massive transfusion (45 in group 1 and 41 in group 2). Both groups were comparable regarding injury severity but showed slight differences in hemostatic results on trauma bay admission, with a trend to worse results in group 2. Differences were recorded for platelet count on trauma bay admission with significantly lower values in group 2. The RISC predicted a significant difference in the mortality rate (46.5% group 1 and 65.3% group 2) but no significant differences in the observed mortality (44.4% group 1 and 47% group 2) were recorded. The SMR decreased from 0.95 in group 1 to 0.72 in group 2, meaning that in group 1 from 21 predicated trauma deaths 20 occurred and in group 2 from 27 predicated trauma deaths 19 occurred. This difference is not statistically significant (p = 0.16) due to the small sample size but is clinically relevant. A significant reduction in the requirement of red blood cell transfusions (22.8 ± 8.1 units vs 17.6 ± 7.6 units) was achieved (p = 0.003). Significant differences between the groups were observed regarding frequency and quantity of the coagulation-promoting drugs. Compared with group 1 the SOP used in group 2 achieved significantly better hemostatic results on ICU admission for fibrinogen and Quick's value and a clear trend to better results for international normalized ratio (INR) and PTT. The SOP based on coagulation factor values and standardized clotting therapy showed a clear trend to reduction of the SMR in massively transfused trauma patients. On the other hand the SOP achieved a significant reduction in the transfusion requirements and a significant improvement in the hemostatic results in the most severely injured patients. This can be interpreted as an effective use of coagulation factors in the early hospital treatment of trauma patients with ongoing bleeding.


Feasibility and availability of ⁶⁸Ga-labelled peptides.
(68)Ga has attracted tremendous interest as a radionuclide for PET based on its suitable half-life of 68 min, high positron emission yield and ready availability from (68)Ge/(68)Ga generators, making it independent of cyclotron production. (68)Ga-labelled DOTA-conjugated somatostatin analogues, including DOTA-TOC, DOTA-TATE and DOTA-NOC, have driven the development of technologies to provide such radiopharmaceuticals for clinical applications mainly in the diagnosis of somatostatin receptor-expressing tumours. We summarize the issues determining the feasibility and availability of (68)Ga-labelled peptides, including generator technology, (68)Ga generator eluate postprocessing methods, radiolabelling, automation and peptide developments, and also quality assurance and regulatory aspects. (68)Ge/(68)Ga generators based on SnO(2), TiO(2) or organic matrices are today routinely supplied to nuclear medicine departments, and a variety of automated systems for postprocessing and radiolabelling have been developed. New developments include improved chelators for (68)Ga that could open new ways to utilize this technology. Challenges and limitations in the on-site preparation and use of (68)Ga-labelled peptides outside the marketing authorization track are also discussed.


Complete genome analysis of coxsackievirus A24 isolated in Yunnan, China, in 2013.
Human coxsackievirus A24 (CVA24) belongs to the species Enterovirus C, and variants of this virus frequently cause acute hemorrhagic conjunctivitis (AHC). The complete genome of the K282/YN/CHN/2013 strain, isolated from a healthy child in Yunnan, China, in 2013, is reported here for the first time. The strain showed 80.0 % and 79.9 % nucleotide sequence identity to CVA24 prototype strain Joseph and CVA24 variant prototype EH24, respectively. The K282/YN/CHN/2013 strain belongs to the CVA24 serotype. Twelve amino acid differences, most of which are in structural regions, were found between the CVA24 and CVA24v strains. In the whole-length genome sequence, only the structural region of K282/YN/CHN/2013 was similar to that of the CVA24 strains; the other genome regions were more similar to those of other members of the species Enterovirus C. Recombination analysis showed evidence of recombination with other viruses of the same species.


Postnatal development of orexin-A and orexin-B like immunoreactivities in the Eastern grey kangaroo (Macropus giganteus) hypothalamus.
The Eastern grey kangaroo (Macropus giganteus) is a marsupial, which is born in an extremely undeveloped state and has a long suckling period in the mother's pouch. In the present study, we examined the immunoreactivities of orexin-A (OXA) and orexin-B (OXB) in the hypothalamus of the Eastern grey kangaroo during the preweaning period, postweaning period and adulthood. In the preweaning period, only a few OXA- and OXB-like immunoreactive (LI) neurons and fibers were present and the intensity of staining was very weak. In the postweaning period, there was a pronounced increase in the numbers of OXA- and OXB-LI neurons and fibers and the intensity of the immunoreactivity was considerably stronger in comparison to the preweaning period. In the adult, the numbers of OXA- and OXB-LI neurons and fibers appeared to be slightly increased and the intensity was slightly stronger in comparison to the postweaning period. At all time periods, the distributions of OXA- and OXB-LI neurons was similar. The postnatal development of hypothalamic orexin neurons may be associated with developmental changes, including feeding behavior.


Platelet activation and prothrombotic properties in a mouse model of peritoneal sepsis.
Sepsis is associated with thrombocytopenia and microvascular thrombosis. Studies have described platelets implication in this pathology but their kinetics of activation and behavior remain poorly known. We show in a mouse model of peritonitis, the appearance of platelet-rich thrombi in organ microvessels and organ damage. Complementary methods are necessary to characterize platelet activation during sepsis as circulating soluble markers and platelet-monocyte aggregates revealed early platelet activation, while surface activation markers were detected at later stage. A microfluidic based ex-vivo thrombosis assay demonstrated that platelets from septic mice have a prothrombotic behavior at shear rate encountered in microvessels. Interestingly, we found that even though phosphoinositide-3-kinase β-deficient platelet mice formed less thrombi in liver microcirculation, peritoneal sepsis activates a platelet alternative pathway to compensate the otherwise mandatory role of this lipid-kinase to form stable thrombi at high shear rate. Platelets are rapidly activated during sepsis. Thrombocytopenia can be attributed in part to platelet-rich thrombi formation in capillaries and platelet-leukocytes interactions. Platelets from septic mice have a prothrombotic phenotype at a shear rate encountered in arterioles. Further studies are necessary to unravel molecular mechanisms leading to this prothrombotic state of platelets in order to guide the development of future treatments of polymicrobial sepsis.


Efficacy and safety of warm needle treatment for scapulohumeral periarthritis: A protocol for systematic review and meta-analysis.
To evaluate the effectiveness and safety of warm needle acupuncture (WNA) treatment for Scapulohumeral periarthritis. Relevant randomized controlled trials will be searched from the databases of Pubmed, the Cochrane Library, Embase, CNKI, Wanfang Database, CBM and VIP Database from their inception to September 2021. The primary outcomes are effective rate, visual analog scale score. The secondary outcomes are Constant-Murley score, Japanese Orthopaedic Association scores, adverse events. Two reviewers will independently select studies, collect data, and assess the methodology quality by the Cochrane risk of bias tool. The Stata 14.0 will be used for meta-analysis. This study is ongoing and will be submitted to a peer-reviewed journal for publication. This study will provide an assessment of the current state of WNA for the scapulohumeral periarthritis, aiming to show the efficacy and safety of WNA treatment. There is no requirement of ethical approval and informed consent, and it will be in print or published by electronic copies. INPLASY2020100049.


Analysis of single-staged resection of a fourth ventricular tumor via a combined infratentorial-supracerebellar and telovelar approach: Case report and review of the literature.
The authors explore a combined infratentorial-supracerebellar and telovelar approach in an adult, while avoiding vermian-splitting methods for a large, midline, fourth-ventricular tumor, unapproachable though a single traditional route. Experience with a combined surgical approach for pediatric patients has been published, but the authors believe that describing this combined method in an adult will provide a preliminary experience for further exploration of this approach in other adult patients. The authors present a review of the literature along with the case of a 60-year-old man with slight ataxia who presented with a 1-month history of gait difficulty and memory lapse. His MRI of the brain showed mild hydrocephalus and a large tumor of the fourth ventricle. Surgical removal through a suboccipital craniotomy was attempted, and part of the tumor overlying the tectum and the superior cerebellar velum was removed without difficulty. However, despite inferior retraction of the vermis, which allowed further resection of the tumor from the fourth ventricle, residual tumor in the caudal surgical resection cavity was present. Partial transection of the vermis was considered, but avoided because of potential neurological deficits. Instead, the authors redirected their approach and exposed the residual tumor by transecting the inferior medullary velum and removed additional tumor while avoiding the floor of the fourth ventricle. The infratentorial-supracerebellar and telovelar approach resulted in total gross resection of the tumor. For patients with large midline tumors that arise from the superior vermis or the quadrigeminal plate and fill the upper third of the fourth ventricular space, this combined approach may offer a unique possibility of safe tumor removal. This case demonstrates the benefit of a combined approach for a select group of patients.


[Total serum IgE: normal pediatric values using the FAST IgE fluoroimmunoenzymatic technic].
This reports covers the application to paediatrics of total IgE determination by the means of a new direct, sandwich type, fluorescence enzyme immuno-assay (Fluoro-allergo sorbent test:FAST IgE). The technical process is adapted for usual determinations, in case of infants and young children, of low normal rates with a good sensitivity, and of high pathological rates. IgE total usual values are established by the FAST IgE test from serums of healthy children, aged from one day to 14 years. Seven age groups are to be distinguished.


Isolated limb perfusion for an irresectable melanoma recurrence in a Jehovah's witness.
Isolated limb perfusion (ILP) is a treatment option for irresectable melanoma lesions, because with ILP 20-fold higher concentrations of chemotherapy can be achieved locally than is systemically possible and high response rates are subsequently achieved. Jehovah's witnesses do not accept any form of blood transfusion, either autologous or homologous blood or only blood products. The use of an extracorporeal circuit, without the use of any blood products is acceptable for Jehovah's witnesses. The case of a 59-year-old Jehovah's witness with an irresectable melanoma recurrence for which an ILP. Because of adequate blood flow through the perfused limb, the limb did not become acidotic, even though there was a significant drop in the Hb concentration in the limb during the ILP. Isolated limb perfusions without the use of any blood transfusion products are technically possible, but an adequate preoperative hemoglobin concentration is a prerequisite.


Interruption of pregnancy with vaginal suppositories containing 16,16-dimethyl-trans-delta 2-prostaglandin E1 methyl ester.
A new synthesized Prostaglandin E1 analogue, 16,16-dimethyl-trans-delta 2-Prostaglandin E1 methyl ester, has been shown to be effective in termination of 1st and second trimester pregnancy following vaginal administration. Suppositories, each containing 1 mg Prostaglandin E1 derivative, were administered five times to each of fifty pregnant women of five to twenty gestational weeks at three-hourly intervals. The procedure was clinically effective in 86% of the patients resulting in 56% complete and 30% incomplete abortions. The cervix of all patients was dilated up to 7 mm in diameter at the second insertion of the suppository. Vaginal bleeding and lower abdominal pain not requiring sedation were observed in all patients. Diarrhea (42%), vomiting (6%), and fever (4%) were the most common side effects. The Karyopyknotic Index of the vaginal smear increased significantly (p less than 0.01) twelve hours after the initial insertion. The superficial cells of the cervix gradually degenerated during the termination procedure.


Patterns of white and gray structural abnormality associated with paediatric demyelinating disorders.
The impact of multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) - associated disorders (MOGAD) on brain structure in youth remains poorly understood. Reductions in cortical mantle thickness on structural MRI and abnormal diffusion-based white matter metrics (e.g., diffusion tensor parameters) have been well documented in MS but not in MOGAD. Characterizing structural abnormalities found in children with these disorders can help clarify the differences and similarities in their impact on neuroanatomy. Importantly, while MS and MOGAD affect the entire CNS, the visual pathway is of particular interest in both groups, as most patients have evidence for clinical or subclinical involvement of the anterior visual pathway. Thus, the visual pathway is of key interest in analyses of structural abnormalities in these disorders and may distinguish MOGAD from MS patients. In this study we collected MRI data on 18 MS patients, 14 MOGAD patients and 26 age- and sex-matched typically developing children (TDC). Full-brain group differences in fixel diffusion measures (fibre-bundle populations) and cortical thickness measures were tested using age and sex as covariates. Visual pathway analysis was performed by extracting mean diffusion measures within lesion free optic radiations, cortical thickness within the visual cortex, and retinal nerve fibre layer (RNFL) and ganglion cell layer thickness measures from optical coherence tomography (OCT). Fixel based analysis (FBA) revealed MS patients have widespread abnormal white matter within the corticospinal tract, inferior longitudinal fasciculus, and optic radiations, while within MOGAD patients, non-lesional impact on white matter was found primarily in the right optic radiation. Cortical thickness measures were reduced predominately in the temporal and parietal lobes in MS patients and in frontal, cingulate and visual cortices in MOGAD patients. Additionally, our findings of associations between reduced RNFLT and axonal density in MOGAD and TORT in MS patients in the optic radiations imply widespread axonal and myelin damage in the visual pathway, respectively. Overall, our approach of combining FBA, cortical thickness and OCT measures has helped evaluate similarities and differences in brain structure in MS and MOGAD patients in comparison to TDC.


Contraception in obese older women.
Obesity is increasing in most western countries and rises significantly with age. Obese women are as sexually active as women of normal weight, and new sexual relationships in the older reproductive years are becoming more commonplace and still require effective contraception. Continuation of pregnancy in a woman over 40 carries health risks which are exacerbated by the presence of obesity. A high proportion of pregnancies in women over 40 are unplanned and end in therapeutic abortion. The prevalence of obesity and the high rates of contraceptive use amongst older women mean that any increase in associated risk is likely to be of public health concern. There are very few data on the specific risks of contraceptive use in obese older women. As fertility declines with age, all methods become increasingly effective. No single method is contraindicated by age alone but particular caution is required where the use of estrogen containing preparations is considered as the risks associated with estrogen are all also independently associated with increasing age and body mass index. Non-estrogen containing methods are available, whether hormonal, barrier or surgical, which are effective, acceptable and safer in the obese older woman. Some methods of contraception may indeed have particular non-contraceptive benefits for this population.


Postoperative change in lumbopelvic alignment after short-segment transforaminal lumbar interbody fusion is related to preoperative postural difference in lumbar lordosis.
Postoperative changes in lumbar lordosis (LL) after transforaminal lumbar interbody fusion (TLIF) and the related factors are not well-understood. Recently, the preoperative difference in LL between standing and supine positions (DiLL) was proposed as a factor for predicting postoperative radiologic outcomes after short-segment TLIF. This study investigated the influence of DiLL on mid-term radiological outcomes after short-segment TLIF. Sixty-six patients with lumbar degenerative disease treated with short-segment TLIF (1-2 levels) who underwent lumbar spine standing radiographs at 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, and 5 years postoperatively were divided into DiLL (+) and DiLL (-) groups (preoperative DiLL ≥0° and <0°, respectively). Associations between the postoperative change in LL and DiLL and clinical outcomes (Oswestry disability index (ODI) and Nakai score) were evaluated. Temporary restoration of LL (+4.5°) until 1 year postoperatively and a subsequent decrease in LL from 1 to 5 years postoperatively (-5.3°) was observed in the DiLL (+) group. No postoperative change in LL was observed in the DiLL (-) group. Postoperative changes in LL were mainly observed in non-fused segments. The postoperative change in LL (ΔLL) until 1 year postoperatively had a significant positive association with DiLL (p = 0.00028), whereas ΔLL from 1 to 5 years postoperatively showed a significant negative association with DiLL (p = 0.010) and a positive association with Nakai score (p = 0.028). ΔLL until 5 years postoperatively showed a significant positive association with postoperative ODI improvement (p = 0.011). DiLL (+) patients showed a specific time course with temporary LL restoration until 1 year postoperatively and a subsequent decrease in LL from 1 to 5 years postoperatively. Patients with larger postoperative increase in LL until 5 years postoperatively and lesser decrease in LL from 1 to 5 years postoperatively tended to show better mid-term clinical outcomes.


Effects of acid proteinase inhibitors on human neutrophil chemotaxis and lysosomal enzyme release. II. Bromphenacyl bromide and 1,2-epoxy-3-(p-nitrophenoxy)propane.
Two active site inhibitors of acid proteinases were tested for their effects on human neutrophil chemotaxis and lysosomal enzyme release. Both bromphenacyl bromide (BPAB) and epoxy-p-nitrophenoxypropane (EPNP) inhibited chemotaxis and chemotaxin-induced enzyme release elicited by pepstatin and formylmethionyl peptides, which share membrane receptors, and also by zymosan-activated serum, the major active component of which (C5a) occupies a different receptor. In contrast to the previously tested acid protease inhibitor diazoacetylnorleucine methyl ester, neither BPAB nor EPNP blocked binding of [3H]fMLP to neutrophils. Thus BPAB and EPNP inhibit chemotaxin-mediated neutrophil functions, but not by interaction with the chemotaxin receptor.


Biomimetic Multispiked Connecting Ti-Alloy Scaffold Prototype for Entirely-Cementless Resurfacing Arthroplasty Endoprostheses-Exemplary Results of Implantation of the Ca-P Surface-Modified Scaffold Prototypes in Animal Model and Osteoblast Culture Evaluation.
We present here-designed, manufactured, and tested by our research team-the Ti-alloy prototype of the multispiked connecting scaffold (MSC-Scaffold) interfacing the components of resurfacing arthroplasty (RA) endoprostheses with bone. The spikes of the MSC-Scaffold prototype mimic the interdigitations of the articular subchondral bone, which is the natural biostructure interfacing the articular cartilage with the periarticular trabecular bone. To enhance the osteoinduction/osteointegration potential of the MSC-Scaffold, the attempts to modify its bone contacting surfaces by the process of electrochemical cathodic deposition of Ca-P was performed with further immersion of the MSC-Scaffold prototypes in SBF in order to transform the amorphous calcium-phosphate coating in hydroxyapatite-like (HA-like) coating. The pilot experimental study of biointegration of unmodified and Ca-P surface-modified MSC-Scaffold prototypes was conducted in an animal model (swine) and in osteoblast cell culture. On the basis of a microscope-histological method the biointegration was proven by the presence of trabeculae in the interspike spaces of the MSC-Scaffold prototype on longitudinal and cross-sections of bone-implant specimens. The percentage of trabeculae in the area between the spikes of specimen containing Ca-P surface modified scaffold prototype observed in microCT reconstructions of the explanted joints was visibly higher than in the case of unmodified MSC-Scaffold prototypes. Significantly higher Alkaline Phosphatase (ALP) activity and the cellular proliferation in the case of Ca-P-modified MSC-Scaffold pre-prototypes, in comparison with unmodified pre-prototypes, was found in osteoblast cell cultures. The obtained results of experimental implantation in an animal model and osteoblast cell culture evaluations of Ca-P surface-modified and non-modified biomimetic MSC-Scaffold prototypes for biomimetic entirely-cementless RA endoprostheses indicate the enhancement of the osteoinduction/osteointegration potential by the Ca-P surface modification of the Ti-alloy MSC-Scaffold prototype. Planned further research on the prototype of this biomimetic MSC-Scaffold for a new generation of RA endoprostheses is also given.


Self-assembly cavitand precisely recognizing hexafluorosilicate: a concerted action of two coordination and twelve CH···F bonds.
Bis-pyridazine tectons support the structure of metallosupramolecular cavitand Cu2L4(4+), which is capable of selective encapsulation of SiF6(2-) anions by a set of multiple host-guest interactions.


RNA N6-Methyladenosine Methyltransferase METTL3 Facilitates Colorectal Cancer by Activating the m6A-GLUT1-mTORC1 Axis and Is a Therapeutic Target.
RNA N6-methyladenosine (m6A) modification has recently emerged as a new regulatory mechanism in cancer progression. We aimed to explore the role of the m6A regulatory enzyme METTL3 in colorectal cancer (CRC) pathogenesis and its potential as a therapeutic target. The expression and clinical implication of METTL3 were investigated in multiple human CRC cohorts. The underlying mechanisms of METTL3 in CRC were investigated by integrative m6A sequencing, RNA sequencing, and ribosome profiling analyses. The efficacy of targeting METTL3 in CRC treatment was elucidated in CRC cell lines, patient-derived CRC organoids, and Mettl3-knockout mouse models. Using targeted clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 dropout screening, we identified METTL3 as the top essential m6A regulatory enzyme in CRC. METTL3 was overexpressed in 62.2% (79/127) and 88.0% (44/50) of primary CRCs from 2 independent cohorts. High METTL3 expression predicted poor survival in patients with CRC (n = 374, P < .01). Functionally, silencing METTL3 suppressed tumorigenesis in CRC cells, human-derived primary CRC organoids, and Mettl3-knockout mouse models. We discovered the novel functional m6A methyltransferase domain of METTL3 in CRC cells by domain-focused CRISPR screening and mutagenesis assays. Mechanistically, METTL3 directly induced the m6A-GLUT1-mTORC1 axis as identified by integrated m6A sequencing, RNA sequencing, ribosome sequencing, and functional validation. METTL3 induced GLUT1 translation in an m6A-dependent manner, which subsequently promoted glucose uptake and lactate production, leading to the activation of mTORC1 signaling and CRC development. Furthermore, inhibition of mTORC1 potentiated the anticancer effect of METTL3 silencing in CRC patient-derived organoids and METTL3 transgenic mouse models. METTL3 promotes CRC by activating the m6A-GLUT1-mTORC1 axis. METTL3 is a promising therapeutic target for the treatment of CRC.


Chasteberry.
For centuries, chasteberry has been used to treat many hormone-related gynecologic conditions. The current literature supports the use of chasteberry for cyclical breast discomfort and premenstrual syndrome; data on its use for menstrual irregularities and fertility disorders are weak. Its traditional use as a galactagogue (i.e., a substance that enhances breast milk production) is not well supported in the literature and should be discouraged. There are no clinical data to support the use of chasteberry for reducing sexual desire, which has been a traditional application. Chasteberry is well tolerated; reported adverse effects are minor and may include gastrointestinal complaints, dizziness, and dry mouth. No herb-drug interactions have been reported, but caution is advised for its concomitant use with dopamine agonists or antagonists. Optimal standardization and dosing recommendations await clarification in clinical studies.


Population-based case-control study of essential tremor.
Current epidemiologic data on the association between environmental factors and essential tremor (ET) are scanty. In a population-based case-control study we investigated the relationship between some putative risk factors and ET. In the present study, we included all subjects identified during a door-to-door prevalence survey in a Sicilian community, affected by ET, and alive on 1 November 1987 (n=31). Of the 31 prevalent cases of ET, we were able to contact 28 subjects. Twenty-eight controls were randomly selected from the general population and matched to each case for age and sex. Exposure variables were investigated by interviewing the patients and their controls or close relatives, using a structured questionnaire. The odds for habitual alcohol consumption were 0.3, indicating a protective effect. The odds for exposure to agricultural chemicals and domestic animals were 2.5 and 2.7, respectively, suggesting a role as potential risk factors. However, the associations found by us were not statistically significant.


Trends in mortality, complications, and demographics for primary hip arthroplasty in the United States.
To determine trends in characteristics of total hip arthroplasty (THA) in the United States, the National Hospital Discharge Survey (NHDS) was analyzed from 1990 to 2004 for trends in in-hospital mortality and complications, length of hospital stay, demographics, and comorbidities. The number of THAs performed increased by 158%, whereas mortality rates remained low and slightly decreased (from 0.32% to 0.29%). Prevalence of procedure-related complications decreased over time, and length of stay decreased from an average of 8.7 days to 4.5 days. These improvements occurred despite an increase in comorbidities in patients. An increase in both the proportion of discharges to long- and short-term care facilities and in the proportion of procedures performed in smaller hospitals was noted. Multiple temporal changes in outcomes and demographics for THA were found. These changes have implications for clinical care and allocation of health resources.


WITHDRAWN: Quantification of changes in eyelid position in patients with dry eye syndrome: A randomized, placebo-controlled multicenter study of application of topical anesthetic.
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Stored packed red blood cells contain a procoagulant phospholipid reducible by leukodepletion filters and washing.
Ageing RBC gradually increase the exposure of phosphatidylserine (PS) on their surface, due to loss of membrane asymmetry. PS expression on red cells is not normally a significant factor in the hemostatic process, because aged RBC are rapidly cleared from the circulation. We propose that the presence of many altered red cells during massive transfusion can lead to increased procoagulant activity similar to what is seen in disease states where it is known to play a pathophysiologic role in microvascular disease. Procoagulant activity of phospholipid generated during storage of PRBC was evaluated using PRBC's as the only source of phospholipid in the determination of modified Russell's viper venom times of 10 PRBC units in which half of each unit was left unfiltered and half of each unit filtered. Florescent labeled annexin V binding by PRBC was also assessed by flow cytometry over time in storage. The effect of washing and filtration on these parameters was also determined. As time of storage increased, the Russell's viper venom time of both the unfiltered and filtered units shortened (p<0.01). There was a significant lengthening of the Russell's viper venom time at all time points measured when unfiltered units were compared to filtered units (p<0.01). In both unfiltered and filtered units, with increased length of storage, there was a gradual increase in the percentage of cells or particles binding annexin V (p<0.01). Filtration resulted in a significant reduction in the percentage of cells or particles binding annexin V at all time points measured (p<0.01). The effect of washing of PRBC units on the RVVT was assessed for unfiltered and filtered units on day 42. Washing resulted in a significant reduction of the RVVT in both unfiltered and filtered groups (p<0.01). Levels of annexin V binding and procoagulant phospholipid activity similar to levels seen in disease states associated with significant vasoocclusive pathophysiology were found toward the end of the storage period of PRBC units. It was possible to reduce both of these parameters by leukodepletion at collection, and with washing of PRBC at the end of storage. Filtration at collection resulted in a 67% increase in RVVT over unfiltered units by day 42 of storage. On day 42 of storage, washing of filtered units resulted in a 21% increase in RVVT, and washing of unfiltered units resulted in a 34% increase in RVVT. The effects seen with filtration and washing were additive suggesting that in spite of filtration at collection, deterioration of cells continues based on age since further removal of phospholipid can be induced with washing of filtered units on day 42.


[SEVERE HYPERNATREMIA IN A TEENAGE GIRL SUFFERING FROM ANOREXIA NERVOSA].
Hypernatremic dehydration is an uncommon condition, whose main treatment is fluid administration. In cases of extreme hypernatremia, that treatment paradoxically poses a real danger to the patient's morbidity and mortality. In very rare cases, restrictive type anorexia nervosa causes extreme dehydration that can result in elevated sodium levels. In this case study we present a teenage girl who suffers from restrictive anorexia nervosa and was admitted to the pediatric intensive care unit (PICU) with an acute confusional state, with extremely severe hypernatremia up to 203 mEq/L, combined with hyperglycemia up to 700 mg/dL. Under hypotonic electrolyte solution treatment, a gradual sodium level decrease of 8 mEq/L per day was achieved with complete normalization of sodium without any neurological damage. Moreover, glucose levels were normalized rapidly and spontaneously without additional treatment with insulin.


Research awareness: managerial challenges for nurses in the Republic of Ireland.
In spite of the growing body of literature, the reality of getting research into practice remains problematic. The present study aimed to establish contemporary levels of research awareness among nurses in Ireland. A random sample of 234 registered nurses (RNs). A self-report survey Research Awareness Questionnaire (RAQ) was used to collect data in March 2005. Most agreed (92%) that research can improve patient care and 93% agreed that it is the way forward to change clinical practice. Most nurses' perceived research as being integral to their role. However, 71% of the nurses within the present study indicated that they had insufficient support and encouragement from peers and professionals. Similarly, 69.2% indicated insufficient support from management. Consistent with other countries, nurses in Ireland have a positive attitude towards evidence-based nursing but face many obstacles which include a lack of time, support, knowledge and confidence. Nurse managers have a vital role in the use and dissemination of research among staff. It is imperative that nurse managers have clinical expertise, research awareness training, and awareness to promote research-based practice and attempt to provide positive role modelling in addition to protected time for research efforts.


Self-assembled multifunctional nanotheranostics against circulating tumor clusters in metastatic breast cancer.
Circulating tumor clusters (CTC) disseminating from the primary tumor are responsible for secondary tumor formation where the conventional treatments such as chemotherapy and radiotherapy does not prevent the metastasis at locally advanced stage of breast cancer. In this study, a smart nanotheranostic system has been developed to track and eliminate the CTCs before it can colonize at a new site, which would reduce metastatic progression and increase the five-year survival rate of the breast cancer patients. Targeted multiresponsive (magnetic hyperthermia and pH) nanomicelles incorporated with NIR fluorescent superparamagnetic iron oxide nanoparticles were developed based on self-assembly for dual modal imaging and dual toxicity for spontaneous killing of CTCs in blood stream. A heterogenous tumor clusters model was developed to mimic the CTCs isolated from breast cancer patients. The nanotheranostic system was further evaluated for the targeting property, drug release kinetics, hyperthermia and cytotoxicity against developed CTC model in vitro. In vivo model in BALB/c mice equivalent to stage III and IV human metastatic breast cancer was developed to evaluate the biodistribution and therapeutic efficacy of micellar nanotheranostic system. Reduced CTCs in blood stream and low distant organ metastasis after treatment with the nanotheranostic system demonstrates its potential to capture and kill the CTCs that minimize the secondary tumor formation at distant sites.


Efficacy of methylprednisolone pulse therapy versus infliximab in the treatment of severe flares of chronic polyarthritis.
To compare short term efficacy of pulse intravenous (iv) Methylprednisolone (MP) versus Infiximab in flares of polyarthritis. Observational study of consecutive patients admitted with flares of chronic polyarthritis. Treatment consisted of three iv doses of MP 1000mg on alternate days (MP-group, n = 10) or of Infliximab will be 3 mg/kg at baseline, two, and six weeks later (I-group, n=9). DMARD therapy was initiated/continued in all patients. Disease parameters at baseline (t=0), two weeks (t=1) and twelve weeks (t=2) were compared by non-parametric testing. Reductions in disease parameters at both t=1 and t=2, the occurrence of side effects and the proportion of patients reaching ACR 20, 50 or 70% response criteria were similar in both groups. Pulse MP resulted in a symptomatic response similar to Infliximab in our patients. The benefit of MP was observed for up to 3 months.


Ligand-induced conformational changes in cytosolic protein kinase C.
The changes in intrinsic spectral properties of protein kinase C were monitored upon association with its divalent cation and lipid activators in a model membrane system. The enzyme demonstrated changes in both its intrinsic fluorescence and far ultraviolet circular dichroism spectra upon association with lipid vesicles in the absence of calcium. The acidic phospholipid, phosphatidylserine, significantly quenched the intrinsic tryptophan fluorescence and was also the most potent lipid support for the phosphorylating activity of the enzyme. The enzyme was fully activated by a number of Ca2(+)-lipid combinations which correlated with maximal fluorescence quenching (40-50%) of available tryptophan residues in hydrophobic domains. The circular dichroism structure of the associated active-protein Ca2(+)-lipid complexes suggested different active enzyme secondary structures. However, the Ca2(+)-dependent changes in fluorescence and circular dichroism spectra were observed only after the enzyme associated with the lipid vesicles. These data suggest that protein kinase C has the properties of a complex multidomain protein and provides an additional perspective into the mechanism of protein kinase C activation.


Correlates of knowledge and beliefs about depression among long-term care staff.
Despite the high prevalence of depression in long-term care (LTC), it often is unrecognized and inadequately treated. Thus, the goals of the present study were to evaluate LTC staff characteristics that are associated with knowledge and beliefs about depression. A cross sectional study of 371 LTC staff members completed a knowledge and beliefs about depression questionnaire, a short demographic questionnaire, a burden measure, and a questionnaire about attitudes associated with working with depressed residents. Relative to nurses, social workers, and activity staff, paraprofessional caregivers had a lower score on the depression measure and a higher score on the burden measure. Paraprofessional caregivers were more likely to view depression as a normal phenomenon, held less accurate beliefs about signs and symptoms of depression, and were less familiar with the effectiveness of specific treatments of depression. Educational interventions about depression should be specifically geared to meet the needs of paraprofessional caregivers who provide the majority of care to LTC residents, yet possess less knowledge about depression and its treatments.


[Interacting insulators from the Drosophila melanogaster bithorax complex can form independent expression domains].
Regulatory region of three bithorax complex genes, Ultrabithorax (Ubx), abdominal-A (abd-A), and Abdominal-B (Abd-B) can be divided into nine iab domains, capable of directing expression of one of the genes in certain abdominal parasegment of Drosophila. In the Abd-B regulatory region, three insulators were identified, including Fab-7 and Fab-8, which flanked the iab-7domain, and Mcp, which separated the Abd-B and abd-A regulatory regions. It was suggested that boundary insulators formed a barrier between active and repressed chromatin. In the present study, using the yellow and white reporter genes and different combinations of known insulators, Mcp, Fab-7, and Fab-8, it was demonstrated that only specific interaction of two insulators was capable of isolation of active and repressed chromatin, i.e., the formation of independent expression domains.


Synaptic Loss in Frontotemporal Dementia Revealed by [11 C]UCB-J Positron Emission Tomography.
Synaptic loss is an early feature of neurodegenerative disease models, and is severe in post mortem clinical studies, including frontotemporal dementia. Positron emission tomography (PET) with radiotracers that bind to synaptic vesicle glycoprotein 2A enables quantification of synaptic density in vivo. This study used [11 C]UCB-J PET in participants with behavioral variant frontotemporal dementia (bvFTD), testing the hypothesis that synaptic loss is severe and related to clinical severity. Eleven participants with clinically probable bvFTD and 25 age- and sex-matched healthy controls were included. Participants underwent dynamic [11 C]UCB-J PET, structural magnetic resonance imaging, and a neuropsychological battery, including the revised Addenbrooke Cognitive Examination, and INECO frontal screening. General linear models compared [11 C]UCB-J binding potential maps and gray matter volume between groups, and assessed associations between synaptic density and clinical severity in patients. Analyses were also performed using partial volume corrected [11 C]UCB-J binding potential from regions of interest (ROIs). Patients with bvFTD showed severe synaptic loss compared to controls. [11 C]UCB-J binding was reduced bilaterally in medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insular cortex, and medial temporal lobe. Synaptic loss in the frontal and cingulate regions correlated significantly with cognitive impairments. Synaptic loss was more severe than atrophy. Results from ROI-based analyses mirrored the voxelwise results. In accordance with preclinical models, and human postmortem evidence, there is widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to severity. [11 C]UCB-J PET could support translational studies and experimental medicine strategies for new disease-modifying treatments for neurodegeneration. ANN NEUROL 2023;93:142-154.


Comparison of KRAS genotype: therascreen assay vs. LNA-mediated qPCR clamping assay.
Kirsten rat sarcoma virus (KRAS) wild-type status determined using a locked nucleic acid (LNA)-mediated quantitative polymerase chain reaction (qPCR) clamping assay (LNA assay) predicted response to therapy in the CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) study. A companion KRAS diagnostic tool has been developed for routine clinical use (QIAGEN therascreen kit) (QIAGEN Manchester Ltd, Manchester, UK). We wanted to assess the concordance between the validated US Food and Drug Administration (FDA)-approved therascreen assay and the LNA assay in determining the KRAS status of a subset of patients enrolled in the CRYSTAL study. DNA extracted from paraffin-embedded tumor sections was tested for KRAS status using the therascreen assay. Efficacy data from the CRYSTAL study were assessed to determine if the overall survival (OS) hazard ratio for cetuximab in patients identified as having KRAS wild-type status using the therascreen assay was equivalent to that in patients identified as KRAS wild-type using the LNA assay. This was determined by assessing if the concordance between the therascreen assay and the LNA assay met the minimum threshold (prespecified as 0.8) to achieve a significant difference in the OS hazard ratio in favor of the cetuximab + FOLFIRI (5-fluorouracil, leucovorin [folinic acid], irinotecan) arm in the KRAS wild-type population as identified using the therascreen assay. Of the 148 samples determined to be KRAS wild-type (therascreen assay), 141 (95.3%) samples were also KRAS wild-type (LNA assay) and 7 samples (4.7%) were KRAS mutant (LNA assay). The prespecified primary concordance measure p was 141/148 = 0.953 (95% confidence interval [CI], 0.905-0.981). The concordance was statistically significantly higher than the prespecified threshold of 0.8 for concordance between the therascreen assay and the LNA assay. Consistent with the concordance exceeding the prespecified threshold, the OS hazard ratio (cetuximab + FOLFIRI arm vs. FOLFIRI arm) in the KRAS wild-type population, determined by the therascreen assay, supported a significant benefit for cetuximab (ie, the 95% CI excluded 1) and was comparable to the OS hazard ratio observed in the CRYSTAL study KRAS wild-type population (LNA assay) even after adjustment for potentially confounding baseline variables. These results support the utility of the therascreen assay for identifying patients who may benefit from cetuximab therapy for metastatic colorectal cancer.


Trends in incidence of ischaemic stroke in people with and without diabetes in Ireland 2005-2015.
We aim to describe the epidemiology of ischaemic stroke and in-hospital mortality associated with stroke among men and women with and without diabetes from 2005 to 2015. Secondary data analysis of national hospital discharge data from the Hospital Inpatient Enquiry database. Stroke incidence and in-hospital mortality rates in people with and without diabetes were calculated. Poisson regression models were used to estimate the incidence rate ratio (IRR) and assess trends over time. The age-adjusted incidence of stroke was twice as high in people with diabetes compared to those without diabetes (men IRR 2.0 [95% CI 1.95-2.06] and women IRR 2.2 [95% CI 2.12-2.27]). The incidence of ischaemic stroke decreased by an average 1.7% per year in men with diabetes and 3.3% per year in women with diabetes. In people without diabetes, the average annual reduction was smaller (0.2% per year in men and 1% per year in women). In-hospital mortality associated with admission with ischaemic stroke was approximately twice as high in those with diabetes compared to those without diabetes among men [IRR 1.81 (1.67-1.97)] and women [IRR 2 (95% CI 1.84-2.18)]. Despite decreases in incidence of ischaemic stroke and associated in-hospital mortality, there remains a twofold increased risk of ischaemic stroke and mortality in people with diabetes. Therefore, priority must be given to management of risk factors for ischaemic stroke in people with diabetes as well as continued development of targeted stroke prevention strategies.


Bunazosin, an alpha-adrenoceptor antagonist, blocks calcium current in guinea-pig ventricular myocytes.
1. Effect of bunazosin, an alpha 1-adrenoceptor antagonist, upon the slow inward Ca2+ current (ICa) was studied in single ventricular myocytes of the guinea-pig using a whole-cell patch-clamp technique. 2. Bunazosin (10-100 microM) decreased ICa in a concentration-dependent manner with an IC50 of 60 microM during depolarization to + 10 mV from the holding potential of -40 mV. 3. As for the inactivation process of ICa, the steady-state inactivation (f infinity) curve was shifted toward more negative potentials from -12 mV to -17 mV and -21 mV at f infinity = 0.5, by 30 microM and 70 microM bunazosin. 4. Inhibition of ICa by the compound (10 microM) was also dependent on stimulation frequency, with greater block induced at 2 Hz (50%) than at 0.33 Hz (13%). 5. It is concluded that bunazosin possesses a direct Ca2+ channel-blocking (class 4) action in a rate-dependent fashion.


Percutaneous versus surgical treatment for patients with hypertrophic obstructive cardiomyopathy and enlarged anterior mitral valve leaflets.
The purpose of this study was to compare percutaneous transluminal septal myocardial ablation (PTSMA) and septal myectomy combined with mitral leaflet extension (MLE) in symptomatic hypertrophic obstructive cardiomyopathy patients with an enlarged anterior mitral valve leaflet (AMVL). Both PTSMA and myectomy reduce septal thickness and left ventricular outflow tract (LVOT) gradient; however, an uncorrected enlarged AMVL may predispose to residual systolic anterior motion (SAM) after successful standard myectomy or PTSMA. Myectomy with MLE previously demonstrated superior hemodynamic results compared with standard myectomy, but its value relative to PTSMA is unknown. Twenty-nine patients (aged 44+/-12 years) underwent myectomy with MLE, and 43 patients (aged 52+/-17 years) underwent PTSMA. Mitral leaflet area was similar in both groups (16.7+/-3.4 versus 15.9+/-2.7 cm2, respectively). After PTSMA, 2 patients died, 4 needed a reintervention, and 4 required a permanent pacemaker for complete heart block. After surgery, only 1 patient needed a reintervention. At 1-year follow-up, LVOT gradients did not differ between surgical and PTSMA patients (17+/-14 versus 23+/-19 mm Hg, respectively). Preinterventional mitral regurgitation grade was more severe in the surgical group, but with myectomy combined with MLE, the residual grade was similar to that of PTSMA. Mean SAM grade decreased significantly more after surgery (from 2.9+/-0.3 to 0.5+/-0.7 mm Hg versus from 2.8+/-0.5 to 1.3+/-0.9 [corrected], P<0.05). PTSMA in these selected patients with hypertrophic obstructive cardiomyopathy had more periprocedural complications and resulted in more reinterventions. Hemodynamic results (SAM grade and reduction in mitral regurgitation) were better in surgical patients.


Detection of a rare beta-globin nonsense mutation [codon 59 (AAG-->TAG)] in an Italian family.
In this study we report on the hematological and molecular findings of a family from Central Italy, whose 33-year-old male proband presented with a beta0-thalassemia (thal) trait associated to a relevant Hb F level. The proband and his family (parents and a sister) were investigated by hematological analysis. The two beta-thal carriers of the beta-globin nonsense mutation [codon 59 (AAG-->TAG)] (the proband and his father) showed the hematological picture of a beta0-thal trait: the only hematological difference between the two beta-thal carriers was in the Hb F level (3.3% in the proband and 1% in his father).


Chromosomal Aberrations, Micronuclei, Blood Parameters and Received Doses in Workers Exposed to Ionizing Radiation.
The aim of this study was to analyze the impact of low doses of ionizing radiation on healthcare workers using dosimeter data and several biomarkers of effects, and to asses the suitability of those tests. Data from the last medical examinations, obtained from the medical records of 148 employees were analysed. They were divided into three groups: nuclear medicine, interventional radiology and general radiology. The examination included hematological parameters and cytogenetical tests: unstable chromosomal aberrations (UCA) and micronucleus test (MNT). The received cumulative 5-year dose was calibrated into personal dose equivalents Hp(10). A statistically significant difference was found between the groups in the UCAs (c2=6.634, p=0.036) with the highest UCA frequency in nuclear medicine. The ANOVA showed a statistically significant difference in the values of erythrocytes (F(2,140)=3.715, p=0.027), monocytes (F(2,127)=3.326, p=0.039) and platelets (F(2,135)=4.209, p=0.017), with higher erythrocytes and lower platelets in interventional radiology and lower monocytes in nuclear medicine, all with small effect size. The dose was significantly different among the groups (c2 =22,191; p<0.001). The nuclear medicine workers received a higher dose compared to interventional radiology (U=458, p<0.001) and general radiology (U=510.5, p<0.001). Nuclear medicine employees are at a higher risk of developing neoplastic and blood-related diseases due to consistent exposure to low doses of ionizing radiation. Results suggest that UCA test might be more suitable for detecting radiation-induced damage at low doses than MNT. Compulsory monitoring of the health status at periodic examinations is required to prevent occupational diseases, esp. among the nuclear medicine workers.