AbobotulinumtoxinA is effective in patients with urinary incontinence due to neurogenic detrusor overactivity regardless of spinal cord injury or multiple sclerosis etiology: Pooled analysis of two phase III randomized studies (CONTENT1 and CONTENT2).
Neurogenic detrusor overactivity incontinence (NDOI) is often inadequately managed with oral therapy. To assess efficacy and safety of abobotulinumtoxinA (aboBoNT-A; Dysport®; Ipsen Ltd.) according to etiology of NDOI. Two phase III, randomized, double-blind studies (CONTENT1 [NCT02660138] conducted in Asia, Europe and North America; CONTENT2 [NCT02660359] conducted in the Americas, Asia, Europe and Oceania) both included patients with spinal cord injury (SCI) or multiple sclerosis (MS), with inadequately managed NDOI, regularly performing clean intermittent catheterization (CIC). Patients in CONTENT1 and CONTENT2 received aboBoNT-A injections 600 U (n = 162)/800 U (n = 161), or placebo (n = 162) into the detrusor muscle. Primary endpoint: mean change from baseline in number of NDOI episodes/week at Week 6. Secondary endpoints: proportion of patients with no NDOI episodes; incontinence-related quality of life (I-QoL); urodynamic parameters; and time-to-retreatment. Safety was also assessed. Statistical analyses were conducted for pooled populations by etiology (aboBoNT-A doses vs. placebo). Of 485 randomized patients, 341 (70%) and 144 (30%) had SCI and MS etiologies, respectively. A significant reduction was observed in mean NDOI episodes/week at Week 6 with both aboBoNT-A doses versus placebo in the SCI (all p < 0.001) and MS (all p < 0.01) groups, as well as significant improvements in I-QoL and urodynamic parameters. Median time-to-retreatment was longer in patients with MS (48-62 weeks across doses) than those with SCI (39-44 weeks). Safety data were similar between etiologies. Urinary tract infection was the most frequent adverse event; similar numbers were reported across treatment groups. AboBoNT-A was well tolerated and significantly improved continence and bladder function, and QoL, in patients with SCI or MS with NDOI performing regular CIC. AboBoNT-A injections improved QoL, symptoms, and bladder function in patients with SCI or MS with bladder muscle overactivity that causes incontinence.


An autoradiographic study of the formation of the lateral motor column in the chick embryo.
An autoradiographic determination of the time of origin of the lateral motor columns (LMC) of the chick embryo has been made. The first motor neurons of the brachial LMC are born at stage 15; the earliest birthdates of lumbar LMC neurons are at stage 17. At least 95% of the motor neurons of both brachial and lumbar columns are produced by stage 23 (4 days). The remaining 5% of the motor neurons are produced during the next two days. A clear rostrocaudal gradient of motor neuron production is seen beoth between the brachial and lumbar LMCs and within the LMCs themselves. The LMCs are assembled in a mediolateral sequence: the early-born motor neurons settle medially, the later-born motor neurons settle more laterally. Observations were made of other large early-born neurons which remain permanently in the dorsal gray of the spinal cord.


Clinical measurement of sit-to-stand performance in people with balance disorders: validity of data for the Five-Times-Sit-to-Stand Test.
People with balance disorders are characterized as having difficulty with transitional movements, such as the sit-to-stand movement. A valid and feasible tool is needed to help clinicians quantify the ability of people with balance disorders to perform transitional movements. The purpose of this study was to describe the concurrent and discriminative validity of data obtained with the Five-Times-Sit-to-Stand Test (FTSST). The FTSST was compared with the Activities-specific Balance Confidence Scale (ABC) and the Dynamic Gait Index (DGI). Eighty-one subjects without balance disorders and 93 subjects with balance disorders were recruited for the study. Each subject was asked to stand from a 43-cm-high chair 5 times as quickly as possible. The ABC and DGI scores were recorded. Subjects with balance disorders performed the FTSST more slowly than subjects without balance disorders. Discriminant analysis demonstrated that the FTSST correctly identified 65% of subjects with balance dysfunction, the ABC identified 80%, and the DGI identified 78%. The ability of the FTSST to identify subjects with balance dysfunction was better for subjects younger than 60 years of age (81%). The FTSST displays discriminative and concurrent validity properties that make this test potentially useful in clinical decision making, although overall the ABC and the DGI are better than the FTSST at discriminating between subjects with and subjects without balance disorders.


Use of fish oil and mortality of patients with cardiometabolic multimorbidity: A prospective study of UK biobank.
Cardiometabolic multimorbidity (CMM) has risen as a global issue of public health, with an in-creasing prevalence and more severe clinical prognosis. This study aimed to estimate the association between use of fish oil and mortality among patients with CMM. In this prospective study based on UK Biobank, participants with ≥2 of cardiometabolic diseases (CMDs, including coronary heart disease [CHD], diabetes, hypertension, and stroke in this study) at recruitment were included. Use of fish oil was derived from touchscreen questionnaires at baseline. All-cause and cardiovascular mortality were accessed via electronic health-related records. Kaplan-Meier curves and flexible parametric Royston-Parmar proportion-hazard models were fitted to assess the as-sociations of fish-oil use with all-cause, cardiovascular mortality, and related life expectancy alterations. Among 30 068 participants from UK Biobank (67.9% men; mean age 61.75 years), 5357 deaths were reported during 12.03 years of follow-up. For patients with CMM, use of fish oil was associated with a 17% lower risk of all-cause mortality (95% confidence interval [95% CI] 0.78-0.88, P < 0.001), and 19% lower risk of cardiovascular mortality (95% CI 0.72-0.90, P < 0.001) in multivariable-adjusted models. At 45 years old, using fish oil was associated with 1.66 years of life expectancy gained. Among patients with CMM, use of fish oil was associated with a significantly reduced risk of all-cause, cardiovascular mortality, and prolonged life expectancy.


Persistence of tight junctions and changes in apical structures and protein expression in choroid plexus epithelium of rats after short-term head-down tilt.
Major alterations of choroidal cell polarity and protein expression were previously shown to be induced in rats by long-term adaptation to space flight (14 days aboard a space shuttle) or anti-orthostatic suspension (14 and 28 days) performed by tilting rats head-down (i.e. using a ground-based model known to simulate several effects of weightlessness). In rabbits, it was hypothesized that the blood-CSF barrier was opened in choroid plexus, after a short head-down suspension. To understand the early responses to fluid shifts induced by head-down tilts and evaluate the tightness of the choroidal junctions, we have investigated the effects of acute adaptations to anti-orthostatic restraints, using hindlimb-suspended Sprague-Dawley and Wistar rats. Ultrastructural and immunocytochemical studies were performed on choroid plexuses from lateral, third and fourth ventricles, after 30, 90 and 180 minutes of head-down tilt. Alterations were not perceptible at the level of choroidal tight junctions, as shown by freeze-fracture, claudin-1 and ZO-1 immunolocalizations and conventional electron microscopy, after intravenous injection of cytochrome C. The apical surface of choroidal cells was clearly more affected. Microvilli were longer and thinner and ezrin was over-expressed during all the periods of time considered, showing an early cytoskeletal response. Several proteins involved in the choroidal production of cerebrospinal fluid (sodium-potassium ATPase, carbonic anhydrase II, aquaporin 1) appeared first increased (30 minutes after the tilt), and then, returned to the control level or were lowered (after a 3-hour head-down suspension). Although head-down tilts do not seem to damage the blood-cerebrospinal fluid barrier in choroid plexus, it seemed that the expression of several apical proteins is affected very early.


Time-to-contact measures capture modulations in posture based on the precision demands of a manual task.
The integration between posture and manual control while performing fitting tasks of varying difficulty was investigated. Participants fit a block into either a small (high precision) or large (low precision) opening while standing on a force plate. Postural time-to-contact was used to quantify changes in posture that occurred during the fitting movement. Results suggest that posture became more stabilized when fitting through the small opening (postural time-to-contact values were higher) compared to when fitting through the large opening. Additionally, when fitting through the small opening, individuals modulated sway based on the instantaneous demands of the task. Specifically, time-to-contact was lower towards the end of a fitting movement (as the individual prepared to fit the block through the opening) compared to the beginning of the movement. These results suggest that the dynamics of postural sway are constantly changing based on the constraints of a concurrent task.


The impact of diapause on the evolution of other life history traits in flesh flies.
Flesh flies (Sarcophagidae) collected in Costa Rica and Panama lack the pupal diapause that is characteristic of flesh flies from the temperate zone and tropical Africa. The absence of a diapause capacity in the neotropical species correlates with several other life history traits: in most species the post feeding wandering phase of the third larval instar is longer and duration is more variable, adult life is longer, clutch size is smaller, and more clutches are produced. Among species that have the capacity for diapause, risk is invested primarily in the diapausing stage and other life stages are brief. Though diapausing species are short-lived, they produce as many or more progeny than nondiapausing species by increasing clutch size. The slower and more variable developmental rate and increased adult longevity desynchronizes development and permits the nondiapausing species to spread an environmental risk over different stages of the life cycle, thus offering an alternative to diapause. Other traits such as body size, developmental velocity, thermal constant thresholds, thermal constants, age at first reproduction, and the interval between clutches do not appear related to the capacity for diapause.


The Beneficial Effects of Astaxanthin on Glucose Metabolism and Modified Low-Density Lipoprotein in Healthy Volunteers and Subjects with Prediabetes.
Astaxanthin (ASTX) is an antioxidant agent. Recently, its use has been focused on the prevention of diabetes and atherosclerosis. We examined the effects of astaxanthin supplementation for 12 weeks on glucose metabolism, glycemic control, insulin sensitivity, lipid profiles and anthropometric indices in healthy volunteers including subjects with prediabetes with a randomized, placebo-controlled trial. We enrolled 53 subjects who met our inclusion criteria and administered them with 12 mg astaxanthin or a placebo once daily for 12 weeks. Subsequently, their HbA1c levels, lipid profiles and biochemical parameters were determined. The participants also underwent a 75 g oral glucose tolerance test (OGTT), vascular endothelial function test and measurement of the visceral fat area. After astaxanthin supplementation for 12 weeks, glucose levels after 120 min in a 75 g OGTT significantly decreased compared to those before supplementation. Furthermore, the levels of HbA1c (5.64 ± 0.33 vs. 5.57 ± 0.39%, p < 0.05), apo E (4.43 ± 1.29 vs. 4.13 ± 1.24 mg/dL, p < 0.05) and malondialdehyde-modified low-density lipoprotein (87.3 ± 28.6 vs. 76.3 ± 24.6 U/L, p < 0.05) were also reduced, whereas total cholesterol (TC), triglyceride (TG) and high-density lipoprotein-C (HDL-C) levels were unaltered. The Matuda index, which is one of the parameters of insulin resistance, was improved in the ASTX group compared to that before supplementation. our results suggest that ASTX may have preventive effects against diabetes and atherosclerosis and may be a novel complementary treatment option for the prevention of diabetes in healthy volunteers, including subjects with prediabetes, without adverse effects.


Easy and direct conversion of tosylates and mesylates into nitroalkanes.
Tosylates and mesylates were directly converted into the corresponding nitroalkanes, by their treatment with tetrabutylammonium nitrite (TBAN) under mild conditions.


Minimum nephrostomy.
A new type of nephrostomy is described with the following main characteristics: it uses a small multiperforated Silastic tube; its crosswise location allows perfect drainage of all of the calyces and the pelvis; it does not become obstructed nor move from its position; and it causes minimum traumatization of the renal parenchyma. It has a double purpose: its serves as a drain and safety measures as well as being used for the treatment of renal infection.


Classification of olive cultivars by machine learning based on olive oil chemical composition.
Extra virgin olive oil traceability and authenticity are important quality indicators, and are currently the subject of exhaustive research, for developing methods to secure olive oil origin-related issues. The aim of this study was the development of a classification model capable of olive cultivar identification based on olive oil chemical composition. To achieve our aim, 385 samples of two Greek and three Italian olive cultivars were collected during two successive crop years from different locations in the coastline part of western Greece and southern Italy and analyzed for their chemical characteristics. Principal Component Analysis showed trends of differentiation among olive cultivars within or between the crop years. Artificial intelligence model of the XGBoost machine learning algorithm showed high performance in classifying the five olive cultivars from the pooled samples.


Intracellular horseradish peroxidase injection for correlation of light and electron microscopic anatomy with synaptic physiology of cultured mouse spinal cord neurons.
Synaptic interactions between spinal cord neurons grown in dissociated cell culture were studied electrophysiologically, and presynaptic cells were subsequently injected by intracellular iontophoresis with horseradish peroxidase (HRP). Following histochemical processing, injected cells were filled with dense reaction product which facilitated the light and electron microscopic identification of the individual physiologically typed neurons. This technique applied to neurons in monolayer culture allowed the visualization of complex intercellular relationships in essentially two dimensions. The number and distribution of morphologically defined synaptic contacts was determined for correlation with individual evoked postsynaptic potentials. HRP-filling of inhibitory and excitatory neurons revealed differences with respect to cellular geometry, axonal projection, and the number, location and ultrastructure of synaptic contacts.


Analysis of double minutes and double minute-like chromatin in human and murine tumor cells using antikinetochore antibodies.
Antikinetochore antibodies from patients with the calcinosis, Raynaud's phenomenon, esophageal dismobility, sclerodactyly, telangiectasia-(CREST)-syndrome of scleroderma were used as immunofluorescent probes to discriminate between the presence and absence of kinetochores in minute chromosomes not previously seen by conventional banding methods. Double minute chromosomes (DM) consistently lack the antigenic component of the kinetochore, which is direct evidence for the fact that they do not have a centromere. Although somatically stable in malignant cell populations, DM are unable to attach to the mitotic spindle. Conversely, despite their structural similarity to DM, chromosome fragments and supernumerary marker chromosomes exhibit intensely fluorescing kinetochores and, thus, are subject to a precise anaphasic distribution.


Isoflurane inhibits protein kinase Cgamma and calcium/calmodulin dependent protein kinase ii-alpha translocation to synaptic membranes in ischemic mice brains.
Volatile anesthetics isoflurane possibly improves the ischemic brain injury. However, its molecular actions are still unclear. In ischemia, protein kinase C (PKC)gamma and calcium/calmodulin dependent protein kinase II (CaMKII)-alpha are persistently translocated from cytosol to cell membranes, and diminish these translocation suggested to be neuroprotective. We thus tested a hypothesis that isoflurane inhibits PKCgamma and CaMKII-alpha translocation after ischemic brain insults. C57Bl/6J male mice were made to inhale 1 or 2 MAC isoflurane, after which 3 or 5 min cerebral ischemia was induced by decapitation. The sampled cerebrum cortex was then homogenized and centrifuged into crude synaptosomal fractions (P2), cytosolic fractions (S3), and particulate fractions (P3). CaMKII-alpha and PKCgamma levels of these fractions were analyzed by immunoblotting. PKCgamma and CaMKII-alpha are translocated to synaptic membrane from cytosol by cerebral ischemia, although isoflurane significantly inhibited such translocation. These results may explain in part the cellular and molecular mechanisms of neuroprotective effects of isoflurane.


Personality moderators of the cross-sectional relationship between job demands and both burnout and work engagement in judges: The boosting effects of conscientiousness and introversion.
The central question of this study is whether buffering, boosting and exacerbating effects of the Big Five personality factors extraversion, openness to experience, agreeableness, conscientiousness and neuroticism can be demonstrated in the relationship between two job demands (i.e., work pressure and working overtime) and both burnout and work engagement in 257 Dutch judges. It is important to better understand the interaction effects between various job demands (work pressure and working overtime) and personality on both burnout and work engagement in judges given their increased risk of burnout and lower work engagement due to cognitively and their emotionally demanding work. Three hypotheses were tested in a cross-sectional design study. Moderation analyses showed that, as expected, conscientiousness significantly boosted the relationship between working overtime and work engagement. Hence, high scorers on conscientiousness showed more work engagement when working overtime. Also, extraversion moderated the relation between working overtime and work engagement, but only at a low level of extraversion. Thus, contrary to expectations, introverts showed more work engagement when they work overtime. Also, significant main effects were found. Work pressure and neuroticism related positively to burnout, while extraversion and agreeableness related negatively to burnout. Moreover, extraversion, agreeableness and conscientiousness related positively to work engagement. In our study, conscientiousness, extraversion and agreeableness can be considered as personal resources for judges, in line with the Conservation of Resources (COR) theory. Especially conscientiousness can facilitate judges to cope with challenging working circumstances and introversion ensures that judges stay engaged despite working overtime.


Transcriptome profiling in crustaceans as a tool for ecotoxicogenomics: Daphnia magna DNA microarray.
Chemicals released into the environment have the potential to affect various species and it is important to evaluate such chemical effect on ecosystems, including aquatic organisms. Among aquatic organisms, Daphnia magna has been used extensively for acute toxicity or reproductive toxicity tests. Although these types of tests can provide information on hazardous concentrations of chemicals, they provide no information on their mode of action. Recent advances in toxicogenomics, the integration of genomics with toxicology, have the potential to afford a better understanding of the responses of aquatic organisms to pollutants. In a previous study, we developed an oligonucleotide-based DNA microarray with high reproducibility using a Daphnia expressed sequence tag (EST) database. In this study, we increased the number of genes on the array and used it for a careful ecotoxicogenomic assessment of Daphnia magna. The DNA microarray was used to evaluate gene expression profiles of neonate daphnids exposed to beta-naphthoflavone (bNF). Exposure to this chemical resulted in a characteristic gene expression pattern. As the number of the genes on an array was increased, the number of genes that were found to respond to the chemicals was also increased, which made the classification of the toxic chemicals easier and more accurate. This newly developed DNA microarray can be useful for a obtaining a better mechanistic understanding of chemical toxicity effects on a common freshwater organism.


Cloning and characterization of hoxH genes from Arthrospira and Spirulina and application in phylogenetic study.
Partial hoxH genes of 2 cyanobacterial genera, including 5 strains of Arthrospira and 2 strains of Spirulina, were cloned and characterized. This gene encodes the large subunit of nickel-iron hydrogenase. The results showed that these genes comprised 1349 nucleotides in Arthrospira and 1343 nucleotides in Spirulina, respectively. The GC contents of hoxH were 45.7% to 47.3% in Arthrospira and up to 50.4% to 50.9% in Spirulina. The hoxH gene was demonstrated to be single copy by Southern analysis, and its transcription was verified by reverse transcriptase polymerase chain reaction in Arthrospira platensis FACHB341. The similarities of nucleotide sequences among the 5 strains of Arthrospira ranged from 95.7% to 99.8%, which are higher than those between Arthrospira and Spirulina (72.9-77.0%). However, similarity between the 2 Spirulina strains was only 72.5%, slightly lower than that between the 2 genera. A phylogenetic tree based on hoxH was constructed. All 5 strains of Arthrospira formed a monophyletic clade, which was highly supported by bootstrap value, while the 2 strains of Spirulina were separated into 2 different clades.


[Bladder schistosomiasis. Report of a case].
We report an additional case of schistosomiasis of the urinary bladder, an unusual parasitic infection in our setting, with special reference to the histomorphological findings that permitted its diagnosis. Biopsy was performed via cystoscopy and bladder tissue was obtained from an area in the trigone with an abnormal appearance. Microscopic examination of the biopsy specimen revealed eggs of the parasite Schistosoma haematobium. The present case shows the importance of close collaboration between clinicians and pathologists and the usefulness of cystoscopy for diagnosis in urological patients.


Neurotrophic effects on the electrical properties of cultured muscle produced by conditioned medium from spinal cord explants.
The passive electrical properties of cultured chick skeletal muscle are significantly altered when the muscle is co-cultured with spinal cord explants. A reduced transverse membrane resistance appears to be responsible for the smaller values of input resistance, space constant, and time constant observed in co-cultures relative to those observed in pure muscle cultures. In this report, we show that neuromuscular junctions are not required in order to observe this neurotrophic effect because medium from spinal cord explant cultures is capable of producing the same reduction in transverse membrane resistance as the co-culturing of spinal cord explants with muscle. Control medium from liver explant cultures has no effect on muscle passive electrical properties. These results indicate that a trophic substance which is capable of regulating the electrical properties of excitable cells is released into the culture medium by spinal cord explants.


Patient and health care professional views and experiences of computer agent-supported health care.
To explore patient and health care professional (HCP) views towards the use of multi-agent computer systems in their GP practice. Qualitative analysis of in-depth interviews and analysis of transcriptions. Urban health centre in Dundee, Scotland. Five representative healthcare professionals and 11 patients. Emergent themes from interviews revealed participants' attitudes and beliefs, which were coded and indexed. Patients and HCPs had similar beliefs, attitudes and views towards the implementation of multi-agent systems (MAS). Both felt modern communication methods were useful to supplement, not supplant, face-to-face consultations between doctors and patients. This was based on the immense trust these patients placed in their doctors in this practice, which extended to trust in their choice of communication technology and security. Rapid access to medical information increased patients' sense of shared partnership and self-efficacy. Patients and HCPs expressed respect for each other's time and were keen to embrace technology that made interactions more efficient, including for the altruistic benefit of others less technically competent. Patients and HCPs welcomed the introduction of agent technology to the delivery of health care. Widespread use will depend more on the trust patients place in their own GP than on technological issues.


Antidiabetic compounds 8a, 8b, 8k, and 9h enhance insulin secretion: activity and mechanism.
This study primarily investigated the effects of hypoglycemic compounds (Imeglimin derivatives) on insulin secretion in type 2 diabetes mellitus (T2DM), and further explored the possible mechanism underlying these effects. Firstly, Metformin was used as the initiating compound to synthesize three sets of derivatives which contained Imeglimin structure core. At the cellular level, we screened compounds with better effect on the activity of insulin receptor tyrosine protein kinase (IFcTPK) after the islet β cells were treated with the compounds of different concentrations. The insulin secretion was assessed using radioimmunoassay and the cytotoxicity to islet β cells was evaluated by means of MTT assay following treatment with the compounds. The Ca2+-related mechanism by which these compounds promote insulin secretion was elucidated with whole cell recordings from current-clamp mode. Totally, 48 synthesized compounds were generated, wherein 10 compounds could increase the activity of IFcTPK in HIT-T15 cells better among these compounds. The modified Imeglimin, especially in the structure of hydrophilic hydroxyl or piperidine rings, could improve the activity of the compound to promote insulin secretion. Furthermore, the compounds 8a, 8b, 8k, and 9h revealed high insulin secretion-promoting activity. These compounds enhanced insulin secretion in islet β cells by repressing the ATP-sensitive K(+) and voltage-gated K+ pathway. Our findings indicate that the hypoglycemic compounds 8a, 8b, 8k, and 9h confer better promotive effect on insulin secretion, which provides a reference for the development of drugs with better hypoglycemic activity.


Is a Venacavogram Necessary after Inferior Vena Cava Filter Retrieval?
To evaluate the utility of venacavography after optional inferior vena cava (IVC) filter retrieval using routine and complex techniques. Patients (N = 224; 228 patient encounters) in whom venacavography was performed before and after IVC filter retrieval were reviewed from a 12-year period ending March 2014. Retrieval was considered complex if it required forceps or other adjuncts. Venacavograms were assessed for abnormalities including stenosis, filling defects, dissection, and extravasation of contrast material. Filling defects (n = 53; 23%) and stenosis (n = 137; 60%) were significantly more frequent after retrieval (P < .05), but they did not change patient management. The only major abnormality after retrieval was extravasation (n = 3), which occurred only in the complex group and was treated with balloon tamponade and observation. No dissection was observed. Dwell time was not correlated with the presence of abnormalities after retrieval (r = 0.002, P = .977). The lack of abnormalities requiring treatment on venacavography after routine IVC filter retrieval may justify omitting venacavography after retrieval regardless of dwell time. Although uncommon, extravasation requiring treatment may be seen after complex retrieval; venacavography remains warranted in this setting.


Aquaporin-1 is associated with arterial capillary proliferation and hepatic sinusoidal transformation contributing to portal hypertension in primary biliary cirrhosis.
Although aquaporins (AQPs) in normal hepatobiliary system have been studied, little is known about AQP localization and changes in the hepatic microvascular system including sinusoids in cholestatic liver. The present study aimed to clarify the localization of AQP-1 in the microvessels in normal human liver and in primary biliary cirrhosis (PBC). Human normal liver (control) and PBC liver specimens were obtained. Immunohistochemistry, Western blotting, in situ hybridization (ISH) and electron microscopic examination for AQP-1 were conducted. In control liver and stages I-II PBC liver, AQP-1 immunoreactivity was mainly localized in portal venules, hepatic arterioles and bile ducts in the portal tract, but was hardly detected in the sinusoids. However, AQP-1 expression was enhanced in the proliferated bile ductules in PBC. In stages III-IV PBC liver tissues, AQP-1 was aberrantly expressed in proliferated arterial capillaries opening into the sinusoids at the peripheral edge of regenerating hepatic nodules and in the fibrotic septa. Overexpression of AQP-1 at protein and mRNA levels was demonstrated by Western blot and ISH, respectively. Angiogenetic and fibrotic responses are probably induced by AQP-1, leading to enhanced pouring of arterial blood into the sinusoids; thus, contributing to progression of portal hypertension in PBC.


The cost of living.
The new biologics have great potential to help patients with hitherto uncurable diseases. But their exorbitant costs challenges the basis of health care systems based on equity.


Some effects of dieldrin and mirex on Ehrlich ascites tumor cells in vivo and in vitro.
The effects of dieldrin and mirex on Ehrlich ascites tumor cells were assessed, using certain in vivo (in mice) and in vitro measurements. Mirex retarded the development of Ehrlich ascites tumor in vivo, but dieldrin did not. Effects of dieldrin on de nova RNA purine synthesis from formate in vivo were slight, while mirex inhibited the synthesis of both RNA purines. Dieldrin inhibited the in vitro incorporation if thymidine, uridine, and L-leucine into DNA, RNA, and protein, respectively, but mirex was virtually without effect.


Combining the Rowland Universal Dementia Assessment Scale and the Informant Questionnaire on Cognitive Decline in the Elderly to Improve Detection of Dementia in an Arabic-Speaking Population.
The aim of this study was to assess whether combining the Rowland Universal Dementia Assessment Scale (RUDAS) and Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) could improve diagnostic accuracy when screening for dementia in an Arabic-speaking population with low levels of literacy. Based on data from 225 elderly participant and informant dyads, the screening performances of the two instruments were compared and three methods for combining them--'or', 'and' and 'weighted sum' rules--were assessed. The 'weighted sum' method had a significantly better area under the curve value compared to the RUDAS used alone. The 'weighted sum' method and the 'and' rule had the highest specificity, while the 'or' rule had the best sensitivity. Harnessing the RUDAS and IQCODE increased diagnostic accuracy when screening for dementia in this study population.


The novel gluconeogenesis inhibitor FR225654 that originates from Phoma sp. no. 00144. II. Biological activities.
The novel gluconeogenesis inhibitor FR225654, isolated from the culture broth of Phoma sp. No. 00144, has an unique structure that consists of a highly oxygenated trans-decalin ring and a beta-keto-enol, with a characteristic side chain. This compound selectively inhibited gluconeogenesis of rat primary hepatocytes and had hypoglycemic effects in several in vivo mouse models.


Approaches to the development of novel antihypertensive drugs: crucial role of the renal kallikrein-kinin system.
The renal kallikrein-kinin system has been shown to be important in the development of hypertension, but its precise role remains to be determined. The recent use of mutant rats that are deficient in plasma kininogens and hence incapable of generating kinin in the renal tubules has facilitated elucidation of the involvement of kinin in hypertension. In this article, Masataka Majima and Makoto Katori provide evidence that the renal kallikrein-kinin system plays a crucial role in the development of hypertension and discuss a novel rationale for developing effective new antihypertensive drugs.


Cortical morphological changes in multiple sclerosis patients: a study of cortical thickness, sulcal depth, and local gyrification index.
Multiple sclerosis (MS) is a disease that progresses not only with demyelination but also with neurodegeneration. One of the goals of drug treatment in MS is to prevent neurodegeneration. Cortical thickness (CT), sulcal depth (SD), and local gyrification index (LGI) are indicators related to neurodegeneration. The aim of this study is to investigate changes in CT, SD, and LGI in patients with relapsing-remitting MS (RRMS). T1 images of 74 RRMS patients and 65 healthy controls were used. T1 hypointense areas in RRMS patients were corrected using fully automated methods. CT, SD, and LGI were calculated for each patient. RRMS patients showed widespread cortical thinning, especially in bilateral temporoparietal areas, decreased SD in bilateral supramarginal gyrus, superior temporal gyrus, postcentral gyrus, and transverse temporal gyrus, and decreased LGI, especially in the left posterior cingulate gyrus and insula. The decrease in cortical thickness was associated with the number of attacks and lesion volume. EDSS was related to CT in the right lingual, inferior temporal, and fusiform gyrus. The LGI was correlated with T2 lesion volume in bilateral insula, with EDSS in the right insula and transverse and superior temporal gyri, and with the number of attacks in the right paracentral gyrus and pre-cuneus. However, SD did not show any correlation with EDSS, T2 lesion volume, or the number of attacks. Our results demonstrate widespread cortical thinning, decreased sulcal depth in local areas, and decreased gyrification in folds in RRMS patients, which are related to clinical parameters.


On-farm experiments over 5 years in a grain maize/winter wheat rotation: effect of maize residue treatments on Fusarium graminearum infection and deoxynivalenol contamination in wheat.
Over the course of 5 years, different maize residue treatments were conducted on 14 zero tillage on-farm sites in Switzerland to evaluate their effect on the development of Fusarium head blight (FHB) and the contamination with the mycotoxin deoxynivalenol (DON) in winter wheat grains and wheat straw following grain maize. Two experimental series with three and five different treatments were carried out, respectively. Fusarium graminearum (Schwabe) was the predominant FHB-causing species with an overall incidence of 15% infected wheat grains. A significant correlation between symptoms in the field, F. graminearum incidence and DON content in wheat grains and wheat straw was observed. The average DON content in both wheat grains and wheat straw was approximately 5,000 μg/kg and thus several times higher than the European maximum limit of 1,250 μg/kg for unprocessed small-grain cereals for human consumption. Of all grain samples, 74% were above the maximum limit. Pooled over both experimental series, the average reduction of DON in grains through treatments of the maize residue compared with a control treatment ranged between 21 and 38%. The effect of various other factors, including the year, the wheat variety, the site, the maize hybrid and the production system was evaluated as well. The year and the wheat variety were the most important FHB influencing factors. Over all treatments, the variety Levis showed a fivefold higher average DON content compared with the variety Titlis. From different categories of maize residue particles, intact pieces of 5-15 cm length were strongly correlated with F. graminearum incidence and DON content in grains. During the time course of this study, the recommendation from a preliminary version of the internet-based DON forecasting system FusaProg to apply or to omit a fungicide treatment was correct in 32 out of 42 cases. The results are currently being used to optimise the FusaProg models. This study has shown that in a grain maize/winter wheat rotation, the DON content in wheat grains frequently exceeded the European maximum limit, even with a thorough treatment of maize residues and less susceptible wheat varieties. Hence, in order to reduce the contamination risk in a zero tillage system, the crop rotation needs to be modified.


Inversion symmetry and local vs. dispersive interactions in the nucleation of hydrogen bonded cyclic n-mer and tape of imidazolecarboxamidines.
Substitutional changes to imidazolecarboxamidine that preserved intermolecular hydrogen bonding in the solid state were used to study the relationship between packing and the hydrogen bond motif. Various motifs competed, but the most common imidazolecarboxamidine crystalline phase was a C(i) symmetric dimer that established inversion centers by associating enantiomeric tautomers. Counter to intuition, the calculated gas-phase energies per molecule of the solid state atomic coordinates of the C(i) dimer motifs were higher than those of the C(1) dimer, trimer, tetramer and tape motifs, while the packing densities of C(i) dimers were found to be higher. This result was interpreted as an enhanced ability of the C(i) dimers to pack. If other motifs competed, the hydrogen bonds and conformations should be lower in energy than the C(i) dimer. The results detail the effect of packing on the conformation in these molecules. The results are interpreted as a rough measure of the energetic compromise between packing and the energies related to the coordinates involving one dihedral angle and hydrogen bonding. The results establish a connection between solution and solid phase conformation.


¹H, ¹³C and ¹⁵N NMR assignments of a mutant of UV inducible transcript (S55A-UVI31+) from Chlamydomonas reinhardtii.
Almost complete sequence specific (1)H, (13)C and (15)N resonance assignments of a mutant of UV inducible transcript (S55A-UVI31+) from Chlamydomonas reinhardtii are reported, as a prelude to its structural and functional characterization. Site-directed mutagenesis of uvi31+ was carried out using complementary mutation harbouring oligonucleotides for S55A mutant. The resulting mutant was sequenced and then S55A mutant of uvi31+ cDNA were expressed in E. coli, and purification were carried out from where the protein was purified to high homogeneity. The point mutation S55A in UVI31+ results in a significant enhancement in its DNA endonuclease activity as compared to its wild type protein.


Population genetic data for 15 STR loci (Identifiler kit) in Honduras.
Allele frequencies for 15 STR autosomal loci (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, TH01, D13S317, D16S539, D2S1338, D19S433, VWA, TPOX, D18S51, D5S818 and FGA) were obtained from a sample of 198 unrelated individuals from Honduras, Central America.


Soluble CD146 is increased in preeclampsia and interacts with galectin-1 to regulate trophoblast migration through VEGFR2 receptor.
To explore the regulatory role of soluble CD146 (sCD146) and its interaction with galectin-1 (Gal1) in placenta-mediated complications of pregnancy. Prospective pilot and experimental studies. University-affiliated hospital and academic research laboratory. One hundred fifteen women divided into three groups: 30 healthy, nonpregnant women, 50 women with normal pregnancies, and 35 with placenta-mediated pregnancy complications. Wound-healing experiments were conducted to study trophoblast migration. Quantification of sCD146 and Gal1 by enzyme-linked immunosorbent assay. Analysis of trophoblast migration by wound closure. Concomitant detection of sCD146 and Gal1 showed lower sCD146 and higher Gal1 concentrations in women with normal pregnancies compared with nonpregnant women. In addition, follow-up of these women revealed a decrease in sCD146 associated with an increase in Gal1 throughout pregnancy. In contrast, in women with preeclampsia, we found significantly higher sCD146 concentrations compared with women with normal pregnancies and no modification of Gal1. We emphasize the opposing effects of sCD146 and Gal, since, unlike Gal1, sCD146 inhibits trophoblast migration. Moreover, the migratory effect of Gal1 was abrogated with the use of an anti-CD146 blocking antibody or the use of small interfering RNA to silence VEGFR2 expression. This suggests that trophoblast migration is mediated though the interaction of Gal1 with CD146, further activating the VEGFR2 signaling pathway. Significantly, sCD146 blocked the migratory effects of Gal1 on trophoblasts and inhibited its secretion, suggesting that sCD146 acts as a ligand trap. Soluble CD146 could be proposed as a biomarker in preeclampsia and a potential therapeutic target. NCT 01736826.


Do Cholesterol and Sphingomyelin Change the Mechanism of Aβ25-35 Peptide Binding to Zwitterionic Bilayer?
Using replica exchange with solute tempering all-atom molecular dynamics, we studied the equilibrium binding of Aβ25-35 peptide to the ternary bilayer composed of an equimolar mixture of dimyristoylphosphatidylcholine (DMPC), N-palmitoylsphingomyelin (PSM), and cholesterol. Binding of the same peptide to the pure DMPC bilayer served as a control. Due to significant C-terminal hydrophobic moment, binding to the ternary and DMPC bilayers promotes helical structure in the peptide. For both bilayers a polarized binding profile is observed, in which the N-terminus anchors to the bilayer surface, whereas the C-terminus alternates between unbound and inserted states. Both ternary and DMPC bilayers feature two Aβ25-35 bound states, surface bound, S, and inserted, I, separated by modest free energy barriers. Experimental data are in agreement with our results but indicate that cholesterol impact is Aβ fragment dependent. For Aβ25-35, we predict that its binding mechanism is independent of the inclusion of PSM and cholesterol into the bilayer.


Challenges experienced during pharmacy automation and robotics implementation in JCI accredited hospital in the Arabian Gulf area: FMEA analysis-qualitative approach.
Pharmacy automation and robotics implementation are essential aspects of healthcare facilities. It streamlines the medication dispensing process and significantly reduces medication errors. However, implementing automation and robotics in pharmacies comes with its challenges. We aim to detect and rectify potential dangers in the pharmacy workflow by utilizing the Failure Mode and Effects Analysis (FMEA) methodology; this is expected to augment performance and increase profitability. In this study, we conducted an FMEA analysis using a qualitative approach to identify the challenges experienced during pharmacy automation and robotics implementation in a Joint Commission International (JCI) accredited hospital in the Arabian Gulf area. The pharmacy processes and procedures were mapped in a Flow chart to visualize the pharmacy workflow, including highlighting the risks that were found. Then these risks were arranged as Potential failure modes and added to the table as 9 main points for each RPNs were calculated, and then the 9 points were prioritized for the action plans. Via applying traditional Risk Priority Number (RPN) FMEA, the Pharmacy board identified the process stages marked risky failure modes through several FMEAs, calculating the total RPNs at the implementation phase. It revealed several challenges, including staff training, technical issues, and inadequate communication. Furthermore, the study resulted in corrective and intervention steps. Pharmacy automation and robotics implementation is a complex process that requires proper planning, preparation, and execution. The FMEA approach effectively identifies potential problems and evaluates their impact on the pharmacy system. Nine major failure modes appeared to be risky stages with high RPN scores. Therefore, multiple interventions were done during the implementation to enhance the knowledge of challenges faced during the implementation of the automation process and solve it. Future studies should address the identified challenges and develop strategies to mitigate them.


Environmental dependence of inbreeding depression in cultured Coho salmon (Oncorhynchus kisutch): aggressiveness, dominance and intraspecific competition.
We evaluated the effects of inbreeding on traits related to territorial dominance and tested whether the magnitude of inbreeding depression (ID) was modified by social environment in Coho salmon. Evaluation of behaviour in paired contests between juvenile salmon with different inbreeding (low, LI=9.5%; medium, MI=29.6%), did not show significant differences between their capacities for establishing territorial dominance (mean aggressiveness score, LI=20.0+/-22; MI=16.7+/-23 or for feeding attempts, LI=18.3+/-12; MI=21.1+/-12). However, fish with low inbreeding (LI) showed almost twice the aggressive pursuit of fish with medium inbreeding (MI), and had a higher specific growth rate (SGR) in culture (SGR(MI)=1.83+/-0.58; SGR(LI)=2.20+/-0.67). Additionally, we found evidence that the magnitude of ID was modified by social environment: (1) Masking: In small groups of fish (N=20), large dominant fish of MI, cultivated with small subordinate fish of LI, showed the same SGR as dominant fish of LI cultivated with small subordinate fish of MI. (2) Magnifying: A significant effect of ID on juvenile survival was detected only in high-density competitive environments. Thus, the number of lethal equivalents was 2.70 at high-density, and only 0.24 in a low-density environment. Our results show that differences in size associated with territorial dominance may mask deleterious effects of inbreeding under certain conditions, and support the concept that intraspecific competition usually magnifies the deleterious effects of inbreeding.


Cystathionine γ lyase-hydrogen sulfide increases peroxisome proliferator-activated receptor γ activity by sulfhydration at C139 site thereby promoting glucose uptake and lipid storage in adipocytes.
Adipocytes express the cystathionine γ lyase (CSE)-hydrogen sulfide (H2S) system. CSE-H2S promotes adipogenesis but ameliorates adipocyte insulin resistance. We investigated the mechanism of how CSE-H2S induces these paradoxical effects. First, we confirmed that an H2S donor or CSE overexpression promoted adipocyte differentiation. Second, we found that H2S donor inhibited but CSE inhibition increased phosphodiesterase (PDE) activity. H2S replacing isobutylmethylxanthine in the differentiation program induced adipocyte differentiation in part. Inhibiting PDE activity by H2S induced peroxisome proliferator activated receptor γ (PPARγ) protein and mRNA expression. Of note, H2S directly sulfhydrated PPARγ protein. Sulfhydrated PPARγ increased its nuclear accumulation, DNA binding activity and adipogenesis gene expression, thereby increasing glucose uptake and lipid storage, which were blocked by the desulfhydration reagent DTT. H2S induced PPARγ sulfhydration, which was blocked by mutation of the C139 site of PPARγ. In mice fed a high-fat diet (HFD) for 4 weeks, the CSE inhibitor decreased but H2S donor increased adipocyte numbers. In obese mice fed an HFD for 13 weeks, H2S treatment increased PPARγ sulfhydration in adipose tissues and attenuated insulin resistance but did not increase obesity. In conclusion, CSE-H2S increased PPARγ activity by direct sulfhydration at the C139 site, thereby changing glucose into triglyceride storage in adipocytes. CSE-H2S-mediated PPARγ activation might be a new therapeutic target for diabetes associated with obesity.


[Usefulness of Bispectral Index (BIS) monitoring for early detection of cerebral hypoperfusions].
The goal of the study was to assess whether clinically significant cerebral hypoperfusion in awake patients would be associated with some alterations in the values of the bispectral index (BIS) monitoring. Observational study. We monitored the BIS during endovascular carotid artery occlusion testing in awake patients. Twenty-eight patients were included. Twenty-one adequately tolerated the procedure. Their BIS value remained stable throughout the procedure. Four patients had poor angiographic tolerance, but no clinical symptoms. Their BIS value slightly decreased during the test (minimal BIS: 83 [79-87]). Three patients had poor clinical and angiographic tolerance of the occlusion. They all experienced an immediate and dramatic decrease in their BIS value (minimal BIS: ipsilateral to clamping: 50 [45-60]; contralateral to clamping: 48 [45-52]). In all patients, the clinical symptoms and the BIS normalized after deflating the occlusion balloon. In awake patients, the observed values of the BIS monitoring seem to be associated with clinically relevant cerebral hypoperfusion.


Dosimetric comparison between treatment plans of patients treated with low-dose-rate vs. high-dose-rate interstitial prostate brachytherapy as monotherapy: Initial findings of a randomized clinical trial.
The aim of this study was to compare the dosimetry of intraoperative dose plans of prostate cancer patients treated with low-dose-rate (LDR) and high-dose-rate (HDR) interstitial brachytherapy (BT). A randomized clinical trial was initiated at our institution to compare the results and side effects of LDR and HDR BT as monotherapy in the treatment of early, organ-confined prostate cancer patients. Eighty-seven patients were randomly assigned to receive HDR afterloading BT with one fraction of 19 Gy or permanent LDR 125I seed BT with 145 Gy. Inverse optimization algorithms were used for planning. Stranded seeds were implanted using live ultrasound imaging after preimplant treatment planning. Final dosimetry of HDR treatments was based on updated needle and contour positions. Statistical comparisons with nonparametric test were performed between the corresponding dose-volume parameters. The V100 and V150 were 99% and 61%, respectively, for LDR, whereas 98% and 32% for HDR treatments. The D90 was less for HDR (122% vs. 110%). The dose distributions were more homogeneous and conformal with HDR technique (dose homogeneity index, 0.39 vs. 0.67; conformal index, 0.65 vs. 0.80). The urethra and rectum received significantly less dose with HDR. The D10 and D30 for urethra were 133% and 128%, respectively, for LDR and 114% and 111% for HDR treatments. The [Formula: see text] for rectum was 68% and 55% for LDR and HDR technique, respectively. Both techniques provided acceptable target volume coverage with a slightly higher value with the LDR technique. The dose distributions were more homogeneous and conformal, and both urethra and rectum were better protected with the HDR technique.


Vapor-phase toxicity of butylbenzyl phthalate to three plant species: white mustard, chinese cabbage, and white clover.
During the manufacture of products containing butylbenzyl phthalate (BBP), low emissions to the air may occur. Due to potential exposure of terrestrial communities to BBP vapors, phytotoxicity tests were conducted using Chinese cabbage, white mustard, and white clover. No significant effects on shoot growth were observed at the higher BBP vapor-phase concentration tested, which measured 5.7 microg/m(3). The overall practicality of vapor-phase testing of chemicals with very low vapor pressures is reviewed. These study results suggest that environmental risk from exposure to BBP vapor is negligible for plants.


Economic impact of clinical pharmaceutical activities in hospital wards: A systematic review.
The positive impact of clinical pharmacy services (CPS) in improving clinical outcomes such as reduction of drug related problems is well demonstrated. Despite these results, the deployment of these activities is not systematically observed in the hospital setting. This systematic review first aimed to describe existing evidence regarding economic evaluation of ward-based CPS focusing on the entire treatment of a patient in a hospital setting. Secondly, the quality of economic evaluations of existing evidence was assessed. A comprehensive literature search was performed in PubMed/Medline, Science Direct and the NHS Economic Evaluation databases from January 2000 to March 2019. English or French language articles describing an economic evaluation of ward-based CPS on inpatients in hospital settings were included. Articles not describing a single study, dealing with a CPS not considering the entire medication regimen of the patient or presenting both inpatient and outpatient CPS were excluded. Selected articles were analyzed according to Drummond's check-list for assessing economic evaluations. Forty-one studies were included. About one third were American publications. CPS implemented in ICU represented about half of the selected articles. Pharmacist-to-bed ratios varied according to countries and care unit type with the most favorable ratios in ICU and in American studies. Cost-avoidance was mostly used to express economic impact and ranged from €1579 to €3,089 328. Studies yielding the greater economic impact were conducted in the USA with implementation of full-time equivalents pharmacists or establishing of collaborative practice agreements. Only 6 articles dealt correctly with at least 7 of the 10 Drummond's checklist assessment criteria. This review suggests that the existing evidence is not sufficient to conclude to a positive economic impact of CPS conducted according to clinical pharmacy guidelines. Funding resources, remuneration of clinical pharmacy activities and provision of standardized national clinical and economic databases appear to be essential evolutions to improve CPS development.


Angiostrongylus cantonensis: role of eosinophils in the neurotoxic syndrome (Gordon-like phenomenon).
The role of eosinophils in the pathophysiology of Angiostrongylus cantonensis infections was investigated in nonpermissive (guinea pig) and permissive (rat) hosts. Neurological symptoms similar to the Gordon phenomenon (ataxia, tremor, paralysis) together with a loss of Purkinje cells in the cerebellum were observed after intracraneal injection of human eosinophil extracts or after infection with A. cantonensis, only in guinea pigs and not in rats. Blood eosinophilia as well as eosinophil numbers present in the cerebellum and in the cerebrospinal fluid were higher in guinea pigs than in rats, at all times after infection with A. cantonensis. Increased levels of cytotoxicity toward L3 larvae in vitro were obtained in the presence of guinea pig eosinophils and IgE antibodies, rather than with the corresponding rat effector system. The detection of one eosinophil granule component, the eosinophil peroxidase, in the cerebrospinal fluid from infected guinea pigs but not from rats suggested that in nonpermissive hosts, neurological disorders, similar to the previously described Gordon phenomenon, might be due to eosinophil neurotoxins released after interaction of eosinophils with the parasites.


Isolation of cells secreting specific polypeptides.
Antibody coupled erythrocytes in an agar overlay were used as a simple, nontoxic technique for the isolation of cell clones secreting proteins and hormones in vitro. The adaptation of the reverse hemolytic plaque assay was developed to provide a rapid, sensitive, and specific method for the screening of any antigen secreting cell without the need of prior isolation. This technique promises to be of use in the characterization and cloning of cells growing in mixed culture.


HIV coreceptor and chemokine ligand gene expression in the male urethra and female cervix.
Isolates with a tropism for the coreceptor CCR5 are the predominant viral strain transmitted following heterosexual transmission. We have investigated coreceptor expression levels within male and female genital epithelia to assess whether selective transmission can be explained by elevated CCR5 expression within the genital epithelia per se. Individuals attending a local genitourinary medicine unit were recruited, and samples of genital epithelia obtained using either a cytobrush (females) or urethral swab (males). Expression of coreceptor and cell marker mRNAs was then determined by reverse transcription (RT)-PCR. RNA was recovered from the epithelial cell samples then used as templates in competitive quantitative RT-PCR to measure mRNA expression of key chemokines, coreceptors and cell-type markers in the epithelial cell samples. Cell-surface coreceptor expression was also assessed in a sample of patients using fluorescent cell staining. CXCR4 and CCR3 coreceptors were expressed at significantly higher levels than CCR5 within the female endo- and ectocervix and distal end of the male urethra. Increased levels of cell surface expressed CXCR4 compared to CCR5 was confirmed in samples obtained from the female genital tract by FACS analysis. The selective transmission of CCR5-tropic viral variants is unlikely to result simply from differential coreceptor abundance at the genital epithelia.


Pregnancy and delivery in a patient with metastatic embryonal sarcoma of the liver.
Embryonal sarcoma of the liver is a rare undifferentiated mesenchymal neoplasm with a grave prognosis. We report a spontaneous uneventful pregnancy in a young woman with recurrent metastatic embryonal sarcoma of the liver after hepatectomy (twice) and radiochemotherapy. The patient chose to continue pregnancy despite her general condition and possible hazards to maternal and fetal well-being. She gave birth to a full-term healthy infant. Her disease recurred shortly after the delivery. According to a computerized search of the National Library of Medicine database, from 1966 to present, using the search terms "embryonal (or undifferentiated) sarcoma" and "liver" without language restrictions, this is the first reported case of pregnancy and delivery in a patient with embryonal sarcoma of the liver. It illustrates the clinical and ethical dilemmas associated with this complicated condition.


Synergistic anti-inflammatory and osteogenic n-HA/resveratrol/chitosan composite microspheres for osteoporotic bone regeneration.
The development of functional materials for osteoporosis is ultimately required for bone remodeling. However, grafts were accompanied by increasing pro-inflammatory cytokines that impaired bone formation. In this work, nano-hydroxyapatite (n-HA)/resveratrol (Res)/chitosan (CS) composite microspheres were designed to create a beneficial microenvironment and help improve the osteogenesis by local sustained release of Res. Study of in vitro release confirmed the feasibility of n-HA/Res/CS microspheres for controlled Res release. Notably, microspheres had anti-inflammatory activity evidenced by the decreased expression of pro-inflammatory cytokines TNF-α, IL-1β and iNOS in RAW264.7 cells in a dose dependent manner. Further, enhanced adhesion and proliferation of BMSCs seeded onto microspheres demonstrated that composite microspheres were conducive to cell growth. The ability to enhance osteo-differentiation was supported by up-regulation of Runx2, ALP, Col-1 and OCN, and substantial mineralization in osteogenic medium. When implanted into bone defects in the osteoporotic rat femoral condyles, enhanced entochondrostosis and bone regeneration suggested that the n-HA/Res/CS composite microspheres were more favorable for impaired fracture healing. The results indicated that optimized n-HA/Res/CS composite microspheres could serve as promising multifunctional fillers for osteoporotic bone defect/fracture treatment.


Effect of molecular helical structure on self-growing and damping of single network κ-carrageenan hydrogel.
Molecular helical is ubiquitous in molecular structures, however, the impact of the structure on mechanical properties has yet to be extensively studied. In this study, we synthesized a single network κ-carrageenan (KC) hydrogel with the molecular double helix structure, and elucidated its unique self-enhancing and damping properties from a molecular structural perspective. During cycle tensile tests, the helical structure was stretched and entangled to form a directional arrangement, increasing the elastic modulus and achieving 'self-reinforcement'. Meanwhile, the molecular helices have a spring-like damping effect, allowing the hydrogel to dampen low-frequency noise while transmitting high-frequency signals. By utilizing the hydrogel to create electrodes for electrocardiogram (ECG) detection, we were able to effectively filter out noise generated by movements while retaining necessary signals. Our work thus presents a potential pathway bridging from microscopic molecular structure to macroscopic mechanical properties of materials.


How do Adolescents' Perceptions of Relationships with Teachers Change during Upper-Secondary School Years?
The student-teacher relationship has mostly been assumed to be static. This approach is limited in providing information on how relationships with teachers evolve over time, and how possible changes affect young people's adjustment. To address this gap in knowledge, the present study examined whether adolescents follow different trajectories in their perceptions of relationship with teachers and whether students on different trajectories differ from each other in their adjustment. The sample included 829 students residing in Sweden (Mage = 13.43, SD = 0.55, 51% girls). Three distinct teacher-relationship trajectories were identified. More than half (66%) of the adolescents (average-stable trajectory) reported an average level of positive relationships with teachers at grade 7, and did not change significantly over the three years. About 24% of the adolescents (high-increasing trajectory) reported a high level of fair and supportive teacher-relationships at T1, and continued to increase in their positive views from grade 7 to grade 9. Ten percent of the adolescents (average-declining trajectory) reported an average level of positive relationships with teachers at grade 7, but showed a decline in their positive views towards teachers over time. Relative to adolescents on an average-stable trajectory, adolescents on a high-increasing trajectory reported greater school satisfaction, higher achievement values, and lower failure anticipation. By contrast, adolescents in the average-declining group reported worsening school adjustment. No significant moderating effects of immigrant status and gender were found. These findings highlight the importance of the association between the continuous experience of supportive and fair teacher treatment and youth adjustment.


Treatment extension may benefit female genotype 1 chronic hepatitis C patients with complete early virological response to peginterferon-alpha-2b and ribavirin combination therapy.
Little is known about the appropriate use of peginterferon-α-2b (PEG IFN-α-2b) or ribavirin (RBV) in genotype 1 chronic hepatitis C (CH-C) patients with complete early virological response (cEVR). Female patients, especially the older, are known to experience inferior treatment outcomes. A total of 150 CH-C patients with cEVR treated for 48 weeks (n = 104) or 52-64 weeks (n = 46) with PEG IFN-α-2b and RBV combination therapy were retrospectively analyzed to evaluate the benefits of extended treatment. In the 48-week group, patients without a sustained virological response (SVR) were more often female (P = 0.004) and had received a significantly lower total RBV dose (P = 0.003) than those with SVR. The SVR rate in these female patients was similar to males with hepatitis C virus (HCV) RNA negativity at treatment week 8 (P = 0.413); however, it was lower than that in males with HCV RNA negativity at treatment week 12 (P = 0.005). In the 52-64-week group, although the total RBV dose (mg/kg) after treatment week 48 was less in females than in males (P = 0.027), the SVR rate in females was equivalent to that in males (P = 0.604). Genotype 1 CH-C patients treated with PEG IFN-α-2b and RBV combination therapy without SVR were more often female and had received a lower total RBV dose than males. The smaller SVR rate in female patients with cEVR compared to males may be overcome by extending treatment even if the RBV dose is lowered due to anemia.


Effect of preinjury use of direct oral anticoagulants vs. Vitamin K antagonists on outcomes of hip fracture: a systematic review and meta-analysis.
Elderly patients with hip fractures are frequently under anticoagulant therapy. We aimed to assess if outcomes of hip fracture patients undergoing surgical intervention differ with prior use of direct oral anticoagulants (DOAC) or Vitamin K antagonists (VKA). PubMed, Embase, and Google Scholar were searched for comparative studies published up to June 20, 2021. Dichotomous variables were summarized using odds ratio (OR) and continuous variables using mean difference (MD). Fourteen studies were included. There was no difference in the time to surgery between patients on DOAC or VKA (MD: 2.50 95% CI -2.10, 7.10 I2=76% p=0.29). Number of undergoing surgeries within 48 hours was not significantly different between the two groups (OR: 0.77 95% CI 0.56, 1.06 I2=10% p=0.10). Mortality rates (OR: 0.84 95% CI 0.62, 1.14 I2=12% p=0.27), blood transfusion requirement (OR: 1.08 95% CI 0.80, 1.47 I2=30% p=0.62) and length of hospital stay (MD: 0.26 95% CI -0.70, 1.21 I2=0% p=0.60) was also not significantly different between patients on DOAC or VKA. There is no difference in surgical delay, early mortality, blood transfusion rates and length of hospital stay between DOAC uses and VKA users undergoing hip fracture surgery.


A review of atopic dermatitis.
Eczema means to boil out. Acute eczematous dermatitis manifests vesiculation and bullae. It occurs whenever the epidermis is altered by external insults. Atopic dermatitis involves the eczematous process and is known as the itch that rashes.


Bovine protothecosis. A brief report of ten cases.
Prototheca zopfii was isolated repeatedly from milk samples from ten cows (of a herd of 192 dairy cows) with reduced milk yield and indurated mammary glands. The strain was moderately sensitive to streptomycin, polymyxin and gentamycin, but resistant or relatively resistant to other antibiotics and antimycotics commonly used in clinical practice. An attempt to treat the infection with Ethidium bromide, which was found effective in vitro, did not succeed. The number of Prototheca excreted decreased, but a complete cure was not obtained. In histological sections of the udder, Prototheca cells were demonstrated both intracellularly and interstitially.


Chronic anterior and posterior uveitis and primary Sjögren's syndrome.
We examined eight patients with primary Sjögren's syndrome and uveitis. In all patients, the uveitis was bilateral, chronic, anterior and posterior, and not associated with active chorioretinitis. Seven of the eight patients were women. The diagnosis of primary Sjögren's syndrome was generally based on results of a Schirmer test, minor salivary gland biopsy, and serologic studies. Frequent findings included keratic precipitates, cataract, a pars plana exudate, an increased sedimentation rate, a positive test for antinuclear antibodies in a speckled pattern, and associated systemic disease compatible with the spectrum of Sjögren's syndrome.


Distal radial cortical bone thickness correlates with bone mineral density and can predict osteoporosis: a cohort study.
The purpose of this study was to evaluate the correlation of the bone mineral density (BMD) of the hip and lumbar spine with the distal radius cortical thickness (DRCT) measured on anteroposterior radiographs and establish a method for predicting osteoporosis. We assessed 147 patients aged ≥50 years with distal radius fractures who underwent wrist radiographs and dual-energy X-ray absorptiometry. The DRCT was measured and calculated at two levels of the distal radius of the injured wrist on the radiographs. The intra-rater and inter-rater reliability of measures was excellent (intraclass correlation coefficient >0.85). In the Pearson correlation and simple linear regression analyses, the DRCT was positively correlated with hip BMD (r = 0.393, P < 0.01) and lumbar spine BMD (r = 0.529, P < 0.01). Each 1-mm increase in DRCT was associated with a 0.051-g/cm2 increase in hip BMD (R2 = 0.154, P < 0.01) and a 0.080-g/cm2 increase in lumbar spine BMD (R2 = 0.280, P < 0.01). A DRCT of 5.1 mm was selected as the cutoff point for predicting osteoporosis, with the highest Youden index of 0.560, 83.3% sensitivity, 72.7% specificity, and a 66.7% negative predictive value. Cortical thickness measurements obtained from anteroposterior wrist radiographs were positively correlated with hip and lumbar spine BMD measurements. This technique is suggested as a rapid, inexpensive, and sensitive method for predicting osteoporosis. Diagnostic II.


Reliable reference genes for expression analysis of proliferating and adipogenically differentiating human adipose stromal cells.
The proliferation and adipogenic differentiation of adipose stromal cells (ASCs) are complex processes comprising major phenotypical alterations driven by up- and downregulation of hundreds of genes. Quantitative RT-PCR can be employed to measure relative changes in the expression of a gene of interest. This approach requires constitutively expressed reference genes for normalization to counteract inter-sample variations due to differences in RNA quality and quantity. Thus, a careful validation of quantitative RT-PCR reference genes is needed to accurately measure fluctuations in the expression of genes. Here, we evaluated candidate reference genes applicable for quantitative RT-PCR analysis of gene expression during proliferation and adipogenesis of human ASCs with the immunophenotype DLK1+/CD34+/CD90+/CD105+/CD45-/CD31-. We evaluated the applicability of 10 candidate reference genes (GAPDH, TBP, RPS18, EF1A, TFRC, GUSB, PSMD5, CCNA2, LMNA and MRPL19) using NormFinder, geNorm and BestKeeper software. The results indicate that EF1A and MRPL19 are the most reliable reference genes for quantitative RT-PCR analysis of proliferating ASCs. PSMD5 serves as the most reliable endogenous control in adipogenesis. CCNA2 and LMNA were among the least consistent genes. Applying these findings for future gene expression analyses will help elucidate ASC biology.


Could academic experience modulate psychophysiological stress response of biomedical sciences students in laboratory?
The aim of the present research was to analyse the subjective and objective psychophysiological stress response of experienced and non-experienced Pharmacy and Biotechnology students in laboratory practices. We analysed in 82 Pharmacy and Biotechnology degree students divided into two groups (non-experienced: n: 53; experienced: n: 29) the autonomic stress response by the analysis of heart rate variability (HRV) before, during and after and distress perception before and after a laboratory practice. Results showed how students in both groups presented a large anticipatory anxiety response at the beginning of the practise (low HRV values). During the entire laboratory practice, non-experienced students showed a maintained sympathetic modulation while experienced students presented a higher parasympathetic modulation (high HRV values) consistent with a habituation process. Laboratory practise performed by Pharmacy and Biotechnology students produced an anticipatory anxiety response independently of their experience, but, non-experienced students showed a lower habituation response in both subjective and objective stress records than experienced students at the end of the laboratory practice.


Avian energetics: The passerine/non-passerine dichotomy.
Whether passerines collectively have a higher mean mass-independent basal rate of metabolism than the mean of other birds has been controversial. The conclusion that no difference exists was based on phylogenetic analyses. Higher basal rates, however, have been repeatedly seen in passerines and demonstrated by ANCOVA analyses. Several studies indicated that the mean mass-independent basal rate of passerines is >30% higher than the collective mean of other birds. Yet, at least three non-passerine orders of 25 have mean mass-independent basal rates equal to that of passerines. They are Anseriformes, Charadriiformes, and Procellariiformes, all characterized by an active lifestyle, including migratory and pelagic habits. In contrast, sedentary ducks endemic to islands have low basal rates. The high basal rates in temperate passerines correlate with migratory habits and life in cool to cold environments, the absence of these factors being partly responsible for the lower basal rates in most tropical passerines. The principal difference in energetics among non-passerines, between passerines and most non-passerines, and among passerines reflects the frequency of habits associated with high or low mass-independent energy expenditures, the habits correlating with body composition. The mean mass-independent basal rate in tropical passerines is slightly lower than in temperate passerines which implies that the collective mean in passerines would be somewhat lower if tropical passerines were included in proportion to their diversity. However, their inclusion will not eliminate the difference presently seen between passerines and other birds because the difference between tropical and temperate passerines is less than that between passerines and other birds.


Stable planar six-pi-electron six-membered N-heterocyclic carbenes with tunable electronic properties.
Carbene analogues of borazines are highly thermally stable. Keeping quasi-identical steric demands, the electronic properties of the carbene can be precisely tuned by varying the nature of the substituents at the boron centers.


Implementing innovative service delivery models in genetic counseling: a qualitative analysis of facilitators and barriers.
Given the increasing demand for genetic counseling, implementation of innovative service delivery models (SDMs) has been proposed to improve access and increase the efficiency of genetic counseling services. This study investigated the key considerations in genetic counseling practices that impact the decision to implement innovative SDMs, as well as barriers and facilitators to implementation. A cross-sectional, qualitative research design was employed, using focus groups. Genetic counselors (GCs) were recruited from respondents to an online survey about SDMs and by posting an invitation to the National Society of Genetic Counselors (NSGC) listserv. A total of 30 participants participated in either in-person (n = 3) or online (n = 5) focus groups, facilitated by members of the Service Delivery Model subcommittee of the NSGC Access and Service Delivery Committee. Transcribed audio and written notes from the focus groups were coded, utilizing an inductive thematic analysis method. Five overarching themes that impact decisions to implement and use innovative SDMs were identified: (a) Patient volume and efficiency are key motivators in trying innovative SDMs; (b) the decision to change is facilitated by available resources; (c) the implementation of innovative SDMs is multidimensional and complex process; (d) there is concern about the impact on patient-provider relationships with the utilization of innovative SDMs; and (e) measuring outcomes of innovative SDM facilitates acquisition of additional resources and support. Approaches to innovative SDM selection and implementation vary by institution needs, resources, and population as demonstrated by the variety of approaches to similar barriers. Outcomes related to the implementation of innovative SDMs in genetic counseling practice should be measured to demonstrate the value of innovative genetic counseling SDMs, improvement of access to care, and to justify need for additional resources to support implementation of these models.


α-1 Adrenergic receptor antagonist doxazosin reverses hepatic stellate cells activation via induction of senescence.
Activated hepatic stellate cells (aHSCs) are the main effector cells during liver fibrogenesis. α-1 adrenergic antagonist doxazosin (DX) was shown to be anti-fibrotic in an in vivo model of liver fibrosis (LF), but the mechanism remains to be elucidated. Recent studies suggest that reversion of LF can be achieved by inducing cellular senescence characterized by irreversible cell-cycle arrest and acquisition of the senescence-associated secretory phenotype (SASP). To elucidate the mechanism of the anti-fibrotic effect of DX and determine whether it induces senescence. Primary culture-activated rat HSCs were used. mRNA and protein expression were measured by qPCR and Western blot, respectively. Cell proliferation was assessed by BrdU incorporation and xCelligence analysis. TGF-β was used for maximal HSC activation. Norepinephrine (NE), PMA and m-3M3FBS were used to activate alpha-1 adrenergic signaling. Expression of Col1α1 was significantly decreased by DX (10 μmol/L) at mRNA (-30 %) and protein level (-50 %) in TGF-β treated aHSCs. DX significantly reduced aHSCs proliferation and increased expression of senescence and SASP markers. PMA and m-3M3FBS reversed the effect of DX on senescence markers. Doxazosin reverses the fibrogenic phenotype of aHSCs and induces the senescence phenotype.


Effect of bandgap alignment on the photoreduction of CO2 into methane based on Cu2O-decorated CuO microspheres.
Semiconductors' band gap alignment is important for the photoreduction of CO2 to methane. In the paper, two kinds of Cu2O-decorated CuO microspheres composed with nanoflakes were prepared by using two different methods. Their electron behaviors were studied from the XPS spectra and photoelectrochemical measurements. Both samples are p-type CuO covered with an amount of Cu2O nanoparticles on their surface. Combined with their bandgaps and flat band potentials, CuO-Mic has a well-matched bandgap alignment between Cu2O and CuO, which is favorable for the separation of photogenerated electron-hole pairs. Those photogenerated carriers are beneficial for the conversion of CO2 to CH4, as an 8-electron process for the conversion of CO2 to CH4 will consume more photogenerated electrons for the chemical reactions than that of the 2-electron process for CO2 reduction to CO. Therefore, CuO-Mic has much better photocatalytic activity for CO2 reduction to CH4 with a CH4 yield ten times higher than that of CuO-Hyd under a visible light irradiation, the CO yields of the CO2 reduction are identical.


MR-DoC2: Bidirectional Causal Modeling with Instrumental Variables and Data from Relatives.
Establishing causality is an essential step towards developing interventions for psychiatric disorders, substance use and many other conditions. While randomized controlled trials (RCTs) are considered the gold standard for causal inference, they are unethical in many scenarios. Mendelian randomization (MR) can be used in such cases, but importantly both RCTs and MR assume unidirectional causality. In this paper, we developed a new model, MRDoC2, that can be used to identify bidirectional causation in the presence of confounding due to both familial and non-familial sources. Our model extends the MRDoC model (Minică et al. in Behav Genet 48:337-349, https://doi.org/10.1007/s10519-018-9904-4 , 2018), by simultaneously including risk scores for each trait. Furthermore, the power to detect causal effects in MRDoC2 does not require the phenotypes to have different additive genetic or shared environmental sources of variance, as is the case in the direction of causation twin model (Heath et al. in Behav Genet 23:29-50, https://doi.org/10.1007/BF01067552 , 1993).


Scenario-based planning for reduction of emitted CO2 from the Pars Special Economic Energy Zone (PSEEZ) of Iran.
The Pars Special Economic Energy Zone (PSEEZ) is one of the largest gas reserves in the world. To reduce the CO2 emission from the area in line with the international climate commitments, two groups of scenario have been developed: the first is using the ecosystem services of mangrove forests, and the second is technology development for oil and gas industries. For the first scenario, the carbon sequestrated by the trees was calculated using the allometric equation, and the carbon of sediments was determined by using the Walkley-Black method. For the second scenario, CO2 emitted from the PSEEZ was calculated by using the Iranian Petroleum Ministry Guidelines. CO2 emission from the PSEEZ was 0.030 Gt year-1. The maximum CO2 sequestered by mangrove scenarios was 0.12% of the PSEEZ emissions, while the flaring elimination technology reduces 36% of the PSEEZ emissions. Generally, the scenario of using oil and gas industry technologies is more effective.


Dissociation of arsenite-peptide complexes: triphasic nature, rate constants, half-lives, and biological importance.
We determined the number and the dissociation rate constants of different complexes formed from arsenite and two peptides containing either one (RVCAVGNDYASGYHYGV for peptide 20) or three cysteines (LECAWQGK CVEGTEHLYSMKCK for peptide 10) via radioactive 73As-labeled arsenite and vacuum filtration methodology. Nonlinear regression analysis of the dissociation of both arsenite-peptide complexes showed that triphasic fits gave excellent r2 values (0.9859 for peptide 20 and 0.9890 for peptide 10). The first phase of arsenite-peptide dissociation had the largest span (decrease in binding), and the rate was too fast to be measured using vacuum filtration methods. The dissociation rate constants of arsenite-peptide complexes for the second phase were 0.35 and 0.54 min(-1) and for the third phase were 0.0071 and 0.0045 min(-1) for peptides 20 and 10, respectively. For peptide 20, the three spans of triphasic decay were 85%, 9%, and 7% of the total binding of 16.1 nmol/mg protein. For peptide 10, which can bind in both an intermolecular and intramolecular manner, the three spans of triphasic decay were 59%, 16%, and 25% of the total binding of 43.7 nmol/mg protein. Binding of trivalent arsenicals to peptides and proteins can alter their structure and function and contribute to adverse health outcomes such as toxicity and carcinogenicity.


[Interest of a specific programme in patient education for dialysis in out-center patients].
The development of therapeutic patient education for dialysis patients is recent and concerns mainly out-center patients. To our knowledge, only two papers centred on therapeutic education with out-center patients have been published. The particularities of this dialysis modality (unit close to the home, more autonomy, a nurse for six patients, organisation of unit, better quality of life and psychological status) highlight the interest to develop specific educational programs for patients treated in out-center sitting. The example of a program in Aquitaine (France) composed of mainly collective sessions (representations of the disease, dietetic recommendations, hygiene and protection of the vascular access, drugs compliance…) allows to propose several practical implications to initiate the development of specific programs in therapeutic education for out-center dialysis: educative sessions during the sessions of dialysis, group patients, multidisciplinary team, evaluation of the program from a medical and psychosocial point of view…


Variations of C14ORF39 and SYCE1 Identified in Idiopathic Premature Ovarian Insufficiency and Nonobstructive Azoospermia.
Premature ovarian insufficiency (POI) and nonobstructive azoospermia (NOA) are the most severe diseases causing irreversible infertility in females and males, respectively. The contribution of synaptonemal complex (SC) gene variations in the pathogenesis of sporadic patients with POI and NOA has not been systematically illustrated. To investigate the role of SC genes in the pathogenesis of sporadic POI and NOA. Genetic and functional study. University-based reproductive medicine center. A total of 1030 patients with sporadic POI and 400 patients with sporadic NOA. The variations of SC genes were filtered in the in-house database of whole exome sequencing performed in 1030 patients with sporadic POI and 400 patients with sporadic NOA. The pathogenic or likely pathogenic variations following recessive inheritance mode were selected according to American College of Medical Genetics and Genomics (ACMG) guidelines and confirmed by Sanger sequencing. The pathogenic effects of the variations were verified by functional studies. ACMG classification and functional characteristics. Two homozygous variations of C14ORF39 and 2 recessive variations of SYCE1 were first identified in sporadic patients with POI and NOA, respectively. Functional studies showed the C14ORF39 variations significantly accelerated the protein degradation and the variations in SYCE1 disrupted its interaction with SYCP1 or C14ORF39, both of which affected SC assembly and meiosis. Our study identified novel pathogenic variations of C14ORF39 and SYCE1 in sporadic patients with POI or NOA, highlighting the essential role of SC genes in the maintenance of ovarian and testicular function.


Script concordance testing: more cases or more questions?
Script concordance test (SCT) is a case based assessment format of clinical reasoning in which questions are nested into several cases. Recent results using Q4 format suggest that nested questions contribute more to reliability of measure than cases. The present study aims at documenting variance components associated with SCT cases and nested questions and to determine what are the optimal number and combinations of cases and nested questions. Data from SCT in three different fields are presented. G study and D study methodology are used to estimate variance component and to determine optimal number and combinations of cases and questions. Questions nested into cases contributed a large amount of score variance (more than 70%). D studies with varying samples show that, depending on the reliability of the test, an optimal number of 2-4 questions nested into 15-25 cases represents the best combination. Nested questions contribute to a significant portion of score variance, with the implication that formulation of up to 5 questions per case is an efficient way to optimize the reliability of SCT scores.


Investigation on the pollution release characteristics of subgrade base materials prepared by oil-based cutting thermal desorption residues.
The preparation of oil-based cutting thermal desorption residues into subgrade materials is one of the methods of their resource utilization. While the environmental safety for subgrade materials is lack of discussions. In this study, through the semi-dynamic leaching tests, the leaching characteristics of pollutants from residues subgrade materials under extremely acidic conditions were simulated. According to Fick's second law, combined with the effective diffusion coefficient (De), the risk of pollutant leaching and release in residue subgrade materials were evaluated. The concentrations of naphthalene, anthracene, benzo(a)anthracene, dibenzo(a,h)anthracene, Cd, and Zn met the requirements of class III water quality in the Chinese standard GB/T14848-2017. The release of naphthalene, anthracene, benzo(a)anthracene, dibenzo(a,h)anthracene, and Cd of leaching was dominated by diffusion. The release of benzo(a)pyrene and Zn of leaching was mainly dissolution. Hence, based on the investigation, the release law and characteristics of pollutants were explored when thermal desorption residues were applied as subgrade materials, which provided an important reference basis for the resource and utilization of oil-based cutting thermal desorption residues.


Mesenchymal stem cells increase expression of heme oxygenase-1 leading to anti-inflammatory activity in treatment of acute liver failure.
Mesenchymal stem cells (MSCs) have been studied for the treatment of acute liver failure (ALF) for several years. MSCs may exert their effect via complex paracrine mechanisms. Heme oxygenase (HO) 1, a rate-limiting enzyme in heme metabolism, exerts a wide range of anti-inflammatory, anti-apoptotic and immunoregulatory effects in a variety of diseases. However, the relationship between MSCs and HO-1 in the treatment of ALF is still unclear. We investigated the preventive and therapeutic potential of intravenously administered BMSCs. Bone marrow-derived mesenchymal stem cells (BMSCs) obtained from Sprague-Dawley rats were isolated and cultured. We employed BMSCs, hemin (a HO-1 inducer) and zinc protoporphyrin (ZnPP, the HO-1 activity inhibitor) in D-galactosamine (D-Gal)/lipopolysaccharides (LPS)-induced ALF rats. Rats were sacrificed at days 1, 3, 5, and 7 post-transfusion, respectively. Blood samples and liver tissues were collected. Hepatic injury, HO-1 activity, chemokines, inflammatory cytokines, the number and oxidative activity of neutrophils, ki67, and TUNEL-positive cells were evaluated. HO-1 induction or BMSCs transplantation attenuated D-galactosamine/lipopolysaccharide-induced increases in alanine aminotransferase, aspartate aminotransferase, total bilirubin (TBIL), ammonia, and inflammatory cytokines. Treatment with hemin or BMSCs also inhibited neutrophil infiltration, oxidative activity, and hepatocyte apoptosis. The protective effect of BMSCs was partially neutralized by ZnPP, suggesting the key role of HO-1 in the process. These findings may correlate with inhibition of nuclear factor-κ B activation. BMSCs ameliorated ALF by increasing the HO-1 expression, which reduced PMN infiltration and function, and played an important anti-inflammatory and anti-apoptotic role. Proposed mechanism by which BMSCs reduce inflammation, neutrophil activation, and hepatocyte apoptosis and promote hepatocyte proliferation via HO-1. BMSCs increase HO-1 expression in liver via Nrf2. HO-1 protects against LPS/D-Gal-induced ALF by inhibiting neutrophil infiltration and inflammatory burst, and hepatocyte apoptosis and necrosis. HO-1 also promotes hepatocyte proliferation.


A new type of silica-induced "moundless" pitting corrosion in copper observed in Japan.
A new type of pitting corrosion in copper, namely "moundless" corrosion, has recently been reported in Japan. This type of pitting corrosion has some unique morphological features that differ from ordinary types of pitting corrosion, such as type I or type II. Firstly, this type of pitting corrosion has no mound of corrosion products that cover the mouth of the pit. In addition, a glassy verdigris exists around the pit. Furthermore, the pit measures <1 mm in diameter, but is extremely deep. In our study, we reproduced moundless pits by field testing in an area where moundless pits have often occurred. Moundless pits were also generated in synthetic freshwater through the dissolution of some selected components in a laboratory test. This synthetic freshwater contained 40 ppm SiO2, 50 ppm SO4 2-, 10 ppm Cl-, and 10 ppm HCO3 -. Surface analysis of the moundless pit revealed that the mouths of the pits were covered with thin films that were mainly composed of silica.


Nose-to-brain delivery of sumatriptan-loaded nanostructured lipid carriers: preparation, optimization, characterization and pharmacokinetic evaluation.
Migraine is a neurological disorder with unilateral pulsatile headache which can affect the functions of sufferers. Migraineurs experience some undesirable symptoms such as pain, nausea, vomiting and in some cases auras which make the oral delivery non-selective. The lipid nanoparticles are considered as good carriers for nose-to-brain drug delivery. The present study aimed to formulate and evaluate a sumatriptan-loaded nanostructured lipid carrier (NLC). A drug-loaded NLC was optimized using D-optimal design of experiment and then the characterization of the formulated NLC including particle size, zeta potential, electron microscopy, thermal analysis, drug loading efficiency and release kinetics were carried out. Pharmacokinetic evaluations were also performed during an in-vivo study on Sprague-Dawley rats and neuropharmacokinetic parameters such as drug targeting efficiency (DTE) and direct transport percentage (DTP) were calculated. The optimization of experiments led to nanoparticles with 101 nm mean diameter and polydispersity index (PDI) of 0.27. The drug entrapment efficiency (EE) for optimized nanoparticle was found to be 91.00%. DTE and DTP of intranasal-administered NLC were calculated 258.02% and 61.23%, respectively. Neuropharmacokinetic evaluation of intranasal NLC dispersion represents a suitable brain delivery system. The DTP of NLC formulation suggests the desirable entrance of sumatriptan into the brain.


Phosphorylation of CREB Ser142 regulates light-induced phase shifts of the circadian clock.
Biological rhythms are driven in mammals by a central circadian clock located in the suprachiasmatic nucleus (SCN). Light-induced phase shifting of this clock is correlated with phosphorylation of CREB at Ser133 in the SCN. Here, we characterize phosphorylation of CREB at Ser142 and describe its contribution to the entrainment of the clock. In the SCN, light and glutamate strongly induce CREB Ser142 phosphorylation. To determine the physiological relevance of phosphorylation at Ser142, we generated a mouse mutant, CREB(S142A), lacking this phosphorylation site. Light-induced phase shifts of locomotion and expression of c-Fos and mPer1 in the SCN are significantly attenuated in CREB(S142A) mutants. Our findings provide genetic evidence that CREB Ser142 phosphorylation is involved in the entrainment of the mammalian clock and reveal a novel phosphorylation-dependent regulation of CREB activity.


Prolactin as a link between behavioral and immune differences between the Roman rat lines.
Roman high (RHA)- and low (RLA)-avoidance rats are two lines of Wistar rats genetically selected on the basis of their active avoidance behavior in a shuttle-box. They also differ in several other behavioral responses, such as their locomotor activity in novel environments (open-field, circular corridor), with the RHA rats being more active than the RLA animals, as well as in endocrine reactivity and immune functions. These experiments were designed to investigate further the neuroendocrine characteristics of these animals as a possible link between the brain and immune functions. Despite the marked behavioral and immune differences observed, no between-lines variation could be found in basal hypothalamo-pituitary-adrenocortical axis activity or in its responses to different protocols of novel environment stress, or after corticotropin-releasing factor (CRF) challenge. On the other hand, stimulated prolactin levels were higher in the low avoidance line. These results exclude the pituitary-adrenocortical axis and suggest prolactin as a link between behavioral and immune differences between the Roman lines. Moreover, these results indicate that these rats may be an excellent model for the study of the relationships between the brain and the immune system.


The role of gender in primary hyperparathyroidism: same disease, different presentation.
Hyperparathyroidism is much more common in women and therefore may represent different diseases in men and women. In order to understand the role of gender in hyperparathyroidism, we reviewed our experience. We analyzed a prospective database of 1309 consecutive patients with primary hyperparathyroidism who underwent parathyroidectomy at our institution between March 2001 and August 2010. The female-to-male ratio was 3.3:1, and female patients were older at presentation (60 ± 0 vs. 57 ± 1 years, p < 0.005). Male patients were more commonly asymptomatic at presentation (25 % vs. 18 %, p = 0.005) and the most common symptom for men was kidney stones (23 % vs. 13 %, p < 0.0001). For patients with bone density scans, osteoporosis was more common in women (34 % vs. 17 %, p < 0.0001). Men had a slightly higher preoperative serum calcium level (11.1 ± 0 vs. 11.0 ± 0 mg/dl, p = 0.03), higher parathyroid hormone level (140 ± 7 vs. 124 ± 4 pg/ml, p = 0.04), higher urinary calcium level (376 ± 10 vs. 314 ± 5 mg/24 h, p < 0.005), and lower vitamin D level (28 ± 1 vs. 32 ± 0 ng/ml, p < 0.005). Men were more likely to have abnormally elevated creatinine values (15 % vs. 9 %, p = 0.004). The operative approach as well as the number of glands involved and their location did not significantly differ between the groups. The mean gland weight for a single adenomas was higher in male patients (1123 ± 128 vs. 636 ± 32 mg, p = 0.001). No significant difference was identified in the immediate and remote postoperative course. Hyperparathyroidism appears to present differently depending on gender. Male patients more often present without symptoms, present with vitamin D deficiency, and have larger parathyroid glands. Importantly, surgical outcomes were equivalent between men and women.


Comparison of preoperative and postoperative diflunisal for suppression of postoperative pain.
Despite the demonstrated therapeutic advantage of preoperatively administered nonsteroidal anti-inflammatory agents (NSAIAs) in suppressing postoperative pain, clinicians are reluctant to administer these drugs orally before surgical procedures performed using sedation or general anesthesia. Using a within-subject, crossover experimental design, this study compared the analgesic efficacies of an NSAIA, diflunisal 1,000 mg, administered either 30 minutes preoperatively or 30 minutes postoperatively to 20 patients undergoing the removal of impacted third molars. Pain intensity was assessed preoperatively and postoperatively for eight hours using category-rating and visual analog scales. Treatment with diflunisal 30 minutes after completion of surgery proved to be just as effective in suppressing postsurgical pain as presurgical administration. Administration of an NSAID in the immediate postoperative period may be indicated for optimum postoperative analgesia for patients in whom preoperative oral intake is contraindicated.