[Survival of lung cancer patients treated at a referral hospital in Zaragoza (Spain)].
The aim of this work is to study the survival of lung cancer patients treated at a referral hospital in Zaragoza (Spain). The Kaplan-Meier test was used to calculate observed survival. The automatic calculation of the Catalan Institute of Oncology was used to analyse relative survival. Mean survival time was 25.74 months. There was no difference when comparing age groups (P=.151), gender (P=.369), and histological type of tumour (P=.086). Survival by stage of the disease at diagnosis revealed statistically significant differences (P<.001). Relative survival 5 years after diagnosis for the group analysed was 14%. Survival was higher for men (15.5%), in patients under 60 (16.7%) and squamous tumours (18.7%). Survival by tumour stage was in line with the TNM Staging System for Lung Cancer. These results suggest that overall survival rate for lung cancer in Zaragoza remains very low in the long term, and this depends on the stage of the disease at diagnosis.


Halogenated aromatic hydrocarbons and toxicity equivalency factors (TEFs) from the public health assessment perspective.
The validity of the toxicity equivalency factors (TEFs) approach to predicting toxicity of mixtures was investigated on the basis of the public health risk assessment that had been posted for different groups of halogenated aromatic hydrocarbons. First, the minimal risk levels (MRLs) were derived based on the databases available for chlorinated dibenzo-p-dioxins (CDDs), chlorinated dibenzofurans (CDFs), and polychlorinated biphenyls (PCBs). The MRL values were then converted to 2,3,7,8-tetrachlorinated dibenzo-p-dioxin (TCDD) toxicity equivalents (TEQs) and compared with each other. There was a good correlation between intermediate duration oral MRLs for TCDD and 2,3,4,7,8-pentaCDF when expressed in TEQs (7 pg/kg/day and 15 pg/kg/day). Although the studies that served for derivation of these MRLs used different species (guinea pigs and rats, respectively), the toxicity endpoints (immunological and hepatic for TCDD and hepatic for 2,3,4,7,8-pentaCDF) were comparable. The hepatic effects were measured by the same techniques (blood chemistry and histopathology), ensuring similar sensitivity. However, there was a discrepancy between acute oral MRLs for TCDD and 2,3,4,7,8-pentaCDF when they were expressed in TEQs (20 pg/kg/day and 500 pg/kg/day, respectively). The studies used for MRL derivation involved not only different species (mice and guinea pigs, respectively), the immunotoxicity endpoints were measured by techniques with different sensitivity (serum complement activity versus histopathology), making comparison difficult. Further calculations showed that the TEFs approach may be feasible for individual coplanar congeners of PCBs, but not for a mixture of Aroclors. Correlations presented here support the concept that the TEFs are valid only if specific criteria for their derivation are met (e.g., a broad database of information, consistency across endpoints, additivity for the effects, a common mechanism of action, etc.). In environmental exposure, the total toxicity of halogenated aromatic hydrocarbons is not necessarily the sum of the total individual congener toxicities because individual congeners compete for the same receptor; therefore, nonadditive behavior may occur.


Metabolic Enzyme Sulfotransferase 1A1 Is the Trigger for N-Benzyl Indole Carbinol Tumor Growth Suppression.
In an attempt to identify novel therapeutics and mechanisms to differentially kill tumor cells using phenotypic screening, we identified N-benzyl indole carbinols (N-BICs), synthetic analogs of the natural product indole-3-carbinol (I3C). To understand the mode of action for the molecules we employed Cancer Cell Line Encyclopedia viability profiling and correlative informatics analysis to identify and ultimately confirm the phase II metabolic enzyme sulfotransferase 1A1 (SULT1A1) as the essential factor for compound selectivity. Further studies demonstrate that SULT1A1 activates the N-BICs by rendering the compounds strong electrophiles which can alkylate cellular proteins and thereby induce cell death. This study demonstrates that the selectivity profile for N-BICs is through conversion by SULT1A1 from an inactive prodrug to an active species that induces cell death and tumor suppression.


Adenylate cyclase in human gastric mucosa: its activation by histamine in morphologically different biopsy specimens.
In morphologically different biopsy specimens from fundic, antral and duodenal mucosa of 134 persons, basal and histamine stimulated adenylate cyclase activity was studied: Basal and stimulated adenylate cyclase activities were log-normally distributed. Only in the fundic but not in the antral and duodenal mucosa adenylate cyclase was sensitive to histamine. The mean basal activity in the fundic gastric mucosa was 148, in response to 10(-5) mol/l histamine 292 pmol cAMP/mg protein/20 min. In human fundic biopsy specimens histologically identified as normal gastric mucosa, the stimulatory effect of histamine on adenylate cyclase decreased with the individual's age. In bioptic material from patients suffering from histologically proven chronic gastritis the histamine effect decreased with the degree of atrophy. A similar loss of histamine sensitivity was found in gastric mucosal biopsies of antrectomized individuals operated at least 5 years before by the Billroth I or II method, whereas in the mucosa of patients with gastric or duodenal ulcer no loss occurred. In contrast, the most pronounced stimulatory action of histamine was found in this latter group. Since a histamine sensitive adenylate cyclase is localized only in the glandular area of the fundic mucosa and the histamine sensitivity depends on a morphological intact structure of the mucosa, it can be concluded, that the effects of histamine on adenylate cyclase and on hydrochloric acid acid secretion have to be considered as a mechanism linked together.


Experience of Disgust and Symptom Severity in Contamination Subtype of Obsessive-Compulsive Disorder: Role of Experiential Avoidance.
The emotion of disgust has been linked with the underlying nature of the contamination subtype of obsessive-compulsive disorder (C-OCD). Prior studies show that disgust contributes to the development of C-OCD by reinforcing avoidance strategies. Therefore, experiential avoidance (EA) may influence the effect between disgust sensitivity (DS) and C-OCD symptom severity. This study aimed to investigate the mediational role of EA between DS and C-OCD severity. A cross-sectional design was adopted with 45 patients of OCD and 45 healthy controls. Both the groups were assessed on the Obsessive-Compulsive Inventory, the Disgust Scale (Revised), and Acceptance and Action Questionnaire-II. Yale-Brown Obsessive Compulsive Scale (Y-BOCS) checklist and symptom severity scale were additionally administered to the patients with OCD. Independent t-tests, Pearson's product-moment correlation, regression analysis, and mediation analysis were used. DS and EA were positively associated with contamination-washing symptoms and symptom severity. Regression analysis indicated that DS and EA were highly associated with contamination/washing severity scores among both the patients with C-OCD and the healthy controls. The study implicates that disgust is a central emotion underlying the presentation of obsessions and compulsions, which are of contamination concerns. Further, EA has a role in the maintenance of OCD through avoidance learning; however, it may not be interacting with DS to cause OCD.


Genetic and molecular approaches to improve nutritional value of Brassica napus L. seed.
Oilseed rape (Brassica napus L.) is a major oil crop that also supplies proteins for the feed industry. In order to reduce total cost production, the objective is to increase oil yield while reducing crop inputs (especially nitrogen and pesticides). Concomitantly, it is necessary to anticipate specific uses (e.g., fatty acid composition) and to ensure the valorisation of the by-products (rapeseed meal). By the past, improvement of seed quality focused on fatty acid balance and low seed glucosinolate content. Current goals include the breeding of yellow-seeded rapeseed lines with high content of seed oil. The use of molecular tools and the exploitation of Arabidopsis knowledge will be presented and discussed.


Association of the Robert Wood Johnson Foundations' Social Determinants of Health and Medicare Ocular Hospitalizations: A Cross Sectional Data Analysis.
Social determinants of health (SDH) may influence inpatient utilization rates and outcomes but have yet to be associated with ocular diagnoses. The purpose of this paper was to determine whether the SDH are associated with ocular hospitalizations. Patients from the national Medicare 100% Inpatient Limited Dataset were examined and linked to SDH measures from the Robert Wood Johnson Foundation (RWJF) County Health Rankings. Patients were included in the study group with either an admitting or primary diagnosis of an ophthalmic condition. All other hospitalized Medicare patients served in the comparison group. Nested logistic regression of these Medicare patients was conducted in their respective communities at the county level. SDH measures were benchmarked above or below the national median. Positively associated SDH factors included communities with air pollution exceeding 11.62 micro grams per cubic meter (OR 1.05; 95% CI 1.01-1.08), communities where severe housing problems exceeding 14.38% (OR 1.13; 95% CI 1.09-1.18), children in single parent households exceeding 32.13% (OR 1.06; 95% CI 1.02-1.11), violent crime rate exceeding 250.54 per 100,000 (OR 1.07; 95% CI 1.03-1.12), diabetes exceeding 10.95% (OR 1.09: 95% CI 1.04-1.14), and drug poisoning deaths including opioids exceeding 14.17 per 100,000 (OR 1.04; 95% CI 1.01-1.08). When compared to an all-condition, hospitalized population, ocular hospitalizations tended to have small, yet statistically significant associations with health behaviors, socioeconomic, and physical environment factors. Further research will be needed on how the physical environment, social, and community variables affect ocular health relative to all-cause hospitalizations.


Continuous Positive Airway Pressure Use for Obstructive Sleep Apnea in Pediatric Patients.
Pediatric obstructive sleep apnea is becoming more common and better diagnosed and treated. It is seen in children with obesity, genetic disorders, neuromuscular disorders, and congenital malformations. After adenotonsillectomy, continuous positive airway pressure (CPAP) is a major mode of treatment. CPAP is traditionally initiated by titrating in the laboratory. However, auto-CPAP titration in the home environment is becoming more accepted as an option. When children are adherent to CPAP, there are significant benefits to treatment, both short-term and long-term. The short-term benefits include improved behavior, focus, attention, and improved sleep. The long-term benefits include improved cardiovascular and metabolic comorbidities.


Conservation of ammonia during food waste composting.
An experiment was conducted to quantify ammonia (NH3) losses during food waste composting and to evaluate the effectiveness of mature aerobic sewage sludge/olive pomace compost and phillipsite/chabazite zeolite in reducing NH3 losses during composting. Food waste amended with chopped barley straw was composted for a period of 68 days in three in-vessel reactors. The mature aerobic sewage sludge/olive pomace compost and the zeolite were placed on a mesh tray above the waste mixture in the first and second reactors, respectively. The third reactor contained straw-amended food waste only and served as a control. It was found that the mature aerobic sewage sludge/olive pomace compost reduced NH3-N losses by 36% of initial TN through nitrifying volatilized NH3 into nitrate (NO3-). Zeolite reduced NH3-N losses by 41% of initial total nitrogen due to adsorption of volatilized NH3. The use of mature compost in conservation of nitrogen is a promising cheap method; however, it needs further optimization and research.


Renal FNA-based typing of renal masses remains a useful adjunctive modality: evaluation of 31 renal masses with correlative histology.
Given the advances in renal imaging modalities in the recent years, a greater number of renal cell carcinomas (RCCs) with tumour size of <3 cm are being detected radiologically. Consequently, there is a pressing need for accurate typing of RCCs which, in turn, will aid in selection of cases of nephron-sparing surgery. A total of 31 cases of renal masses with available fine needle aspiration (FNA) material and concomitant histopathology details were retrieved. They included 27 RCCs (17 clear cells, eight papillary and two chromophobe), one oncocytoma, one liposarcoma and two benign lesions - one xanthogranulomatous pyelonephritis (XPN) and one benign cyst. Two investigators reviewed all FNA material. The degree of concordance between cytological typing and histological typing was assessed. There was excellent agreement between the FNA typing and the final diagnosis, with correct classification in 28 of 31 cases. Among the three discordant cases, two were RCCs. The first was a papillary RCC (PRCC) that was misdiagnosed on FNA as clear cell RCC. Another case that was typed as a PRCC on final histopathology was diagnosed 'suspicious cells' on FNA. The third case was an XPN that was misdiagnosed on FNA as RCC with necrosis. There is an excellent concordance (90.3%) between the FNA diagnosis and the final histological diagnosis, especially in RCCs. There is a tendency for misdiagnosis with PRCC. Lesions with extensive necrosis and relatively insufficient diagnostic material on FNA specimens must be interpreted with caution. Better concordance might be observed with more extensive sampling.


Primary pulmonary high grade non-Hodgkin's lymphoma in an elderly patient. A case report.
An 82-year-old non-smoker female was admitted with cough, fever and poor general health. Radiological examination revealed a right parahilar mass and a transbronchial biopsy confirmed the presence of a tumor. Immunohistochemical analysis established the diagnosis of high-grade primary pulmonary lymphoma. The rare nature of this disease, its non-specific clinical presentation and particular prognosis, also in elderly patients, are discussed in this article.


Efficacy of supplemental peripheral nerve blockade for hip fracture surgery: multiple treatment comparison.
This study was designed to determine the most effective peripheral nerve block supplement to standard anesthesia management for hip fracture patients. We systematically reviewed randomized controlled trials (RCTs) published from 1990 to 2010 and conducted multiple treatment comparisons using direct and indirect evidence for two outcomes, i.e., acute pain intensity and delirium. We combined trials by type of injection (regardless of time of insertion during the perioperative phase, use of nerve block catheter, local anesthetic type, additives, or duration of treatment). Twenty-one RCTs comprising 1,422 participants were included. In most cases, the trials were conducted in Europe; they excluded patients with cognitive impairment, and they were unclear or at high risk of bias. The combination of obturator and lateral femoral cutaneous nerve blockade had the highest probability of being the most effective against acute postoperative pain. Fascia iliaca blockade had the highest probability of being the most effective against delirium. There was no difference in outcomes among other nerve blocks. Not all nerve blocks are equally effective in improving outcomes after hip fracture. Multiple treatment comparison, a tool to compare the effectiveness of multiple treatments simultaneously, provides useful guidance to anesthesia providers seeking effective treatment when faced with a body of RCTs wherein each investigates one treatment. More RCTs comparing multiple nerve blocks in hip fracture are needed.


Improving the quality of survival for infants of birthweight < 1000 g born in non-level-III centres in Victoria. The Victorian Infant Collaborative Study Group.
To compare between eras the early care of extremely low birthweight (birthweight < 1000 g) infants born in non-level-III centres, that is, centres without a neonatal intensive care nursery, in Victoria, to identify changes associated with the improved quality of survival over time. The early care and outcome for infants of birthweight 500 to 999 g born in a non-level-III centre in Victoria were compared between two distinct eras, 1979-1980 and 1985-1987. PATIENTS AND OUTCOMES: Mortality data to two years of age were available for all infants liveborn in non-level-III centres in the two eras (1979-1980, n = 106; 1985-1987, n = 129). In 1979-1980, 47 of 52 infants transferred to a level-III centre were transported by the Newborn Emergency Transport Service (NETS); in 1985-1987, all 49 infants transferred were transported by NETS. Data concerning the immediate care after birth and during transport to a level-III centre were available for all infants transferred by NETS. All survivors were assessed for sensorineural impairments and disabilities at two years of age, corrected for prematurity. In both eras, 18 children born outside and transferred to a level-III centre survived to two years of age. Survivors in both eras had almost identical mean birthweights and gestational ages. There were trends for more survivors to be referred by paediatricians--1979-1980, 61%; 1985-1987, 83%; odds ratio (OR), 2.94; 95% confidence interval (CI), 0.7-12.4--and for quicker referral times to NETS in 1985-1987 (1979-1980, median 34.5 minutes after birth; 1985-1987, median 21.5 minutes after birth; z = 1.91, P = 0.056). It was possible only during 1985-1987 to monitor transcutaneous PO2 during transport. Durations of transport were similar in both eras. However, only in 1985-1987 was it possible in survivors to reduce significantly the inspired oxygen concentration during transport (median reductions in inspired oxygen, 1979-1980 3.5%; 1985-1987 20%; P = 0.028). Neurological impairment rates were substantially lower in survivors transported in the latter era (1979-1980 72% impaired; 1985-1987 22% impaired; OR 0.14, 95% CI 0.04-0.52). Of the neurological impairments, fewer had severe developmental delay alone (1979-1980 22%; 1985-1987 0%; OR 0.09, 95% CI 0.018-0.46), and the rate of blindness was lower, but the latter difference was not quite statistically significant (1979-1980 28%; 1985-1987 6%; OR 0.21, 95% CI 0.037-1.19). Over all, neurological disabilities were significantly reduced in the latter era (z = 2.93, P < 0.005). More active management of extremely low birthweight infants before transfer to a level-III centre, including prompt referral and transcutaneous PO2 monitoring during transport, may be important in improving the sensorineural outcome of survivors.


ADRA1A-Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP.
Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis1. Aside from cAMP signalling downstream of β-adrenergic receptor activation, how NA promotes thermogenic output is still not fully understood. Here, we show that coordinated α1-adrenergic receptor (AR) and β3-AR signalling induces the expression of thermogenic genes of the futile creatine cycle2,3, and that early B cell factors, oestrogen-related receptors and PGC1α are required for this response in vivo. NA triggers physical and functional coupling between the α1-AR subtype (ADRA1A) and Gαq to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase B and tissue-non-specific alkaline phosphatase. Combined Gαq and Gαs signalling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and creatine kinase B is required for this effect. Thus, the ADRA1A-Gαq-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.


Development of a high-throughput β-Gal-based neutralization assay for quantitation of herpes simplex virus-neutralizing antibodies in human samples.
Measurement of neutralizing antibodies against herpes simplex virus (HSV) is important for evaluation of candidate vaccines. The established plaque-reduction neutralization assay is time consuming, labor intensive, and difficult to validate and transfer. Here, we describe the characterization of a HSV-neutralization assay based on the expression of a reporter gene, β-galactosidase (β-Gal). Using previously constructed HSV-β-Gal recombinant viruses, HSV-2/Gal and HSV-1/tk12, we developed a colorimetric β-Gal-based neutralization assay that is sensitive and highly reproducible, and performed in less than 48h. HSV-1 and HSV-2 neutralizing titers measured by the β-Gal-based neutralization assay were equivalent to those obtained by a plaque reduction neutralization assay. Intra- and inter-assay precision studies demonstrated that the β-Gal-based assay was repeatable and yielded low and acceptable variation. In addition, comparison of HSV-2 neutralizing antibody (NAb) titers measured in two independent laboratories by two unique β-Gal-based assays showed a highly significant correlation (r=0.9499, p<0.0001) between the two assays. The new assay will serve as an important tool both for preclinical and clinical trials of new HSV vaccines.


Mother lowers glucocorticoid levels of preweaning rats after acute threat.
Exposure to a deadly threat, an adult male rat, induced the release of corticosterone in 14-day-old rat pups. The endocrine stress response was decreased when the pups were reunited with their mother immediately after exposure. These findings demonstrate that social variables can reduce the consequences of an aversive experience.


Myometrial contractility influences oxytocin receptor (OXTR) expression in term trophoblast cells obtained from the maternal surface of the human placenta.
Oxytocin (OXT) acts through its specific receptor (OXTR) and increased density of OXTR and/or augmented sensitivity to OXT were postulated as prerequisites of normal onset of labor. Expression of OXTR in the placental term trophoblast cells has not yet been analyzed in the context of contractile activity of the uterus. Here we examine comparatively OXT contents in the placental tissue adjacent to the uterine wall and expressions of OXTR in this tissue and corresponding isolated placental trophoblast cells. Twenty eight placentae after normal labors at term (group I, N = 14) and after cesarean sections performed without uterine contractile activity (group II, N = 14) have been collected. Tissue excised from the maternal surface of examined placenta was used for OXT concentration measurement, cytotrophoblast cell cultures preparation and immunohistochemistry of OXTR. Concentration of OXT was estimated in the tissue homogenates by an enzyme immunoassay with colorimetric detection. Cytotrophoblast cells were isolated using Kliman's method based on trypsin, DNase, and a 5-70% Percoll gradient centrifugation. The cultures were incubated for 5 days in normoxia. Both placental specimens and terminated cytotrophoblast cultures were fixed and embedded in paraffin before being immunostained for OXTR. Using light microscopy with computed morphometry for quantitative analysis, OXTR expressions were estimated in calibrated areas of the paraffin sections. There were not significant differences between the groups in respect to the mean OXT concentration. However, in both groups the median value of OXT concentration was significantly (p < 0.05) higher in the tissue obtained from the peripheral regions of the maternal surface of the placenta, compared to the samples from the central region of this surface. In placental tissue the mean expression of OXTR in group I was significantly (p < 0.05) increased by approximately 3.2-fold and 3.45-fold (the samples collected from central and peripheral regions, respectively) compared to the values obtained in group II. In the isolated primary trophoblast cultures the differences were even more evident (p < 0.02) and the mean change in OXTR expression in group I comprised approximately 6.9-fold increase and 6.5-fold increase (the samples collected from central and peripheral regions, respectively) compared to the values obtained in group II. Upregulation of OXTR within placental trophoblast cells localized close or adherent to uterine wall may play a crucial role in labor with efficient contractile activity (vaginal delivery). Further studies may disclose if this local OXT/OXTR signaling is utilized in the third stage of labor to elicit placental detachment or contribute in a more versatile way throughout the labor period.


Human polyomavirus JCV late leader peptide region contains important regulatory elements.
Transcription is a complex process that relies on the cooperative interaction between sequence-specific factors and the basal transcription machinery. The strength of a promoter depends on upstream or downstream cis-acting DNA elements, which bind transcription factors. In this study, we investigated whether DNA elements located downstream of the JCV late promoter, encompassing the late leader peptide region, which encodes agnoprotein, play regulatory roles in the JCV lytic cycle. For this purpose, the entire coding region of the leader peptide was deleted and the functional consequences of this deletion were analyzed. We found that viral gene expression and replication were drastically reduced. Gene expression also decreased from a leader peptide point mutant but to a lesser extent. This suggested that the leader peptide region of JCV might contain critical cis-acting DNA elements to which transcription factors bind and regulate viral gene expression and replication. We analyzed the entire coding region of the late leader peptide by a footprinting assay and identified three major regions (region I, II and III) that were protected by nuclear proteins. Further investigation of the first two protected regions by band shift assays revealed a new band that appeared in new infection cycles, suggesting that viral infection induces new factors that interact with the late leader peptide region of JCV. Analysis of the effect of the leader peptide region on the promoter activity of JCV by transfection assays demonstrated that this region has a positive and negative effect on the large T antigen (LT-Ag)-mediated activation of the viral early and late promoters, respectively. Furthermore, a partial deletion analysis of the leader peptide region encompassing the protected regions I and II demonstrated a significant down-regulation of viral gene expression and replication. More importantly, these results were similar to that obtained from a complete deletion of the late leader peptide region, indicating the critical importance of these two protected regions in JCV regulation. Altogether, these findings suggest that the late leader peptide region contains important regulatory elements to which transcription factors bind and contribute to the JCV gene regulation and replication.


Circulating immune complex concentrations in selected cases of skin disease in dogs.
Serum samples from 25 clinically normal dogs and 137 base-line serum samples from dogs with skin disease were assayed blindly for presence of circulating immune complexes (CIC). The method used was a solid-phase C1q-binding enzyme-linked immunosorbent assay. This assay detected only IgG-containing CIC that were capable of binding C1q. Statistical analysis revealed that dogs with systemic lupus erythematosus, discoid lupus erythematosus, generalized demodicosis, and recurrent staphylococcal pyoderma had significantly higher mean CIC concentrations than did normal dogs. Dogs with other skin diseases had mean CIC concentrations indistinguishable from those of normal dogs. Presence of CIC in dogs with these dermatopathies may have pathogenetic significance or may be the result of the disease process. Further studies are necessary to define the antigens contained in the immune complexes and the importance of CIC in skin disease of dogs.


Distribution of substance P-responsive and nociceptive neurones in relation to substance P-immunoreactivity within the caudal trigeminal nucleus of the rat.
Substance P is a peptide which is found in small diameter primary afferent fibres and may have a function in nociceptive afferent transmission. In order to study the role of substance P in sensory processes in depth, we have compared the distributions of nociceptive neurones and substance P-responsive neurones with the distribution of substance P in the caudal trigeminal nucleus of the rat. It was found that substance P-like immunoreactivity was located primarily in the superficial layers of nucleus caudalis (equivalent to laminae I and II of the dorsal horn) and in more ventromedially located areas (equivalent to laminae V and VI). The distribution was found to be in good agreement with the distribution of nociceptive neurones. Iontophoretically applied substance P had predominantly excitatory actions on both nociceptive and non-nociceptive nucleus caudalis neurones, although the peptide did appear to be slightly more likely to excite nociceptive neurones. Similarly, the peptide appeared slightly more likely to be excitatory in areas of nucleus caudalis showing substance P staining, but excitations were also predominantly seen in areas containing little or no apparent substance P staining. These results are consistent with the proposed role for substance P as a nociceptive afferent neurotransmitter. However, it is also possible that the peptide performs other functions in the processing of sensory information.


Fear the serpent: A psychometric study of snake phobia.
Millions of people worldwide suffer from specific phobias. Almost any stimulus may trigger a phobic reaction, but snakes are among the most feared objects. Half of the population feel anxious about snakes and 2-3% meet the diagnostic criteria for snake phobia. Despite such a high ratio, only one instrument is commonly used, the Snake Questionnaire (SNAQ). The aim of this study was to develop a standardized Czech translation, describe its psychometric properties and analyze the distribution of snake fears. In a counter-balanced design 755 respondents were asked to complete the English and Czech SNAQ (first or last) with a 2-3 month delay; 300 of them completed both instruments. We found excellent test-retest reliability (0.94), although the total scores differed significantly when the English version was administered first. The mean score was 5.80 and Generalized Linear Models revealed significant effects of sex and field of study (women and people with no biology education scored higher than men and biologists). A cut-off point for snake phobia as derived from a previous study identified 2.6% of the subjects as phobic. Finally, the score distribution was similar to other countries supporting the view that fear of snakes is universal.


Oridonin attenuates the progression of atherosclerosis by inhibiting NLRP3 and activating Nrf2 in apolipoprotein E-deficient mice.
Oridonin, a well-known traditional Chinese herbal medicinal product isolated from Isodon rubescens (Hemsl.) H.Hara, has many potential properties, including anti-inflammatory and antioxidant activities. However, there is no evidence whether oridonin have a protective effect on atherosclerosis. This study focused on the effects of oridonin on oxidative stress and inflammation generated from atherosclerosis. The therapeutic effect on atherosclerosis was evaluated by intraperitoneal injection of oridonin in a high-fat fed ApoE-/- mouse model. We isolated mouse peritoneal macrophages and detected the effect of oridonin on oxidized low-density lipoprotein-induced lipid deposition. Oil red O staining, Masson's staining, dihydroethidium fluorescence staining, immunohistochemical staining, western blotting analysis, immunofluorescence, enzyme-linked immunosorbent assay and quantitative real-time PCR were used to evaluate the effect on atherosclerosis and explore the mechanisms. Oridonin treatment significantly alleviated the progression of atherosclerosis, reduced macrophage infiltration and stabilized plaques. Oridonin could significantly inhibit inflammation associated with NLRP3 activation. Oridonin significantly reduced oxidative stress by blocking Nrf2 ubiquitination and degradation. We also found that oridonin could prevent the formation of foam cells by increasing lipid efflux protein and reducing lipid uptake protein in macrophages. Oridonin has a protective effect on atherosclerosis in ApoE-/- mice, which may be related to the inhibition of NLRP3 and the stabilization of Nrf2. Therefore, oridonin may be a potential therapeutic agent for atherosclerosis.


Novel technique for peripheral nerve reconstruction in the absence of an artificial conduit.
The purpose of this study is to promote nerve regeneration across a peripheral nerve gap, using a biologic, tissue-engineered nerve (TEN), containing a high density of viable Schwann cells (SCs) in the absence of supportive foreign materials and a tubular system. Isolated SCs from adult rat sciatic nerve were seeded onto biodegradable constructs and implanted into the backs of nude mice to create TENs. Six weeks later, the constructs were harvested, implanted into surgically created sciatic nerve gaps in rats without supportive artificial conduits and compared with both an autograft group and a silicone conduit group using SCs. Two months later, functional assessment was evaluated by walking track analysis and the implanted lesions were imaged by transmission electron microscopy. The axonal number and sciatic function index of the TEN were significantly higher than those of the silicone group and achieved a comparable level to the autograft group. The results indicate that the large number of SCs within their own extracellular matrix appeared sufficient to enable neuronal growth across a nerve gap in the absence of an artificial conduit and that these circumstances may have a positive effect on the supplement of growth factors from the surrounding tissues of implanted TEN.


Mesothelial Stem Cells and Stromal Vascular Fraction: Use in Functional Disorders, Wound Healing, Fat Transfer, and Other Conditions.
Autologous human fat-derived mesenchymal stem cells are present in stromal vascular fraction. Stromal vascular fraction can be easily and safely extracted from lipoaspirate. The regenerative, antiinflammatory and immunomodulatory effects of stromal vascular fraction are being documented in ongoing therapeutic response studies.


Tracheostomy decannulation rates in Japan: a retrospective cohort study using a claims database.
Despite the exponential increase in the use of tracheostomy worldwide, rates of tracheostomy decannulation are unknown. We conducted a retrospective cohort study to investigate tracheostomy decannulation rates among adult patients over a two-year period and explored factors associated with prolonged tracheostomy. A health insurance claims database including 3,758,210 people in Japan was used. The primary outcome was time to decannulation. Assessed patient and hospital factors included age, sex, emergency endotracheal intubation, disease, and hospital size. A total of 917 patients underwent tracheostomy, and 752 met the eligibility criteria. Decannulation rates were 40.8% (95% confidence interval 36.8-44.9) at 3 months, 63.9% (58.4-69.0) at 12 months, and 65.0% (59.2-70.3) at 24 months. Hazard ratios of patient and hospital factors for tracheostomy decannulation were 0.44 for age (65-74 years) (95% confidence interval 0.28-0.68), 0.81 (0.63-1.05) for female sex, and 0.59 (0.45-0.76) for emergency endotracheal intubation. Cerebrovascular disease, head injuries, and cardiac arrest had lower hazard ratios compared to other diseases. Decannulation rates among adult patients in Japan increased rapidly up to 3 months after tracheostomy, reaching a plateau after 12 months. Older age, female sex, emergency endotracheal intubation, cerebrovascular disease, head injuries, and cardiac arrest were associated with prolonged tracheostomy.


The intestinal barrier in disorders of the central nervous system.
The intestinal barrier, which primarily consists of a mucus layer, an epithelial barrier, and a gut vascular barrier, has a crucial role in health and disease by facilitating nutrient absorption and preventing the entry of pathogens. The intestinal barrier is in close contact with gut microbiota on its luminal side and with enteric neurons and glial cells on its tissue side. Mounting evidence now suggests that the intestinal barrier is compromised not only in digestive disorders, but also in disorders of the central nervous system (CNS), such as Parkinson's disease, autism spectrum disorder, depression, multiple sclerosis, and Alzheimer's disease. After providing an overview of the structure and functions of the intestinal barrier, we review existing preclinical and clinical studies supporting the notion that intestinal barrier dysfunction is present in neurological, neurodevelopmental, and psychiatric disorders. On the basis of this evidence, we discuss the mechanisms that possibly link gut barrier dysfunction and CNS disorders and the potential impact that evaluating enteric barriers in brain disorders could have on clinical practice, in terms of novel diagnostic and therapeutic strategies, in the near future.


A ratiometric fluorescence platform for lead ion detection via RNA cleavage-inhibited self-assembly of three-arm branched junction.
Heavy metal pollution can pose a threat to food safety and human health, and accurate quantification of heavy metal ions is a vital requirement. Emerging DNA nanostructures-based biosensors offer attractive tools toward ultra-sensitive or rapid analysis of heavy metal ions. However, the problems including complex design, severe reaction conditions and undesirable reliability are inevitable obstacle in advancing their extension and application. Herein, a ratiometric fluorescent platform was established for monitoring lead ion (Pb2+) in food based on dual Förster resonance energy transfer (FRET) and RNA cleavage-inhibited self-assembly of three-arm branched junction (TBJ). GR-5 DNAzyme was employed for Pb2+ recognition, and enzyme-free amplification technique catalytic hairpin assembly (CHA) served to form FRET probes-carried TBJ. The substrate strand (S) of DNAzyme triggered the generation of CHA-TBJ, and Pb2+-responsive cleavage of S hindered the assembly of CHA-TBJ, causing opposite changes in the FRET states of FAM/BHQ1 and ROX/BHQ2 pairs. The fluorescence responses were recorded through synchronous fluorescence spectrometry to indicate Pb2+ concentration, allowing sensitive and reliable identification of Pb2+ in the linear range of 0.05-5 ng mL-1 with the detection limit of 0.03 ng mL-1. The Pb2+ detection can be achieved under conventional reaction conditions, simple mixing procedures and one-step measurement operation. The approach can afford excellent specificity for Pb2+ against competing metal ions, and can be applied to analyze Pb2+ in tea samples with satisfactory results. This facile fluorescence platform shows a capable method for Pb2+ detection, and provides new avenue in the development of ratiometric approaches and DNAzyme strategies for monitoring heavy metal pollution, facilitating the transformation of DNAzyme-based biosensors for food safety control.


Morfo-functional nutritional status in patients with gastroenteropancreatic neuroendocrine tumors (GEPNET).
Patients with gastroenteropancreatic neuroendocrine tumors (GEPNET) can suffer from malnutrition. This is the first descriptive study of morfo-functional evaluation in GEPNET. To describe a morfo-functional evaluation, and to compare with reference population available, and to correlate different nutritional parameters. Moreover, to compare nutritional evaluation in our study with another same location non-neuroendocrine tumors. A retrospective observational study, 50 patients with GEPNET, medium age 61 years. It was collected clinico-pathological characteristics and nutritional status was assessed by anthropometric, laboratory test, bioelectrical impedance analysis, phase angle, hand grip strength, and rectus femoris ultrasound for the assessment of muscle mass. We used SPSS statistics to describe and to analyze correlations of different variables. Most frequent location of tumor was pancreas and small bowel, tumor grade 1 and advance stage. In morfo-functional evaluation highlighted: a low fat mass percentage (23,5 vs 34,4%), low muscle mass percentage (36,5 vs 41,2%) and low body mass cell percentage (40,4 vs 48,8%) compared with reference population available by sex and age. Standarized phase angle by sex and age result as positive (+0,851). There was no difference in hand grip strength compared with reference population. After a review of differents studies available, phase angle and hand grip strength of non neuroendocrine tumors in same location, could suggest a minor affection of nutritional state in our GEPNET sample. A positive correlation was observed between non classic methods of nutritional evaluation such as bioelectrical impedance analysis, hand grip strength and rectus femoris ultrasound. Patients with gastroenteropancreatic neuroendocrine tumors (GEPNET) show a moderate affection of nutritional status in comparison to general population. Morphofunctional assessment provide us a precise knowledge about nutritional status.


Water scarcity in agriculture: An overview of causes, impacts and approaches for reducing the risks.
Freshwater is a vital resource for both ecosystem health and human survival, and it is the natural resource that is the most extracted at the global level. Excessive freshwater consumption can be responsible for a scarcity in the circulation rate, which occurs when the freshwater demand exceeds its availability. Hence, water consumption needs to be optimised in all human activities, given the increasing freshwater scarcity due to climate changes and to the annual net increase in the human population of 81,000,000. Freshwater plays many important roles in daily life for example, agriculture is responsible for nearly 70% of that withdrawal volume, and it is therefore, the most water-intensive sector. This puts emphasis upon the urgent need of transitioning towards more sustainable agricultural and food-production/consumption systems. Water Footprint (WF) is increasingly playing a guiding role in that context. Indeed, it makes it possible to quantify water consumption and related environmental consequences. With the objective of contributing to enhancement of research and of supporting practitioners and decision-makers in environmentally sustainable and resilient food production/consumption, the authors of this article addressed the relevant issues connected with: a) physical and economic water scarcity in agriculture, b) practices and tools to reduce water wastage, c) WF assessment methodologies. A number of environmental, economic, and engineering solutions were proposed to mitigate water scarcity. The improvement of irrigation technologies and practices was identified as an important major way to reduce water scarcity. Additionally, solar powered 'reverse-osmosis' is being used in many parts of the world to produce irrigation water from saline water, thereby reducing the need to extract freshwater from underground aquifers. This article confirmed the importance of research on water scarcity; moreover, it can stimulate development and application of solutions that make agricultural production/consumption more efficient and resilient.


Specific management of lipodermatosclerosis (sclerotic hypodermitis) in acute and chronic phase.
Lipodermatosclerosis or sclerotic hypodermitis is presented as a complication of venous insufficiency and in particular of post-thrombotic syndrome with a high risk of progression to leg ulcers. However, it has also been described in obese patients without venous insufficiency, and even in the course of various systemic diseases including scleroderma. It most often affects middle-aged women and is usually bilateral, with a typically "inverted champagne bottle" leg appearance. The pathogenic role of venous hypertension explains why compression with bands or stockings is the basis of treatment. In acute phase, which may precede or complicate chronic forms, the pain is so severe that compression is not tolerated. In acute phase, non-steroidal anti-inflammatory drugs, intra-lesional use of triamcinolone, and capsaicin transdermal patches indicated for neuropathic pain have been proposed. In chronic forms, the treatment of superficial venous insufficiency and/or incontinent perforating veins, documented during a Duplex ultrasound scan, is usually proposed, whenever possible. In association with elastic compression, pentoxifylline and colchicine have been used without clear evidence of clinical efficacy. Finally, in the most advanced clinical presentation with the appearance of a sclerotic gaiter associated with ulcerations, surgical treatment with excision-cutaneous grafting associated or not with perforating veins ligation and a fasciotomy may be discussed as a last resort for treatment.


A common origin of the very low frequency heart rate and blood pressure variability--a new insight into an old debate.
The purpose of this study was to assess the exact temporal and amplitude relationship between very low frequency heart rate variability waves and very low frequency blood pressure variability waves. We developed a computerized system based on a modified proportional-integral controller for the controlled increase of heart rate by isoproterenol. Heart rate and blood pressure were measured continuously in conscious tethered rats. Using time domain methods, we found that the very low frequency heart rate variability waves and the very low frequency blood pressure variability waves are irregular, while at the same time strikingly 1:1 synchronized with each other. In 78% of the cases, the phase between the peaks of the very low frequency heart rate variability waves and very low frequency blood pressure variability waves was negative (blood pressure leads). Their amplitudes were linearly related with a degree of hysteresis. As blood pressure went up, heart rate went down. Our results suggest with a high degree of probability that the very low frequency heart rate variability waves do not cause very low frequency blood pressure variability waves, and that these two signals are probably driven by the same autonomic nervous system controller/oscillator.


Pregnancy-associated plasma protein A: a possible marker in the classification and prenatal diagnosis of Cornelia de Lange syndrome.
The concentration of human platelet lactogen (hPL), pregnancy specific beta-1 glycoprotein (SP-1) and pregnancy-associated plasma protein A (PAPP-A) were analysed in consecutive serum samples from a patient who gave birth to a child with Cornelia de Lange syndrome. HPL and SP-1 were present in normal concentrations from week 20 to week 35 of gestation whereas PAPP-A could not be detected in any of the samples examined. Immunohistochemical examination of two placentae from Cornelia de Lange syndrome revealed normal localization of hPL and SP-1 but the absence of PAPP-A from the syncytiotrophoblast. The significance of association between Cornelia de Lange syndrome and compromised synthesis of PAPP-A is discussed.


Transfusion-free reduced-intensity conditioned allogeneic stem cell transplantation in a Jehovah's witness.
With an estimated 6000000 Jehovah's witnesses worldwide, haematologists may encounter patients who decline blood transfusions as a matter of personal belief. Here, we describe the first case of a transfusion-free allogeneic stem cell transplant (SCT) in a Jehovah's witness with CML. The patient underwent HLA-identical peripheral blood SCT after reduced-intensity conditioning with total body irradiation and fludarabine. Conditioning and the period after transplantation were uneventful, complete donor chimerism was achieved and the patient continues to be in molecular remission without significant chronic graft-versus-host disease. When treating Jehovah's witnesses with diseases that may be cured by allogeneic SCT, this approach should be kept in mind.


Intracellular ATP delivery to in vitro expanded mouse CD27- γδ T cells.
Intracellular ATP supports the function of γδT17 cells in mice. Here, we present a protocol for intracellular ATP delivery to in vitro expanded mouse CD27- γδ T cells. We describe steps for pre-coating well plates, preparing lymphocytes, culturing CD27- γδ T cells, and ATP delivery. We then detail functional evaluation of γδ T cells by flow cytometry. Appropriate concentrations of control and ATP vesicles are detailed for intracellular ATP delivery, which can also be applied to other immune cells. For complete details on the use and execution of this protocol, please refer to Wang et al. (2023).1.


Thresholds of tone burst auditory brainstem responses for infants and young children with normal hearing in Taiwan.
With respect to follow-up from newborn hearing screening, click evoked auditory brainstem response provides relatively accurate estimates of auditory thresholds at a broad frequency range between 1,000 Hz and 4,000 Hz. Further on the frequency-specific hearing evaluation, recent studies conclude that tone burst auditory brainstem response estimates the behavioral thresholds reasonably well. This study reports the preliminary data of tone burst auditory brainstem response measurements of infants and young children with normal hearing in Taiwan. Ninety-four infants and young children aged from 3 months to 3 years of age were recruited as they were eventually determined to have normal hearing after a series of tests. They underwent tone burst auditory brainstem response measurements at four selected frequencies. Statistical methods were applied to study the relationship among recorded variables. The results indicated that the averaged tone burst auditory brainstem response thresholds of infants and young children with normal hearing in Taiwan are typically 10-20 dB nHL at 500, 1,000, 2,000, and 4,000 Hz, which is similar to the reported tone burst auditory brainstem response thresholds in adults with normal hearing. There was no statistically significant difference for the thresholds with regard to gender, laterality, and age distribution in this study. Based on the published research and our study, we suggest setting the normal criterion levels for infants and young children in Taiwan of the tone burst auditory brainstem response to air-conducted tones as 30 dB nHL for 500 and 1,000 Hz, and 25 dB nHL for 2,000 and 4,000 Hz.


Efficacy of Nyoshinsan/TJ-67, a traditional herbal medicine, for menopausal symtoms following surgery and adjuvant chemotherapy for premenopausal breast cancer.
We report a 39-year-old woman with premenopausal breast cancer who developed estrogen-deficiency symptoms associated with chemotherapy-related amenorrhea, and was successfully treated with Nyoshinsan/TJ-67, a Japanese traditional herbal medicine (Kampo). Six other breast cancer survivors with menopausal symptoms were also treated with Nyoshinsan/TJ-67, and five of the six patients showed noticeable improvement without adverse effects. Managing estrogen-deficiency symptoms in breast cancer survivors is still problematic, and Nyoshinsan/TJ-67 may be a useful and safe agent for such symptoms in these patients.


Economics, focus on pre-dialysis may help stabilize peritoneal dialysis in Canada.
PD use has stabilized somewhat in Canada after five years of relative decline. Fiscal constraints on health care funding in general and fiscal incentives in some provinces to do PD may be contributing to this, and may lead to PD growth in the years ahead. Other factors that may help PD to grow are the proliferation of predialysis clinics with an associated emphasis on the patient's right to make an elective modality choice, new innovations in treatment, ongoing evidence of improving outcomes, and perhaps, more simplicity in prescribing the modality in the post-ADEMEX era.


Voxel-based relaxometry: a new approach for analysis of T2 relaxometry changes in epilepsy.
The measurement of the T2 relaxation time (T2 relaxometry) had been established as a reliable tool for the assessment of certain conditions such as temporal lobe epilepsy. The standard procedure for analysis of T2 data uses manually drawn regions of interest (ROIs). This approach is limited by its subjective nature and its restricted scope of investigation within selected regions of the brain. In this study, we introduce a voxel-based analysis approach termed voxel-based relaxometry (VBR). Tissue signal changes were assessed in 19 patients with hippocampal sclerosis (HS) and in 38 healthy controls using (i) conventional ROI-based analysis with several bilateral ROIs and also (ii) the VBR method in which the T2 maps are warped to a stereotactic space, smoothed and statistically compared. Conventional ROI analysis identified the expected T2 increase in the sclerotic hippocampus in all HS patients. Furthermore, 13 of the 19 patients displayed a T2 increase in at least one of the other ROIs. The VBR analysis showed a similar pattern of statistically significant areas of increased T2 within the sclerotic hippocampus. In addition, extrahippocampal areas of increased T2 were apparent including the anterior temporal lobe white matter and the parahippocampal gyrus. The results of the VBR analysis are in agreement with the conventional ROI analysis. The VBR analysis has the advantage of providing an even-handed assessment of T2 differences through the brain. We recommend VBR as an alternative means of relaxometry data analysis that provides an objective assessment of differences between subjects.


Novel hydrophilic cyclic monomers in hydrogel synthesis.
A range of hydrogels was prepared by the copolymerisation of 2-hydroxyethyl methacrylate (HEMA) with various hydrophilic cyclic monomers (CM) derived from cis-1,2-dihydroxy-3,5-cyclohexadiene (DHCD). The specific systems investigated were the cis-1,2-bis(2,3-epoxybutanoyloxy)-, cis-1,2-bis(10,11-epoxyundecanoyloxy)-, cis-1,2-bis(trimethylsiloxy)- and cis-1,2-bis(tert-butyldimethylsiloxy)-3,5-cyclohexadienes. The EWC, tensile strength and initial modulus of the poly HEMA-CM hydrogels derived from the epoxy compounds showed lower EWCs but similar mechanical properties compared with polyHEMA itself. Treatment of the hydrogel derived from cis-1,2-bis(2,3-epoxybutanoyloxy)-3,5-cyclohexadiene with 20% sodium hydroxide increased the EWC value markedly but produced highly fragile materials.


A Vagal-NTS Neural Pathway that Stimulates Feeding.
A fundamental question of physiology is how gut-brain signaling stimulates appetite. While many studies have emphasized the importance of vagal afferents to the brain in inducing satiation, little is known about whether and how the vagal-mediated gut-brain pathway senses orexigenic signals and stimulates feeding. Here, we identified a previously uncharacterized population of fasting-activated catecholaminergic neurons in the nucleus of the solitary tract (NTS). After characterizing the anatomical complexity among NTS catecholaminergic neurons, we surprisingly found that activation of NTS epinephrine (ENTS) neurons co-expressing neuropeptide Y (NPY) stimulated feeding, whereas activation of NTS norepinephrine (NENTS) neurons suppressed feeding. Monosynaptic tracing/activation experiments then showed that these NTS neurons receive direct vagal afferents from nodose neurons. Moreover, activation of the vagal→NPY/ENTS neural circuit stimulated feeding. Our study reveals an orexigenic role of the vagal→NTS pathway in controlling feeding, thereby providing important insights about how gut-brain signaling regulates feeding behavior.


A High-Performance Nonlinear Optical Crystal with a Building Block Containing Expanded π-Delocalization.
Common nonlinear optical (NLO) crystals consist of traditional functional building blocks with inherent optical limitation. Herein, inspired by traditional (B3 O6 )3- inorganic building block, we theoretically identified a new type of organic functional building blocks and then successfully synthesized the first cyamelurate NLO crystal, Ba(H2 C6 N7 O3 )2 ⋅ 8 H2 O. To our surprise, the constituent (H2 C6 N7 O3 )- building block is not in structurally optimal arrangement, but Ba(H2 C6 N7 O3 )2 ⋅ 8 H2 O exhibits excellent optical properties including wide band gap of 4.10 eV, very large birefringence of 0.24@550 nm, and exceptionally strong second-harmonic generation (SHG) response of about 12×KH2 PO4 . Both the SHG response and birefringence are much larger than those of commercial NLO crystal β-BaB2 O4 with optimally aligned (B3 O6 )3- building block. Theoretical calculations suggest that the expanded π-conjugation delocalization within (H2 C6 N7 O3 )- vs (B3 O6 )3- should be responsible to the enhanced performance. This work implies that there is still much room to develop new NLO crystals with excellent functional building blocks that may be longly neglected.


Expressed emotion in the relatives of people with epileptic or nonepileptic seizures.
This study investigated Expressed Emotion (EE) in relatives of people with epileptic or nonepileptic seizures (NES). In a cross-sectional study, we used the Five-Minute Speech Sample to explore EE in the key relative of people with epilepsy (n = 36) and those with NESs (n = 21), as well as levels of anxiety and depression and use of coping strategies. A significantly greater proportion of relatives of NES than epilepsy patients were rated as high EE. Hostility was evident in more high-EE epilepsy than high-EE NES relatives, whereas emotional overinvolvement and positive relationship ratings tended to be more common in high-EE NES relatives. High- and low-EE epilepsy relatives used problem-focused as opposed to emotion-focused coping strategies significantly more than half the time. High EE and seizure frequency were not associated. Age at onset of the disorder was higher in epilepsy patients with high- than with low-EE relatives. Irrespective of etiology, carers for people with seizure disorders may find it hard to adjust to the difficulties these disorders create. Interventions that encourage problem-solving, reappraisals of "loss" and education regarding the causes of some of the patients' behavioral and mood problems seem likely to be beneficial.


Pharmacodynamic and pharmacokinetic effects of S086, a novel angiotensin receptor neprilysin inhibitor.
Angiotensin receptor-NEP inhibitor (ARNi), which includes an angiotensin receptor blocker (ARB) and a neprilysin inhibitor (NEPi), has been proven safe and effective for treating heart failure with reduced ejection fraction (HF-REF). S086 is a novel single-molecule ARNi that includes the molecular moieties of EXP3174 (the active metabolite of the ARB losartan) and sacubitril (a NEP inhibitor prodrug) in a 1:1 M ratio. We performed preclinical animal model studies to evaluate the efficacy of S086 in treating HF. Rat and dog models of myocardial ischemia-induced chronic heart failure were used in this research. The oral administration of S086 dose-dependently lowered the heart weight index, attenuated cardiac fibrosis, and improved left ventricular ejection fraction, shortening fraction, and cardiac output, without effects on hemodynamics in animal models of myocardial ischemia-induced chronic heart failure. A comparable protective effect to LCZ696 was observed for S086 at an equal molar dose in dog models. In addition, S086 was superior to LCZ696 since it significantly reversed the decrease in left ventricular posterior wall end-systolic thickness. This animal study suggests that S086 is effective in treating myocardial ischemia-induced chronic heart failure.


Time- and concentration-dependent cytotoxicity of antibiotics used in endodontic therapy.
New drugs have to be assessed in endodontic therapy due to the presence of microorganisms resistant to therapeutic procedures. Thus, this study evaluated the time- and concentration-dependent cytotoxicity of different antibiotics used in endodontic therapy. Human gingival fibroblasts were treated and divided into the following experimental groups: Group I - control; Group II - ciprofloxacin hydrochloride; Group III - clyndamicin hydrochloride; and Group IV - metronidazole. Each drug was used at concentrations of 5, 50, 150, and 300 mg/L for 24, 48, 72, and 96 h. Cytotoxicity was evaluated by the MTT assay [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and spectrophotometric reading of ELISA plates. The results were analyzed by BioEstat 4.0 software using Kruskal-Wallis and Dunn's tests at a significance level of 5%. Cell viability was assessed for the different concentrations and times. All drugs presented dose-dependent cytotoxicity. Concentrations of 5 and 50 mg/L produced viable fibroblasts at all experimental times in all groups. Cell viability at 24 h was greater than in the other experimental times. Comparison between the same concentrations of antibiotics at different times showed that metronidazole presented the highest cell viability at 72 and 96 h compared to the other antibiotics, whereas clyndamicin hydrochloride showed higher cell viability at 72 h than ciprofloxacin hydrochloride.


Targeted RNA sequencing for upfront analysis of actionable driver alterations in non-small cell lung cancer.
Targeted RNA-based Next-Generation Sequencing (tRNA-seq) is increasingly being used in molecular diagnostics for gene fusion detection in non-small cell lung cancer (NSCLC). However, few data support its clinical application for the detection of single nucleotide variants (SNVs) and small insertions/deletions. In this study, we evaluated the performance of tRNA-seq using Archer FusionPlex for simultaneous detection of actionable gene fusions, splice variants, SNVs and indels in formalin-fixed, paraffin-embedded NSCLC tissue. A total of 126 NSCLC samples, including 20 validation samples and 106 diagnostic cases, were analyzed by targeted DNA-based Next-Generation Sequencing (tDNA-seq) followed by tRNA-seq. All 28 SNVs and indels in the validation set, and 34 out of 35 mutations in the diagnostic set were identified by tRNA-seq. The only mutation undetected by tRNA-seq, ERBB2 p.(Ser310Tyr), was not included in the current Archer panel design. tRNA-seq revealed one additional BRAF p.(Val600Glu) mutation not found by tDNA-seq. SNVs and indels were correctly called by the vendor supplied software, except for ERBB2 duplication p.(Tyr772_A775dup) which was only detected by an additional in-house developed bio-informatics pipeline. Variant allelic frequency (VAF) values were generally higher at the expression level compared to the genomic level (range 6-96% for tRNA-seq versus 6-61% for tDNA-seq) and low VAF mutations in DNA (6-8% VAF) were all confirmed by tRNA-seq. Finally, tRNA-seq additionally identified a driver fusion or splice variant in 10 diagnostic NSCLC samples including one MET exon 14 skipping variant not detected by tDNA-seq. Our results demonstrate that tRNA-seq can be implemented in a diagnostic setting as an efficient strategy for simultaneous detection of actionable gene fusions, splice variants, SNVs and indels in NSCLC provided that adequate RNA-seq analysis tools are available, especially for the detection of indels. This approach allows upfront identification of currently recommended targetable molecular alterations in NSCLC samples.


Synthesis of chemically cross-linked polyvinyl alcohol-co-poly (methacrylic acid) hydrogels by copolymerization; a potential graft-polymeric carrier for oral delivery of 5-fluorouracil.
The propose of the present work was to develop chemically cross-linked polyvinyl alcohol-co-poly(methacrylic acid) hydrogel (PVA-MAA hydrogel) for pH responsive delivery of 5-Fluorouracil (5-FU). PVA based hydrogels were prepared by free radical copolymerization. PVA has been cross-linked chemically with monomer (methacrylic acid) in aqueous medium, cross-linking agent was ethylene glycol di-methacrylate (EGDMA) and benzoyl peroxide was added as reaction initiator. 5-FU was loaded as model drug. FTIR, XRD, TGA and DSC were performed for characterization of copolymer. Surface morphology was studied by SEM. pH sensitive properties were evaluated by swelling dynamics and equilibrium swelling ratio at low and higher pH. FTIR, XRD, TGA and DSC studies confirmed the formation of new copolymer. Formulations with higher MAA contents showed maximum swelling at 7.4 pH. High drug loading and higher drug release has been observed at pH 7.4. The current study concludes that a stable copolymeric network of PVA was developed with MAA. The prepared hydrogels were highly pH responsive. This polymeric network could be a potential delivery system for colon targeting of 5-FU in colorectal cancers.


Acetylcholinesterase inhibition starting from extracts of Bauhinia variegata L., Bauhinia var. candida (Aiton) Buch.-Ham., and Bauhinia ungulata L.
A treatment to the Alzheimer's disease consists inhibition of the acetylcholinesterase, which is responsible for the acetylcholine control in the synapses. We have investigated the potential of inhibition of the acetylcholinesterase produced by hexane extracts of leaves, branches, and flowers from three Bauhinia specimens, which is based on the technique of thin layer chromatography and on identifying the organ of the plant that possesses larger concentration of inhibitors. Retention factor analysis shows values of 0.31aA, 0.31aA, and 0.46aB for flowers B. variegata, B. var. candida, and B. ungulata, respectively. The flower extract of B. ungulata is the most suitable for further studies on this inhibition.


High-resolution colonic motility recordings in vivo compared with ex vivo recordings after colectomy, in patients with slow transit constipation.
The pathogenesis of slow transit constipation (STC) remains poorly understood, with intrinsic and extrinsic abnormalities implicated. Here, we present high-resolution colonic manometry recordings from four STC patients recorded before total colectomy, and subsequently, ex vivo, after excision. In four female, treatment-resistant STC patients (median age 35.5 years), a fiber-optic manometry catheter (72 sensors spaced at 1 cm intervals) was placed with the aid of a colonoscope, to the mid-transverse colon. Colonic manometry was recorded 2 h before and after a meal. After the colectomy, ex vivo colonic manometry was recorded in an organ bath. Ex vivo recordings were also made from colons from 4 patients (2 male; median age 67.5 years) undergoing anterior resection for nonobstructive carcinoma ('control' tissue). A large increase in 'short single propagating contractions' was recorded in STC colon ex vivo compared to in vivo (ex vivo 61.3 ± 32.7 vs in vivo 2.5 ± 5/h). In STC patients, in vivo, the dominant frequency of contractile activity was 2-3 cycle per minute (cpm), whereas 1-cpm short-single propagating contractions dominated ex vivo. This same 1-cpm frequency was also dominant in control colons ex vivo. In comparison to control adults, the colon of STC patients demonstrates significantly less propagating motor activity. However, once the STC colon is excised from the body it demonstrates a regular and similar frequency of propagating activity to control tissue. This paper provides interesting insights into the control of colonic motor patterns.


[AcrySof® Toric (SN60T) intraocular lens implantation: refractive predictibility and aberrometric impact of decentration].
To evaluate refractive outcomes of toric intraocular lens (IOL) implantation with a detailed analysis of decentration and its effect on aberrometry. This retrospective study enrolled 19 eyes implanted with SN60T AcrySof(®) Toric (Alcon - USA) IOL's. Spherocylindric correction was studied in depth by the Alpins method, and retro-illumination images were used to analyze the alignment of the IOL with its intended axis. IOL decentration as well as its aberrometric impact were evaluated with a strict, novel protocol. Three months postoperatively, uncorrected distance visual acuity was greater or equal to 20/40 in 94.74% of cases, postoperative subjective cylinder was less or equal to 0.5 D in 68.42% of eyes, with a mean index of success of 0.24. Mean error of toric IOL alignment was 5.68° (0 to 14). Mean IOL decentration was 0.78 mm (0 to 1.78) with a mean coma and trefoil of 0.18 μ (0.06 to 0.33) and 0.19 μ (0.05 to 0.51), respectively. The larger the IOL decentration, the higher the optical aberrations were. Toric intraocular lens implantation is an effective, safe and predictable method of spherocylindrical correction during cataract surgery, with a refractive accuracy similar to that of LASIK in the treatment of astigmatism in young patients. IOL decentration produces optical aberrations including coma and trefoil, which interfere with visual performance.


An epidemiological evaluation of Mycobacterium bovis infections in wild game animals of the Spanish Mediterranean ecosystem.
Recreational hunting of indigenous wild artiodactyls has been one of the most lucrative and rapidly growing industries in Western Spain over the last five years. In the absence of careful ecological management, one consequence of the commercial exploitation of this natural resource has been the appearance of outbreaks of infectious disease; most notably bovine tuberculosis. From the outset of the study in 1997, we have observed a steady increase in prevalence of Mycobacterium bovis (M. bovis) in both species reaching 1.74 (+/-0.17) in deer in 2002 and 2.32 (+/-0.24) in wild boar. The latter species seems to be most severely affected with pulmonary lesions appearing more chronic than those observed in deer. In this study, we describe the epidemiology of M. bovis in European wild boar (Sus scrofa) and Iberian red deer (Cervus elaphus hispanicus) in Extremadura (W. Spain); a region where there are large areas of natural habitat for these species.


Three-dimensional fully coupled hydro-mechanical-chemical model for solute transport under mechanical and osmotic loading conditions.
Mechanical deformation and chemico-osmotic consolidation of clay liners can change its intrinsic transport properties in all direction and can alter fluid and solute transport processes in the entire model domain. These phenomena are described inadequately by lower-dimensional models. Based on the Biot's consolidation theory, fluid and solute mass conservation equations, a three-dimensional (3D) fully-coupled hydro-mechanical-chemical (HMC) model has been proposed in this study. The impacts of mechanical consolidation and chemico-osmotic consolidation on permeability, hydrodynamic dispersion, solute sorption, membrane efficiency, and chemical osmosis are considered in the model. The model is applied to evaluate performances of a single compacted clay liner (CCL) and a damaged geomembrane-compacted clay composite liner (GMB/CCL) to contain a generic landfill contaminant. Effect of model dimensionality on solute spread for CCL is found to be marginal, but for GMB/CCL the effect is significantly large. After 50-year simulation period, solute concentration at the half-length of the GMB/CCL liner is predicted to be 40% of the source concentration during 1D simulation, which is only 6% during the 3D simulation. The results revealed approximately 74% over-estimation of liner settlement in 1D simulation than that of the 3D for GMB/CL system. Solute spread accelerates (over-estimates) vertically than horizontally since overburden load and consequent mechanical loading-induced solute convection occurs in the same direction. However, in homogeneous and isotropic soils, horizontal spread retards the overall migration of contaminants, and it highlights the importance of 3D models to study solute transports under mechanical and chemico-osmotic loading conditions in semi-permeable clays, especially, for damaged geomembrane-clay liners. The results show the utility of geomembranes to reduce soil settlement, undulation, and restriction of solute migration. Furthermore, application of geomembrane can inhibit development of elevated negative excess pore water pressure at deeper portion of a clay liner.


Spatial S-R compatibility with orthogonal stimulus-response relationship.
Spatial stimulus-response (S-R) compatibility with unimanual two-finger choice reactions was investigated under conditions in which the spatial orientation of response keys was either parallel to or perpendicular to the orientation of the stimuli. Subjects responded to green or red lights in the left or right visual field (irrelevant stimulus location). The response keys were oriented horizontally on the left or right side of the body midline parallel to the stimuli, and were pressed with the palms facing down (Condition A), or were oriented orthogonally to the stimuli in the midsaggital plane, either horizontally and pressed with palms facing down (B) or facing up (C), or vertically and pressed with palms facing the body (D). The results for Condition A demonstrate the usual spatial S-R compatibility effect between field of stimulation and spatial position of responding finger. For Conditions B and D, a strong reaction time advantage still obtained for those stimulus-finger pairings that are compatible under Condition A. Condition C revealed an RT advantage for the opposite pairings. This shift of the compatibility effect from Condition B to Condition C indicates that the left/right distinction of fingers does not follow a simple, fixed spatio-anatomical mapping rule. The results are discussed within the framework of a hierarchical model of spatial S-R compatibility, with spatial coding and spatio-anatomical mapping as factors.


Identifying and modelling key physiological traits that confer tolerance or sensitivity to ozone in winter wheat.
Tropospheric ozone threatens crop production in many parts of the world, especially in highly populated countries in economic transition. Crop models suggest substantial global yield losses for wheat, but typically such models fail to address differences in ozone responses between tolerant and sensitive genotypes. Therefore, the purpose of this study was to identify physiological traits contributing to yield losses or yield stability under ozone stress in 18 contrasting wheat cultivars that had been pre-selected from a larger wheat population with known ozone tolerance. Plants were exposed to season-long ozone fumigation in open-top chambers at an average ozone concentration of 70 ppb with three additional acute ozone episodes of around 150 ppb. Compared to control conditions, average yield loss was 18.7 percent, but large genotypic variation was observed ranging from 2.7 to 44.6 percent. Foliar chlorophyll content represented by normalized difference vegetation index and net CO2 assimilation rate of young leaves during grain filling were the physiological traits most strongly correlated with grain yield losses or stability. Accumulative effects of chronic ozone exposure on photosynthesis were more detrimental for grain yield than instantaneous effects of acute ozone shocks, or accelerated senescence of older leaves represented by changes in the ratio of brown leaf area/green leaf area index. We used experimental data of two selected tolerant or sensitive varieties, respectively, to parametrize the LINTULCC2 crop model expanded with an ozone response routine. By specifying parameters representing the distinct physiological responses of contrasting genotypes, we simulated yield losses of 7 percent (tolerant) or 33 percent (sensitive). By considering genotypic differences in ozone response models, this study helps to improve the accuracy of simulation studies, estimate the effects of adaptive breeding, and identify physiological traits for the breeding of ozone tolerant wheat varieties that could deliver stable yields despite ozone exposure.


Transpulmonary thermodilution before and during veno-venous extra-corporeal membrane oxygenation ECMO: an observational study on a potential loss of indicator into the extra-corporeal circuit.
Haemodynamic monitoring before extra-corporeal membrane oxygenation (ECMO) might help to optimize the effectiveness of ECMO. However, there are concerns that pulmonary arterial and trans-pulmonary thermodilution (TPTD) might be confounded by a loss of indicator into the ECMO-circuit, resulting in an overestimation of volumetric parameters. Since there is a lack of data on indicator dilution techniques during ECMO, we compared TPTD-measurements before and during ECMO. TPTD-derived parameters before and after initiation of ECMO were compared in 14 intensive care unit-patients with veno-venous ECMO and TPTD-monitoring (PiCCO®). Eight patients had a jugular and six patients a femoral central venous catheter (CVC). Cardiac index, global end-diastolic volume index (GEDVI) and extra-vascular lung water index (EVLWI) before ECMO as well as the ECMO-flow were comparable in patients with jugular and femoral CVC. Pre-ECMO, cardiac index (CI) was not significantly different compared to values during ECMO (4.5 ± 1.7 vs. 4.4 ± 2.1 L/min/m2; p = 0.43). By contrast, GEDVI (791 ± 179 vs. 974 ± 384 mL/m2; p = 0.04) and EVLWI (21 ± 9 vs. 28 ± 11 mL/kg; p < 0.01) were higher during ECMO than before. Increases in GEDVI (36 ± 210 vs. 378 ± 247 mL/m2; p = 0.02) and EVLWI (3 ± 2 vs. 11 ± 8 mL/kg; p = 0.06) were substantially more pronounced in patients with femoral compared to jugular indicator injection. In multivariate analysis, femoral indicator injection was independently associated with larger increases in GEDVI (p < 0.01) and EVLWI (p = 0.04) during ECMO. However, CI and haemodynamic parameters not derived from TPTD, but from pulse contour analysis (systolic and diastolic arterial pressure, stroke volume variation and pulse pressure variation) were not affected by the start of ECMO. Our study demonstrates marked increases in GEDVI and EVLWI after the onset of ECMO. These increases were more pronounced for femoral compared to jugular indicator injection. CI and haemodynamic parameters not derived from TPTD were not affected by the extra-corporeal circuit.


Snare Entrapment During EVAR Limb Cannulation Resulting in Open Conversion. A Rare Complication.
We present an unreported complication that occurred during an accidental loss of the ipsilateral limb's wire during EVAR. During an endovascular repair of an abdominal aortic aneurysm (EVAR), unintentional loss of the ipsilateral limb's wire during deployment and withdrawal of the endogaft's main body occurred. The snare's loops were entrapped while attempting to catch the wire through the limb. Multiple maneuvers were performed to detach the snare, but all were unsuccessful. We then performed a conversion to open repair. In conclusion, commercially available endografts should include standard radiopaque markers in the ipsilateral limb to facilitate retrograde cannulation. Retrieval via the snare should not be performed proximal to the gate of the limb.


Arterial reservoir-excess pressure and ventricular work.
This study is based on the hypothesis that the pressure within the arterial network can be usefully decomposed as the sum of a reservoir pressure and an excess pressure. The reservoir pressure waveform is defined to be the same in each vessel but delayed by the wave travel time from the root of the aorta. Using calculus of variations and mass conservation, which relates the flow and rates of change of pressure in the vessels, we show that the reservoir pressure waveform minimises the ventricular hydraulic work for any physiologically or clinically reasonable ejection waveform and arterial properties, i.e. vessel compliances and terminal resistances. We conclude that the excess pressure determines the excess work done by the ventricle, which may have clinically important implications.


Preferred surface microscopic geometric features on floors as potential interventions for slip and fall accidents on liquid contaminated surfaces.
Surface roughness affects friction, so selection of floor surfaces with certain roughness characteristics could potentially reduce slip and fall accidents. This article summarizes the preferred surface microscopic geometric features that could increase friction on surfaces covered with liquid contaminants. Three types of surface features, represented by the average of the maximum height above the mean line in each cut-off length (R(pm)), the arithmetical average of surface slope (Delta(a)), and the kernel roughness depth (R(k)), are identified as preferred surface microscopic geometric features for a higher friction. The proper settings on the profilometers (instruments used to measure surface roughness) for optimizing these surface parameters are specified. The friction mechanisms involved reveal why these features are more desirable. Although surface roughness is important in determining slipperiness, there is still insufficient information to establish a safety criterion based on roughness; however, the method presented in this paper can readily provide a relative comparison. The summary presented will help safety professionals properly select new floor surfaces or assess existing floors to reduce slip and fall accidents.


ZNF804A Genetic Variation Confers Risk to Bipolar Disorder.
Genetic variation in the gene encoding zinc finger protein 804A gene (ZNF804A) has been identified to be associated with bipolar disorder in genome-wide association studies, while little is known regarding their association in Asian populations. In this study, we aimed to examine whether ZNF804A may confer susceptibility to BD in Han Chinese. We measured the mRNA expression level of ZNF804A in patients with BD and controls. Two functional variants (rs1344706 and rs359895) in ZNF804A were genotyped among 1508 individuals with or without BD. We then performed a meta-analysis based on present literature. Our results showed that ZNF804A mRNA level in peripheral blood mononuclear cells was significantly higher in BD patients than that in controls (P = 0.01). The rs1344706 showed significant allelic association with BD (P = 0.034). The frequency of T allele of rs1344706 was higher in patients than that in controls (odds ratio = 1.19, 95 % confidence interval 1.03-1.37). After pooling all data, meta-analysis indicated a significant association of rs1344706 with BD (P = 0.0003). Furthermore, we performed an eQTL analysis and observed significant associations between rs1344706 and ZNF804A expression level in hippocampus (P = 0.032) and occipital cortex (P = 0.036). After stratified by diagnosis, the association of rs1344706 with BD was only survived in BD-I (genotypic P = 0.04, allelic P = 0.014), but not in BD-II. Our findings provided supportive evidence for the involvement of ZNF804A rs1344706 in BD, especially in BD-I.


InAsSb/InAsPSb multiple quantum well disk cavities with pedestal structures on a GaSb substrate for mid-infrared whispering-gallery-mode emission beyond 4 μm.
The mid-infrared whispering-gallery-mode disk cavities with InAs0.85Sb0.15/InAs0.53P0.23Sb0.24 multiple quantum wells active medium on a GaSb substrate were fabricated. For this material system in the mid-infrared range, fabrication techniques were developed to form the disk cavity structure. The smooth sidewalls of the disk cavities were achieved by appropriate gas mixture flow ratio of BCl3/Ar in the inductively coupled plasma-reactive ion etching. In addition, selective wet etching technique was used to form the pedestal of the disk cavity using dilute hydrofluoric acid with good selectivity. For efficient confinement of the whispering gallery modes along the radial direction, the extent of the lateral etching was carefully controlled. The processed 30-μm-diameter disk cavities were optically pumped, and the whispering gallery modes with wavelengths around 4.1 μm can be observed up to 90 K.


Echinococcus multilocularis metacestodes: biochemical and ultrastructural investigations on the effect of isatin (2-3 indoline dione) in vivo.
A study on the biochemical and ultrastructural effects of isatin on Echinococcus multilocularis metacestodes in Meriones unguiculatus is reported. In the metacestode, after an 18 day treatment period, the alkaline phosphatase and lactate dehydrogenase activities decreased and the acid phosphatase activity increased. Glucose and glycogen stores declined significantly. Examinations of the ultrastructure revealed an increase of lysosomes and phagocytic reactions. The protoscolesces were damaged and an abnormal striated process appeared. The tegumental cytoplasmic syncytium remained unaltered. These observations suggest that isatin derivatives may have a role in the chemotherapy of infections caused by Echinococcus spp.


Autistic spectrum disorder, epilepsy, and vagus nerve stimulation.
In individuals with a comorbid autistic spectrum disorder and medically refractory epilepsy, vagus nerve stimulation may offer the potential of seizure control and a positive behavioral side effect profile. We aimed to examine the behavioral side effect profile using longitudinal and quantitative data and review the potential mechanisms behind behavioral changes. We present a case report of a 10-year-old boy with autistic spectrum disorder and epilepsy, who underwent vagus nerve stimulation subsequent to unsuccessful treatment with antiepileptic medication. Following vagus nerve stimulation implantation, initial, if temporary, improvement was observed in seizure control. Modest improvements were also observed in behavior and development, improvements which were observed independent of seizure control. Vagus nerve stimulation in autistic spectrum disorder is associated with modest behavioral improvement, with unidentified etiology, although several candidates for this improvement are evident.


Urinary 6-sulfatoxymelatonin excretion in hyperandrogenic women with polycystic ovary syndrome: the effect of ethinyl estradiol-cyproterone acetate treatment.
The role of melatonin in human reproduction is still unknown. Data obtained in patients with hypogonadism and precocious puberty suggest that melatonin and the reproductive hormones are interrelated. The aim of this study was to determine melatonin production in hyperandrogenic women. We studied 12 women with polycystic ovary syndrome (PCOS) and 10 women with idiopathic hirsutism (IH). Patients were treated with cyproterone acetate-ethinyl estradiol (Diane 35) for 4 months. Fasting blood samples for the determination of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone and dehydroepiandrosterone sulfate (DHEAS) and 24-h urine collections for the determination of 6-sulfatoxymelatonin (alpha MT6s) excretion were obtained from all patients at baseline and after 4 months of treatment. The results were compared with those obtained in 15 control women. At baseline, women with PCOS had significantly higher LH and testosterone levels than those with IH and controls. Their alpha MT6s values (52.6 +/- 20.3 micrograms/24 h) were significantly higher than the values in women with IH (34.3 +/- 7.1) and controls (30.5 +/- 6.5) (p < 0.001). Diane 35 treatment significantly decreased LH, FSH, testosterone and alpha MT6a values in PCOS (28.0 +/- 13.9 micrograms/24 h) (p < 0.0001). These results indicate that women with PCOS have increased melatonin production. The normalization of alpha MT6s and testosterone values during Diane 35 treatment suggests that sex steroids modulate melatonin secretion in these patients either directly or through the suppression of gonadotropin.


Effects of a CCR2 antagonist on macrophages and Toll-like receptor 9 expression in a mouse model of diabetic nephropathy.
The pathogenesis of diabetic nephropathy (DN) is related to macrophage (Mφ) recruitment to the kidneys, tumor necrosis factor-α (TNF-α) production, and oxidative stress. Toll-like receptor 9 (TLR9) activation is reportedly involved in systemic inflammation, and it exacerbates this condition in metabolic syndrome. Therefore, we hypothesized that TLR9 plays a role in the pathogenesis of DN. Two subsets of kidney Mφs in DN model (db/db) mice were analyzed using flow cytometry to evaluate their distribution and TLR9 expression and function. Mice were administered the CCR2 antagonist INCB3344 for 8 wk; changes in Mφ distribution and function and its therapeutic effects on DN pathology were examined. Bone marrow-derived CD11bhigh (BM-Mφ) and tissue-resident CD11blow Mφs (Res-Mφ) were identified in the mouse kidneys. As DN progressed, the BM-Mφ number, TLR9 expression, and TNF-α production increased significantly. In Res-Mφs, reactive oxygen species (ROS) production and phagocytic activity were enhanced. INCB3344 decreased albuminuria, serum creatinine level, BM-Mφ abundance, TLR9 expression, and TNF-α production by BM-Mφs and ROS production by Res-Mφs. Both increased activation of BM-Mφ via TLR9 and TNF-α production and increased ROS production by Res-Mφs were involved in DN progression. Thus, inactivating Mφs and their TLR9 expression by INCB3344 is a potential therapeutic strategy for DN.NEW & NOTEWORTHY We classified kidney macrophages (Mφs) into bone marrow-derived Mφs (BM-Mφs) expressing high CD11b and tissue-specific resident Mφ (Res-Mφs) expressing low CD11b. In diabetic nephropathy (DN) model mice, Toll-like receptor 9 (TLR9) expression and TNF-α production via TLR9 activation in BM-Mφs and ROS production in Res-Mφs were enhanced. Furthermore, CCR2 antagonist suppressed the kidney infiltration of BM-Mφs and their function and the ROS production by Res-Mφs, with concomitant TLR9 suppression. Our study presents a new therapeutic strategy for DN.


Asymptomatic form of left pulmonary artery sling.
Eight patients with left pulmonary artery sling, which were asymptomatic at the time of the last consultation, are described: 2 adults and 1 child with no history of symptoms, 3 children with mild forms of airways obstruction and 2 patients with typical severe symptoms of airways obstruction in infancy. The mean follow-up of these 8 patients was 10 years (range 4 to 23), and in 1986, all were in good health and free of respiratory symptoms. The long-term prognosis is usually good.


Differences in salivary secretory function between patients with erosive esophagitis and those with nonerosive reflux disease.
It has been speculated that impaired salivary flow contributes to abnormal acid clearance in patients with erosive esophagitis (EE). For easy and objective assessment of salivary function, we developed a salivary gland blood flow measurement technique using continuous-wave Doppler sonography. In the present study, we evaluated the salivary secretory function in patients with EE and those with nonerosive reflux disease (NERD) using this method. Doppler waveform analysis was performed on the facial artery to assess blood inflow to the submandibular gland of 30 healthy subjects (HS). Blood flow was compared before and after secretory stimulation with 1 mL of lemon juice. Saliva was simultaneously collected and weighed before and after stimulation. Continuous-wave Doppler sonography was also performed in patients with EE and NERD. The size of the submandibular gland was compared in 26 patients with EE, 41 patients with NERD, and 86 HS. The submandibular gland blood flow increased after stimulation in all HS. Both within-day and day-to-day reproducibility were good. There was a significant correlation between the percent increase in the maximum velocity and the percent increase in salivary secretion. Although the size of the submandibular gland was not significantly different among the three groups, the percent increase in the maximum velocity in patients with EE was significantly smaller than that in HS. We have established an easy method of assessing salivary function in daily practice. This study revealed that a decrease in salivary secretory function is involved in the pathology of EE.


A short-term sublethal in situ toxicity assay with Hediste diversicolor (Polychaeta) for estuarine sediments based on postexposure feeding.
This study evaluated a short-term sublethal endpoint for in situ toxicity assays for estuarine sediments, based on postexposure feeding of the polychaete Hediste (Nereis) diversicolor Müller. A method for precisely quantifying postexposure feeding rates of H. diversicolor was established under laboratory conditions using Artemia franciscana Kellog nauplii. The sensitivity of the postexposure feeding response to copper was investigated by comparing postexposure feeding rates to growth and lethality. The 48-h and 96-h median lethal concentration (LC50) of copper were 241 and 125 microg/L, respectively, whereas the 48-h median inhibitory concentration (IC50) for postexposure feeding and the 20-d IC50 for growth were 52 and 25 microg/L of copper, respectively. The influence of different exposure conditions (substrate, temperature, salinity, food availability, and light) on H. diversicolor postexposure feeding was assessed; temperature and salinity were found to influence significantly postexposure feeding. The effectiveness of the proposed in situ assay was investigated by deploying it at two reference and six contaminated Portuguese estuaries. A 48-h exposure period was followed by a 1-h postexposure feeding period. High organism recoveries (89-100%) were obtained. Postexposure feeding was depressed significantly (17-90%) at all contaminated sites relatively to reference sites. The proposed in situ assay with H. diversicolor was shown to be a potential useful tool for estuarine sediment toxicity testing.


Lower limb post-traumatic osteomyelitis: a systematic review of clinical outcomes.
The aim of this study was to examine the patient-reported outcomes of patients presenting with post-traumatic osteomyelitis (PTOM) of the lower limb over the past 15 years. This period was chosen to reflect modern treatment principles and increased centralisation of care. An electronic literature search of the relevant databases (PubMed, Ovid Medline, Embase, and the Cochrane library) was conducted to identify studies published between January 2006 and July 2021 reporting series of greater than 10 patients with PTOM of the tibia or femur at the site of a previous fracture. Studies reporting septic non-union were excluded. Sixteen eligible studies were identified and included in the final report. Remission of infection was achieved in 93.2% of cases (range 70-100%), whilst amputation was reported in 1-7% of cases. A variety of patient-reported outcome measures were utilised including the lower extremity functional scale, short musculoskeletal functional assessment, Enneking score, and EQ-5D-3L. Limb-specific functional outcomes returned to levels similar to that of the general population although poorer outcomes were noted in specific cohorts including those with complex anatomic disease and active medical comorbidities. Infection following fracture fixation remains a difficult problem to treat. Regardless, using modern treatments and techniques patients can have comparable functional outcomes to that of the general population. High-quality studies are required to advance our knowledge into which types of treatments offer a benefit and how to further improve outcomes.


The decline in 'free' general practitioner care in Australia: reasons and repercussions.
The Australian public insurer, Medicare, allows general practitioners (GPs) to bulk bill patients, or accept the government rebate as full payment for their services. The percentage of GP consultations bulk billed, however has declined from 78.6% in June 2000 to 65.7% in December 2003. The immediate impact of a declining level of bulk billing is a decrease in the availability of free GP health care for patients. This has implications for copayments and access to GPs for low income groups in particular. In this paper, we explore the reasons for and repercussions of the decline in bulk billing. We analyse two main reasons for the decline. The first is a failure of the rebate to maintain a level consistent with increases in medical practice costs. The second is a decline in GPs in some regional and rural areas resulting in a decrease in price competition. The government has recently made changes to deal with the decline in bulk billing and based on three quarters of data, there has been a modest improvement in bulk billing.


Juvenile acinar atrophy of the pancreas of a dog.
A dog with juvenile acinar atrophy of the pancreas had degranulation and loss of the acinar cells. Transitional features from normal to degranulation were seen. Electron microscopically, the atrophic pancreas mainly consisted of epithelial cells of duct system, islet cells and multivesicular cells.


Geotrichum candidum arthrospore cell wall particles as a novel carrier for curcumin encapsulation.
We report for the first time that curcumin is successfully encapsulated into a new natural pre-formed carrier, which was derived from arthrospore cell wall particles (APs) of probiotic Geotrichum candidum LG-8 and mainly composed of beta-1,4-glucan. Vacuum infusion process was used for efficient encapsulation of curcumin. The results showed that the encapsulation efficiency and yield of APs were 36.5 ± 0.9 % and 730.6 ± 26.5 μg/g (wet basis), respectively. Compared with the other probiotic carriers such as Saccharomyces cerevisiae, it could more effectively maintain the antioxidant property and storage capacity of curcumin under high temperature conditions. Simulated digestion was conducted to study in vitro release of curcumin encapsulated in APs, and showed a maximum bioaccessibility of 65.6 ± 3.8 %. In view of low-cost culture method, simple encapsulation process and high encapsulation capacity, G. candidum arthrospores as new natural encapsulation carriers have potential superiority in the practical application in food industry.