Efficacious use of a Calgigraf Ag foam dressing in complete healing of a difficult-to-heal, long-standing ulcer of osteoradionecrosis.
A number of dressings containing silver have been recently introduced into the wound care market as increased resistance to antibiotics has become a problem in treating infected wounds. A 54-year-old male, with adenoid cystic carcinoma treated by segmental resection and reconstruction of mandible using reconstruction plate with concomitant radiotherapy, resulted in a deep extraoral nonhealing necrotic, exuding, malodorous, and painful wound. Erythema, eczema, and trophic changes were surrounding the skin. Previous treatment was removal of exposed reconstruction plate and primary closure. Culture samples reported methicillin-resistant Staphylococcus aureus positive and sensitivity to linezolid. Repeated failed attempts to approximate the wound, prompted the use of Calgigraf Ag foam as dressing for the wound. Evidence of new tissue growth and subsequent reduction in wound area and exudate were significant. Chronic nonhealing wounds involving progressive tissue loss give rise to the biggest challenge to wound-care researchers. Despite proper care, some wounds fail to heal in normally and become chronic. The use of ionic silver with negative pressure therapy is safe and effective in difficult nonhealing wounds. This case illustrates the potential benefit of ionic silver combined with negative pressure and moist wound healing as management of a patient with long-standing, nonhealing, and osteoradionecrosis wound. Calgigraf Ag Foam a silver alginate dressing is optimal for maintaining moist environment vital to promote wound healing. It needs less frequent dressing changes with additional benefits such management of excessive exudate minimising malodour and maintaining a moist wound environment.


Intravitreal injection of exendin-4 analogue protects retinal cells in early diabetic rats.
To evaluate the protective effect of intravitreal injection of exendin-4 analogue (E4a) in early diabetic retinopathy (DR) and to explore its possible mechanism. Forty Sprague-Dawley rats were divided into three groups: normal (N), diabetic (D), and E4a-treated diabetic rats (E4a). Diabetes was induced by streptozotocin. Rats in the E4a group were treated with E4a (0.1 μg/2μL/eye), whereas the N and D groups were treated with the equivalent volume of normal saline. Electroretinography was performed at 1 month and 3 months after diabetes onset. Thicknesses and cell counts in each layer of the retina were evaluated. The concentration of glutamate was measured by high-performance liquid chromatography (HPLC). Expressions of glucagon-like peptide-1 receptor (GLP-1R) and GLAST (excitatory amino acid transporter) were detected at mRNA and protein levels and verified by immunohistochemistry in vitro and in vivo. The rMc-1 cells were cultured under high-glucose medium (25 mM), which mimicked diabetic conditions. Effects of E4a (10 μg/mL) were also tested in the rMc-1 culture system. E4a prevented the reduction in b-wave amplitude and oscillatory potential amplitude caused by diabetes. It also prevented the cell loss of outer nuclear layer and inner nuclear layer; the thickness and cell count in the outer nuclear layer were decreased in 1-month diabetic rats. The concentration of glutamate in the retina was higher in diabetic rats and was significantly reduced in the E4a-treated group. Consistent with such changes, retinal GLP-1R and GLAST expression were reduced in the diabetic retina but upregulated in E4a-treated rats. No improvement was found in the retina in both functional and morphologic parameters 3 months after treatment. Intravitreal administration of E4a can prevent the retina, functionally and morphologically, from the insults of diabetes in rats. GLP-1R and GLAST were proved to exist in the rat retina, and their lowered expressions in the diabetic retina might be related to retinal damage by increasing the retinal glutamate. E4a might protect the retina by reducing the glutamate level through upregulating GLP-1R and GLAST, as observed in retinal Müller cells in this study, but this protective effect was transient. Thus, this could be a potential approach for the treatment of DR.


Probing peroxisomal beta-oxidation and the labelling of acetyl-CoA proxies with [1-(13C)]octanoate and [3-(13C)]octanoate in the perfused rat liver.
We reported previously that a substantial fraction of the acetyl groups used to synthesize malonyl-CoA in rat heart is derived from peroxisomal beta-oxidation of long-chain and very-long-chain fatty acids. This conclusion was based on the interpretation of the 13C-labelling ratio (malonyl-CoA)/(acetyl moiety of citrate) measured in the presence of substrates that label acetyl-CoA in mitochondria only (ratio < 1.0) or in both mitochondria and peroxisomes (ratio > 1.0). The goals of the present study were to test, in rat livers perfused with [1-(13C)]octanoate or [3-(13C)]octanoate, (i) whether peroxisomal beta-oxidation contributes acetyl groups for malonyl-CoA synthesis, and (ii) the degree of labelling homogeneity of acetyl-CoA proxies (acetyl moiety of citrate, acetate, beta-hydroxybutyrate, malonyl-CoA and acetylcarnitine). Our data show that (i) octanoate undergoes two cycles of peroxisomal beta-oxidation in liver, (ii) acetyl groups formed in peroxisomes contribute to malonyl-CoA synthesis, (iii) the labelling of acetyl-CoA proxies is markedly heterogeneous, and (iv) the labelling of C1+2 of beta-hydroxybutyrate does not reflect the labelling of acetyl-CoA used in the citric acid cycle.


Synovial hemangioma in the stifle joint of a dog.
Synovial hemangioma was diagnosed in an 8-year-old castrated male Belgian Sheepdog with lameness of 3 months' duration. Pain, soft-tissue swelling, and hemarthrosis were localized to the left stifle joint. Projections of synovial membrane with reddish-purple nodules, excised via arthrotomy, were composed histologically of variably sized vascular channels that were lined by well-differentiated endothelial cells and separated by fibrous septa. Distension of some channels resulted in endothelial disruption, thrombosis, hemorrhage, necrosis, and focal spindle-cell proliferation. The limb was amputated to remove remaining neoplastic tissue. The hemangioma extended focally into the joint capsule and popliteal soft tissue but did not invade skeletal muscle or bone. The dog was free of detectable neoplasia 6 months after amputation. Synovial hemangioma is a rare benign vascular proliferation in people, most commonly in the knee, and should be included in the differential diagnosis for canine synovial tumors.


Molecular cloning of a human RP105 homologue and chromosomal localization of the mouse and human RP105 genes (Ly64 and LY64).
RP105 is a mouse B cell surface molecule that transmits a growth-promoting signal and is implicated in the life/death decision of B cells. RP105 has tandem repeats of a leucine-rich motif in the extracellular domain that is expected to be involved in protein-protein interactions. In the present study, a cDNA clone encoding the human homologue of RP105 was isolated. The amino acid sequence of human RP105 is highly homologous to that of mouse RP105 with 74% identity, and the leucine-rich repeats are well conserved. The expression of the human RP105 transcript was detected in some B cell lines, a histiocytic leukemia cell line, and peripheral blood leukocytes. We also determined the chromosomal locations of the mouse RP105 gene (Ly64 locus) and the human RP105 gene (LY64 locus). Interspecific mouse backcross analysis was used to map the Ly64 locus at the distal region of chromosome 13. The human LY64 locus was localized to 5q12 by fluorescence in situ hybridization, confirming the syntenic relationship between these regions of the mouse and human chromosomes.


Putting them on a strong spiritual path: Indigenous doulas responding to the needs of Indigenous mothers and communities.
In the past few years, increasing numbers of Indigenous doula collectives have been forming across Canada. Indigenous doulas provide continuous, culturally appropriate support to Indigenous women during pregnancy, birth, and the post-partum period. This support is critical to counter systemic medical racism and socioeconomic barriers that Indigenous families disproportionately face. This paper analyzes interviews with members of five Indigenous doula collectives to demonstrate their shared challenges, strategies, and missions. Qualitative interviews were conducted with members of five Indigenous doula collectives across Canada in 2020. Interviews were transcribed and returned to participants for their approval. Approved transcripts were then coded by all members of the research team to ascertain the dominant themes emerging across the interviews. Two prominent themes emerged in the interviews. The first theme is "Indigenous doulas responding to community needs." Participants indicated that responding to community needs involves harm reduction and trauma-informed care, supporting cultural aspects of birthing and family, and helping clients navigate socioeconomic barriers. The second theme is "Indigenous doulas building connections with mothers." Participants' comments on providing care to mothers emphasize the importance of advocacy in healthcare systems, boosting their clients' confidence and skills, and being the "right" doula for their clients. These two inter-related themes stem from Indigenous doulas' efforts to counter dynamics in healthcare and social services that can be harmful to Indigenous families, while also integrating cultural teachings and practices. This paper illustrates that Indigenous doula care responds to a wide range of issues that affect Indigenous women's experiences of pregnancy, birth, and the post-partum period. Through building strong, trusting, and non-judgemental connections with mothers and responding to community needs, Indigenous doulas play a critical role in countering medical racism in hospital settings and advancing the resurgence of Indigenous birthing sovereignty.


State of the science. HIV vaccine development.
Developing a vaccine able to prevent HIV infection would be a great benefit to the world. Vaccines have contributed to substantially reduced morbidity and mortality from several important infectious diseases. However, HIV has some characteristics that distinguish it from many other viruses and make vaccine development challenging. This article discusses scientific strategies, obstacles, and progress to date towards the development of a preventive HIV vaccine.


Cross-sectional study of perioperative drug and allergen exposure in UK practice in 2016: the 6th National Audit Project (NAP6) Allergen Survey.
Details of the current UK drug and allergen exposure were needed for interpretation of reports of perioperative anaphylaxis to the 6th National Audit Project (NAP6). We performed a cross-sectional survey of 356 NHS hospitals determining anaesthetic drug usage in October 2016. All cases cared for by an anaesthetist were included. Responses were received from 342 (96%) hospitals. Within-hospital return rates were 96%. We collected 15 942 forms, equating to an annual caseload of 3.1 million, including 2.4 million general anaesthetics. Propofol was used in 74% of all cases and 90% of general anaesthetics. Maintenance included a volatile agent in 95% and propofol in 8.7%. Neuromuscular blocking agents were used in 47% of general anaesthetics. Analgesics were used in 88% of cases: opioids, 82%; paracetamol, 56%; and non-steroidal anti-inflammatory drugs, 28%. Antibiotics were administered in 57% of cases, including 2.5 million annual perioperative administrations; gentamicin, co-amoxiclav, and cefuroxime were most commonly used. Local anaesthetics were used in 74% cases and 70% of general anaesthetics. Anti-emetics were used in 73% of cases: during general anaesthesia, ondansetron in 78% and dexamethasone in 60%. Blood products were used in ≈3% of cases, gelatin <2%, starch very rarely, and tranexamic acid in ≈6%. Chlorhexidine and povidone-iodine exposures were 74% and 40% of cases, and 21% reported a latex-free environment. Exposures to bone cement, blue dyes, and radiographic contrast dye were each reported in 2-3% of cases. This survey provides insights into allergen exposures in perioperative care, which is important as denominator data for the NAP6 registry.


Effect of adding letrozole to gonadotropin on in vitro fertilization outcomes: An RCT.
Aromatase inhibitors prevent the aromatization of androgens into estrogens, which reduces the negative feedback of estrogen on the hypothalamic-pituitary axis. It is clear that increasing the secretion of follicle-stimulating hormones results in an increased follicular growth. This study aimed to evaluate the effect of adding letrozole to gonadotropin on in vitro fertilization outcomes in normal responders. In this randomized clinical trial, 100 normal responder women candidate for controlled ovarian stimulation were randomly enrolled in two groups (n = 50/each). In the case group letrozole was added to gonadotropin in the antagonist protocol. The control group received the conventional antagonist protocol. The main outcome was clinical and chemical pregnancy; and the second outcomes were the number of mature oocytes, the fertilization rate, estradiol level, and the total dose of gonadotropins. Basic clinical and demographic features were comparable between the groups. Estradiol level on the day of human-chorionic-gonadotropin administration and the total gonadotropin consumption were significantly higher in the control group than the case group (p = 0.045). In addition, the number of MII oocytes was higher (but not significantl) in the case group than the control group (p = 0.09). Moreover, the endometrial thickness was significantly lower in the case group. There were no significant differences in fertilization rate and chemical and clinical pregnancy rates between the two groups. Although adding letrozole to gonadotropin in normal responders reduces the total dose of gonadotropin, it does not improve the pregnancy outcomes.


Fetal and neonatal abnormalities due to congenital herpes simplex virus infection: a literature review.
Herpes simplex virus (HSV) infection during pregnancy can cause severe neonatal infections. It is also a rare cause of congenital infections. We aimed to describe fetal and neonatal abnormalities of congenital HSV infection in order to define the features that are accessible to prenatal diagnosis during ultrasound screening and/or during a work-up for congenital malformations. We analysed all cases of congenital HSV infection (CHI) described before and/or after birth and identified in Pubed and classified the findings as accessible or not to prenatal diagnosis. Thirty-six cases of congenital herpes infection were reported, of which 15 were described prenatally and 21 postnatally. The most frequently reported malformations accessible to prenatal diagnosis were cerebral anomalies. The most common abnormalities described after birth were skin lesions and keratitis, which are not considered amenable to prenatal ultrasound detection. CHI can due to either HSV1 or HSV2 infection, whether primary or non-primary infection, with or without the presence of maternal symptoms. Prenatal ultrasound abnormalities due to CHI are rare, varied and non-specific. There is no clear role for fetal ultrasound in the routine management of women with primary or non-primary HSV infection in pregnancy. However, in fetuses with ultrasound abnormalities suggestive of congenital infection, HSV should still be considered as a differential diagnosis after the more common in utero infections, such as cytomegalovirus, are excluded.


Hepatitis B virus X gene 1751 to 1764 mutations: implications for HBeAg status and disease.
A translational stop in the hepatitis B virus (HBV) precore codon 28 and specific changes in the core promoter region of the X gene have been suggested to influence the level of circulating HBeAg in patients. We analysed the core promoter region and precore sequences from 59 HBV strains (including 14 from the databank) of different genotypes and from patients with different HBeAg/anti-HBe patterns. The initiator and TATA elements for transcription of precore and pregenomic RNA were highly conserved. The majority of X gene deletions in the core promoter region would lead to translational frame-shifts and stops, truncating the C-terminal end of the X protein. We found significant associations between specific changes in core promoter positions 1762 to 1764, or in precore codon 28, and absence of circulating HBeAg. For the core promoter mutations alone, this association was related to the apparent degree of liver damage (as estimated by alanine aminotransferase levels) at the time of sampling. Mutations at nucleotides 1762 and/or 1764 were often accompanied by point mutations at positions 1751 to 1755. Since mutations at nucleotide positions 1762 and 1764 have recently been shown by in vitro studies to suppress HBeAg production with a concomitant enhancement of virus production, disappearance of the HBeAg-positive phenotype associated with 1762 to 1764 mutations may thus have at least as much significance for the course of infection as HBeAg absence associated with precore codon 28 stop mutations. These observations are considered against a secondary structural model for the 3' end of HBV pregenomic RNA which also predicts enhancement of virus replication after mutation at positions 1762 and 1764.


Systemic retinoids in chemoprevention of non-melanoma skin cancer.
The incidence of non-melanoma skin cancer is increasing worldwide. Systemic retinoids are useful for the chemoprophylaxis of non-melanoma skin cancers. Retinoids have pleiotropic effects, but their exact cancer chemopreventive mechanism is still not clear. The aim of this study was to review published literature evaluating the use of oral retinoids in the chemoprevention of non-melanoma skin cancers. The study reviewed all relevant papers found through a search of the electronic databases MEDLINE (from 1966 to January 2008) and Embase (from 1974 to January 2008). General and specific indications for retinoid chemoprophylaxis are defined. The pharmacokinetics and dose regimens of the two most commonly used oral retinoids (isotretinoin and acitretin) in the chemoprevention of non-melanoma skin cancers are presented. The use of oral retinoids is associated with adverse effects, which are discussed in detail. The future of retinoid cancer chemoprevention depends on the development and research of novel retinoids with improved bioavailability and minimized toxicity.


Angiographic findings in multiple bile-duct hamartomas of the liver.
The angiographic appearance in a patient with multiple bile-duct hamartomas of the liver is described. The lesions showed abnormal vascularity, consisting of grapelike clusters of small rings, which could be confused with other benign and malignant conditions demonstrable by angiography; however, it may ultimately prove to be characteristic of this uncommon lesion. The angiographic differential diagnosis is discussed.


The outcome of decompressive laminectomy for degenerative lumbar stenosis.
The outcome of laminectomy for the relief of symptoms resulting from degenerative lumbar stenosis is not well established. Eighty-eight consecutive patients who had had a laminectomy for degenerative lumbar stenosis between 1983 and 1986 were studied. Eight of the patients had had a concomitant arthrodesis. The follow-up evaluation included a review of charts and standardized questionnaires that were completed by the patients. One year postoperatively, five patients (6 per cent) had had a second operation and five still had severe pain. By the time of the latest follow-up, in 1989, fifteen (17 per cent) of the original eighty-eight patients had had a repeat operation because of instability or stenosis; twenty-one (30 per cent) of the seventy patients who were evaluated by questionnaire in 1989 had severe pain. The factors found to be associated with a poor long-term outcome, defined as severe pain or the need for a repeat operation, or both, included co-existing illnesses (such as osteoarthrosis, cardiac disease, rheumatoid arthritis, or chronic pulmonary disease) (p = 0.004), the duration of follow-up (p = 0.01), and an initial laminectomy involving a single interspace (p = 0.04). We concluded that the long-term outcome of decompressive laminectomy is less favorable than has been previously reported, and that co-morbidity and a single-interspace laminectomy are risk factors for a poor outcome.


Murine monoclonal antibodies to Klebsiella pneumoniae protect against lethal endotoxemia and experimental infection with capsulated K. pneumoniae.
To prepare monoclonal antibodies (MAbs) directed against the core-lipid A fractions of smooth lipopoly-saccharide (LPS) from Klebsiella pneumoniae O1:K2, we immunized BALB/c mice with the LPS-associated proteins plus LPS. This preparation exposed the core-lipid A moiety, which is normally hidden in the micellar structure of classical LPS preparations. Among 10 MAbs selected for their reactivity with LPS-associated proteins plus LPS from K. pneumoniae O1:K2, 6 (3A3, 3C2, 3C4, 7D2, 11C3, and 12B6) were directed against the core fraction and 2 (6C5 and 10A5) were directed against the lipid A fraction. Only one (2A4) recognized the O antigen, and one (6D5) had an undefined specificity. When injected before challenge with K. pneumoniae O1:K2 LPS in galactosamine-sensitized mice, five of the MAbs (3C4, 6D5, 7D2, 11C3, and 12B6) provided protection in this model of lethal endotoxemia. MAb 7D2 was also protective in an experimental infection with capsulated K. pneumoniae O1:K2.


Pressure-induced phase transition in N-H···O hydrogen-bonded molecular crystal oxamide.
The effect of high pressure on the structural stability of oxamide has been investigated in a diamond anvil cell by Raman spectroscopy up to ∼14.6 GPa and by angle-dispersive X-ray diffraction (ADXRD) up to ∼17.5 GPa. The discontinuity in Raman shifts around 9.6 GPa indicates a pressure-induced structural phase transition. This phase transition is confirmed by the change of ADXRD spectra with the symmetry transformation from P1 to P1. On total release of pressure, the diffraction pattern returns to its initial state, implying this transition is reversible. We discuss the pressure-induced variations in N-H stretching vibrations and the amide modes in Raman spectra and propose that this phase transition is attributed to the distortions of the hydrogen-bonded networks.


Factors that relate to good and poor handwriting.
This study investigated the relationships between specific performance components, eye-hand coordination, visuomotor integration, in-hand manipulation, and handwriting skill. A sample of 48 typical first grade students were identified as good and poor handwriters by their teachers. Each child completed the Motor Accuracy Test; the Developmental Test of Visual-Motor Integration (VMI); two tests of in-hand manipulation, including a rotation and a translation task; and the Minnesota Handwriting Test (MHT). All test scores for the subjects with good handwriting were significantly higher than those of the subjects with poor handwriting. Each performance component test was significantly correlated to MHT scores. Translation, VMI, and rotation scores were significant predictors of MHT scores, accounting for almost 73% of variance. A discriminant analysis using the performance components correctly classified 98% of the students as good or poor handwriters. In-hand manipulation has significant association to handwriting skill.


Measurement of a compact colorless 3 dB hybrid plasmonic directional coupler.
We fabricated and measured a compact 3 dB hybrid plasmonic directional coupler for silicon photonics integrated circuits with a length of 21.2 μm. The coupler has a 50∶50 coupling ratio over a spectral bandwidth of more than 100 nm around a wavelength of 1.55 μm and has an insertion loss of less than 1 dB.


Developing capacity-building activities for mental health system strengthening in low- and middle-income countries for service users and caregivers, service planners, and researchers.
There is increasing international recognition of the need to build capacity to strengthen mental health systems. This is a fundamental goal of the 'Emerging mental health systems in low- and middle-income countries' (Emerald) programme, which is being implemented in six low- and middle-income countries (LMICs) (Ethiopia, India, Nepal, Nigeria, South Africa, Uganda). This paper discusses Emerald's capacity-building approaches and outputs for three target groups in mental health system strengthening: (1) mental health service users and caregivers, (2) service planners and policy-makers, and (3) mental health researchers. When planning the capacity-building activities, the approach taken included a capabilities/skills matrix, needs assessments, a situational analysis, systematic reviews, qualitative interviews and stakeholder meetings, as well as the application of previous theory, evidence and experience. Each of the Emerald LMIC partners was found to have strengths in aspects of mental health system strengthening, which were complementary across the consortium. Furthermore, despite similarities across the countries, capacity-building interventions needed to be tailored to suit the specific needs of individual countries. The capacity-building outputs include three publicly and freely available short courses/workshops in mental health system strengthening for each of the target groups, 27 Masters-level modules (also open access), nine Emerald-linked PhD students, two MSc studentships, mentoring of post-doctoral/mid-level researchers, and ongoing collaboration and dialogue with the three groups. The approach taken by Emerald can provide a potential model for the development of capacity-building activities across the three target groups in LMICs.


The first data on the innervation of the lophophore in the rhynchonelliform brachiopod Hemithiris psittacea: what is the ground pattern of the lophophore in lophophorates?
The nervous system in brachiopods has seldom been studied with modern methods. An understanding of lophophore innervation in adult brachiopods is useful for comparing the innervation of the same lophophore type among different brachiopods and can also help answer questions about the monophyly of the lophophorates. Although some brachiopods are studied with modern methods, rhynchonelliform brachiopods still require investigation. The current study used transmission electron microscopy, immunocytochemistry, and confocal laser scanning microscopy to investigate the nerve system of the lophophore and tentacles in the rhynchonelliform Hemithiris psittacea. Four longitudinal nerves pass along each brachium of the lophophore: the main, accessory, second accessory, and lower. The main brachial nerve extends at the base of the dorsal side of the brachial fold and gives rise to the cross nerves, passing through the extracellular matrix to the tentacles. Cross nerves skirt the accessory brachial nerve, branch, and penetrate into adjacent outer and inner tentacles, where they are referred to as the frontal tentacular nerves. The second accessory nerve passes along the base of the inner tentacles. This nerve consists of Ʊ-like parts, which repetitively skirt the frontal and lateral sides of the inner tentacle and the frontal sides of the outer tentacles. The second accessory nerve gives rise to the latero-frontal nerves of the inner and outer tentacles. The abfrontal nerves of the inner tentacles also originate from the second accessory nerve, whereas the abfrontal nerves of the outer tentacles originate from the lower brachial nerve. The lower brachial nerve extends along the outer side of the lophophore brachia and gives rise to the intertentacular nerves, which form a T-like branch and penetrate the adjacent outer tentacles where they are referred to as abfrontal nerves. The paired outer radial nerves start from the lower brachial nerve, extend into the second accessory nerve, and give rise to the lateroabfrontal tentacular nerves of the outer tentacles. The innervation of the lophophore in the rhynchonelliform Hemithiris psittacea differs from that in the inarticulate Lingula anatina in several ways. The accessory brachial nerve does not participate in the innervation of the tentacles in H. psittacea as it does in L. anatina. The second accessory nerve is present in H. psittacea but not in L. anatina. There are six tentacular nerves in the outer tentacles of H. psittacea but only four in all other brachiopods studied to date. The reduced contribution of the accessory brachial nerve to tentacle innervation may reflect the general pattern of reduction of the inner lophophoral nerve in both phoronids and brachiopods. Bryozoan lophophores, in contrast, have a weakened outer nerve and a strengthened inner nerve. Our results suggest that the ancestral lophophore of all lophophorates had a simple shape but many nerve elements.


[Soluble receptors of cytokines in sera of patients with systemic sclerosis--clinical correlation].
The aim of this study was to examine the levels of some soluble receptors of cytokines in sera from patients with systemic sclerosis (SSc) and to evaluate their role as parameters of disease activity and severity. Fifty-four patients with SSc were included in the study. Concentrations of the soluble receptors: sIL-2R, sTNF alpha RI and sIL-6R were determined by an enzyme-linked immunosorbent assay-ELISA. Controls were healthy age- and sex-matched volunteers. The study demonstrated that soluble receptors levels: sII-2R, sIL-6R and sTNF alpha RI were elevated in SSc patients and correlated with progress and severity of the disease. The most important correlations were found for sIL-2R levels, which were increased in 66.7% of patients. The raised levels of sTNF alpha RI were found in 32.4% of patients, and sIL-6R in 23.7% of patients. The concentrations were elevated in diffuse form of SSc and in patients with rapid systemic progression.


The Synthesis and Evaluation of RGD-Conjugated Chitosan Gel as Daily Supplement for Body Weight Control.
(1) Background: Obesity is one of the most widespread chronic diseases and increases the risk of several other chronic diseases, especially type 2 diabetes. (2) Methods: Endobarrier is a new medical device what is worn in the small intestines for the treatment of type 2 diabetes and obesity. However, given the invasive and other adverse effects of the Endobarrier, we propose the use of RGD peptide conjugated with chitosan (RC) as an alternative. (3) Results: The FTIR and NMR spectrum showed RGD peptide was successfully conjugated on chitosan and RGD-CT is retained in the small intestine even after digestion. In vitro of wst-1 and live and dead staining studies show that the RGD-CT gel is highly biocompatible and non-toxic. Rats treated with the RGD-CT gel for a short term showed significant decrease change more than 30% in body weight, while the blood and hematic biometrics were within normal values. (4) Conclusions: The RGD-CT gel is safe, suitable for the short-term, reducing visceral fat rate health food to control weight. In the future, it is expected to develop a safe, long-term effective, flexibility of use and low-side-effect anti-obesity therapy in the era of precision medicine by further modification.


Cullin 3 promotes proteasomal degradation of the topoisomerase I-DNA covalent complex.
DNA topoisomerase I (TOP1)-DNA covalent complexes are the initial lesions produced by antitumor camptothecins (CPTs). The TOP1-directed drugs stimulate degradation of TOP1 via the ubiquitin-proteasome pathway. We found that proteasome inhibition prevents degradation of DNA-bound TOP1 and sustains high levels of covalent complexes, thus enhancing CPT-induced cell death. Consistent with this, increased degradation of TOP1-DNA covalent complexes was seen in acquired CPT-resistant cells. We found that the resistant cells showed elevated expressions of Cul3, a member of the cullin family of E3 ubiquitin ligases. The reduction in Cul3 expression by small interfering RNA decreased degradation of TOP1-DNA covalent complexes. Conversely, Cul3 overexpression by stable transfection promoted covalent complex degradation and reduced CPT-induced cell death without affecting basal TOP1 expression levels. These results indicate that Cul3, by promoting proteasomal degradation of TOP1-DNA covalent complexes, becomes an important regulator for cellular CPT sensitivity.


NOLB: Nonlinear Rigid Block Normal-Mode Analysis Method.
We present a new conceptually simple and computationally efficient method for nonlinear normal-mode analysis called NOLB. It relies on the rotations-translations of blocks (RTB) theoretical basis developed by Y.-H. Sanejouand and colleagues [ Durand et al. Biopolymers 1994 , 34 , 759 - 771 . Tama et al. Proteins: Struct., Funct., Bioinf . 2000 , 41 , 1 - 7 ]. We demonstrate how to physically interpret the eigenvalues computed in the RTB basis in terms of angular and linear velocities applied to the rigid blocks and how to construct a nonlinear extrapolation of motion out of these velocities. The key observation of our method is that the angular velocity of a rigid block can be interpreted as the result of an implicit force, such that the motion of the rigid block can be considered as a pure rotation about a certain center. We demonstrate the motions produced with the NOLB method on three different molecular systems and show that some of the lowest frequency normal modes correspond to the biologically relevant motions. For example, NOLB detects the spiral sliding motion of the TALE protein, which is capable of rapid diffusion along its target DNA. Overall, our method produces better structures compared to the standard approach, especially at large deformation amplitudes, as we demonstrate by visual inspection, energy, and topology analyses and also by the MolProbity service validation. Finally, our method is scalable and can be applied to very large molecular systems, such as ribosomes. Standalone executables of the NOLB normal-mode analysis method are available at https://team.inria.fr/nano-d/software/nolb-normal-modes/ . A graphical user interface created for the SAMSON software platform will be made available at https://www.samson-connect.net .


Pesticide Mixtures in Surface Waters of Two Protected Areas in Southwestern Germany.
Pesticides enter non-target surface waters as a result of agricultural activities and may reach water bodies in protected areas. We measured in southwestern Germany pesticide concentrations after heavy rainfalls in streams of a drinking water protection area near Hausen (Freiburg) and in the catchment of the Queich (Landau), which originates from the biosphere reserve Palatinate Forest. On average, 32 (n = 21) and 21 (n = 10) pesticides were detected per sample and event in the area of Hausen (n = 56) and in the Queich catchment (n = 17), respectively. The majority of pesticides detected in > 50% of all samples were fungicides, with fluopyram being detected throughout all samples. Aquatic invertebrates exhibited highest risks with 16.1% of samples exceeding mixture toxicity thresholds, whereas risks were lower for aquatic plants (12.9%) and fish (6.5%). Mixture toxicity threshold exceedances indicate adverse ecological effects to occur at half of sites (50%). This study illustrates the presence of pesticide mixtures and highlights ecological risks for aquatic organisms in surface waters of protected areas in Germany.


Drug labeling and exposure in neonates.
Federal legislation has led to a notable increase in pediatric studies submitted to the Food and Drug Administration (FDA), resulting in new pediatric information in product labeling. However, approximately 50% of drug labels still have insufficient information on safety, efficacy, or dosing in children. Neonatal information in labeling is even scarcer because neonates comprise a vulnerable subpopulation for which end-point development is lagging and studies are more challenging. To quantify progress made in neonatal studies and neonatal information in product labeling as a result of recent legislation. We identified a cohort of drug studies between 1997 and 2010 that included neonates as a result of pediatric legislation using information available on the FDA website. We determined what studies were published in the medical literature, the legislation responsible for the studies, and the resulting neonatal labeling changes. We then examined the use of these drugs in a cohort of neonates admitted to 290 neonatal intensive care units (NICUs) (the Pediatrix Data Warehouse) in the United States from 2005 to 2010. Infants exposed to a drug studied in neonates as identified by the FDA website. Number of drug studies with neonates and rate of exposure per 1000 admissions among infants admitted to an NICU. In a review of the FDA databases, we identified 28 drugs studied in neonates and 24 related labeling changes. Forty-one studies encompassed the 28 drugs, and 31 (76%) of these were published. Eleven (46%) of the 24 neonatal labeling changes established safety and effectiveness. In a review of a cohort of 446,335 hospitalized infants, we identified 399 drugs used and 1,525,739 drug exposures in the first 28 postnatal days. Thirteen (46%) of the 28 drugs studied in neonates were not used in NICUs; 8 (29%) were used in fewer than 60 neonates. Of the drugs studied, ranitidine was used most often (15,627 neonates, 35 exposures per 1000 admissions). Few drug labeling changes made under pediatric legislation include neonates. Most drugs studied are either not used or rarely used in US NICUs. Strategies to increase the study of safe and effective drugs for neonates are needed.


Evaluation of Influencing Factors on Tubal Sterilization Regret: A Cross-Sectional Study.
The aim of this study is to evaluate the menstrual pattern, sexual function, and anxiety, and depression in women with poststerilization regret, and potential influencing factors for regret following tubal ligation (TL) in Iranian women. In this cross-sectional study, 166 women with TL were subdivided into two groups including women with poststerilization regret (n=41) and women without poststerilization regret (n=125). They were selected from a health care center in Guilan province (Iran) during 2015-2016. Menstrual blood loss was measured using the Pictorial Blood Loss Assessment Chart (PBLAC) and through a self-administered questionnaire. In addition, sexual function was assessed by the Female Sexual Function Index (FSFI), and psychological distress was measured by employing the Hospital Anxiety and Depression Scale (HADS). Student's t test and Chi-square test were used to reveal the statistical differences between the two groups. We used logistic regression to determine the influencing factors associated with regretting sterilization. Women with poststerilization regret had more menorrhagia (78 vs. 57.6%, P=0.03) than those who did not regret sterilization. A significant difference was found in sexual dysfunction in orgasm (P=0.02), satisfaction (P=0.004), pain (P=0.02), and total FSFI scores (P=0.007) between the two groups. Also, there was a significant difference between the two groups in anxiety, depression and total scores HADS (P=0.01). In the logistic regression model, age of sterilization [odds ratio (OR=2.67), confidence interval (CI): 1.03-7.81, P=0.04)], pre-sterilization counseling (OR=19.92, CI: 6.61-59.99, P<0.001), score of PBLAC (OR=1.01, CI: 1.004-1.01, P=0.001), the number of days of bleeding (OR=1.37, CI: 1.01-1.99, P=0.04), and the length of menstrual cycles (OR=0.91, CI: 0.84-0.99, P=0.03) were significantly associated with regretting sterilization. Complications due to sterilization are the main causes of regret; therefore, it is necessary to pay due attention to mentioning the probable complications of the procedures such as menstruation disorders, sexual dysfunction, and anxiety and depression in women during pre-sterilization counseling.


Fish (Oncorhynchus mykiss) spermatozoa cryoprotectant-free vitrification: stability of mitochondrion as criterion of effectiveness.
The aim of the present investigations was to test a novel technology comprising cryoprotectant-free vitrification of the spermatozoa of rainbow trout and to study the ability of sucrose and components of seminal plasma to protect these cells from cryoinjuries. Spermatozoa were isolated and vitrified using five different mediums: Group 1: standard buffer for fish spermatozoa, Cortland(®)-medium (CM, control); Group 2: CM+1% bovine serum albumin (BSA); Group 3: CM+1% BSA+0.125 M sucrose; Group 4: CM+1% BSA+40% seminal plasma; and Group 5: CM+1% BSA+40% seminal plasma+0.125 M sucrose. For cooling, 20 μL suspensions of cells from each group were dropped directly into liquid nitrogen. For warming, the spheres containing the cells were quickly submerged in CM+1% BSA at 37 °C with gentle agitation. The quality of spermatozoa before and after vitrification was analysed by the evaluation of motility, cytoplasmic membrane integrity (SYBR-14/propidium iodide staining technique), and mitochondrial membrane integrity (JC-1 staining). Motility (86%, 71%, 80%, 81%, and 82%, for Groups 1, 2, 3, 4, and 5, respectively) and cytoplasmic membrane integrity (90%, 82%, 83%, 84%, and 87%, respectively) of spermatozoa in all the 5 groups were not decreased significantly. All tested solutions can be used for vitrification of fish spermatozoa with good post-warming motility and cytoplasmic membrane integrity. However, mitochondrial membrane potentials of the spermatozoa in Groups 1, 2, 3, 4, and 5 were changed significantly (6%, 50%, 37%, 55%, and 34%, respectively) (P(1,2,3,4,5)<0.001; P(2,3,4,5) <0.01)(P(3-5)>0.1). This rate was maximal in Group 4 (CM+1% BSA+40% seminal plasma). In conclusion, this is the first report about successful cryoprotectant-free cryopreservation of fish spermatozoa by direct plunging into liquid nitrogen (vitrification). Vitrification of fish spermatozoa without permeable cryoprotectants is a prospective direction for investigations: these cells can be successfully vitrified with 1% BSA+40% seminal plasma without significant loss of important physiological parameters.


A comparison of the effects of 2 doses of soy protein or casein on serum lipids, serum lipoproteins, and plasma total homocysteine in hypercholesterolemic subjects.
Studies have shown that soy protein reduces some atherogenic lipid and lipoprotein concentrations, although lipoprotein(a) concentrations may be increased. The dose response of soy protein has not been established; neither has its effect on plasma total homocysteine. Our objective was to evaluate the effect of 2 doses of soy protein on lipid, lipoprotein, and homocysteine concentrations. Four to 24 wk after being instructed to consume a lipid-lowering diet, 130 men and women with LDL-cholesterol concentrations > or = 4 mmol/L were studied during a parallel group trial in which 4 interventions were assigned randomly. Thirty grams isolated soy protein (ISP) and 10 g cotyledon fiber or 50 g ISP and 16.6 g cotyledon fiber or equivalent doses of casein and cellulose were consumed daily as a beverage for 16 wk. When the 2 groups who consumed ISP were compared with the 2 groups who consumed casein, the differences in the net changes from baseline to week 16 in the concentrations of LDL cholesterol and plasma total homocysteine were -0.26 mmol/L (95% CI: -0.43, -0.09 mmol/L; P = 0.01) and -0.8 micromol/L (-1.4, -0.2 micromol/L; P = 0.005), respectively. The effect of the ISP dose was not significant. There were no significant differences between the 2 ISP and the 2 casein groups in changes in lipoprotein(a), HDL-cholesterol, or triacylglycerol concentrations. Adding 30-50 g soy protein/d to a lipid-lowering diet significantly reduced LDL-cholesterol concentrations without increasing lipoprotein(a) concentrations. Plasma total homocysteine concentrations also decreased, suggesting a novel, possibly antiatherosclerotic effect.


Silencing Fc Domains in T cell-Engaging Bispecific Antibodies Improves T-cell Trafficking and Antitumor Potency.
Bispecific antibodies (BsAb) that engage T cells bind to tumor cells via a tumor-associated antigen and to T cells through surface CD3. BsAbs have promising antitumor properties in vivo Here, we describe the effects of Fc silencing on BsAb-driven T-cell trafficking to solid tumors. We used BsAbs specific for disialoganglioside GD2 or oncoprotein ErbB2 (HER2) and built on the IgG(L)-scFv platform with or without Fc silencing. We studied the kinetics of T-cell infiltration from blood into solid tumor masses when driven by these BsAbs. We also investigated the therapeutic efficacy of these BsAbs in two mouse models: immunodeficient mice xenografted with patient-derived GD2+ neuroblastoma or HER2+ breast cancer, and human CD3ε transgenic mice implanted with a GD2+ murine tumor. BsAbs built with intact Fc domain were unable to drive T cells to tumor, thereby failing to achieve an antitumor effect in mice. T cells became sequestered in lungs by myeloid cells or depleted in circulation. In contrast, when Fc function was silenced by N297A ± K322A mutations, T cells were able to infiltrate into subcutaneous solid tumors, a prerequisite for successful therapy outcome.


MicroRNA-31 is a transcriptional target of histone deacetylase inhibitors and a regulator of cellular senescence.
MicroRNAs (miRNAs) have emerged as important regulators of tumorigenesis. Several miRNAs, which can function either as oncomiRs or tumor suppressive miRs are deregulated in cancer cells. The microRNA-31 (miR-31) has been shown to be overexpressed in metastatic breast cancer. It promotes multiple oncogenic phenotypes, including proliferation, motility, and invasion of cancer cells. Using a breast cancer-related miRNA array analysis, we identified miR-31 as a novel target of histone deacetylase inhibitors (HDACi) in breast cancer cells. Specifically, we show that sodium butyrate (NaB) and panobinostat (LBH589), two broad-spectrum HDAC inhibitors up-regulate hsa-miR-31 (miR-31). The up-regulation of miR-31 was accompanied by repression of the polycomb group (PcG) protein BMI1 and induction of cellular senescence. We further show that inhibition of miR-31 overcomes the senescence-inducing effect of HDACi, and restores expression of the PcG protein BMI1. Interestingly, BMI1 also acts as a repressor of miR-31 transcription, suggesting a cross-negative feedback loop between the expression of miR-31 and BMI1. Our data suggest that miR-31 is an important physiological target of HDACi, and that it is an important regulator of senescence relevant to cancer. These studies further suggest that manipulation of miR-31 expression can be used to modulate senescence-related pathological conditions such as cancer, and the aging process.


Binding of methotrexate to dihydrofolate reductase and its relation to protonation of the ligand.
Stopped-flow spectrophotometry and stopped-flow fluorometry have been used to study the binding of methotrexate (MTX) and 3-deazamethotrexate (3-deazaMTX) to dihydrofolate reductase (DHFR) isoenzymes from Streptococcus faecium and from Lactobacillus casei. The absorbance change and fluorescence quenching that occur when MTX binds to DHFR isoenzyme II from S. faecium (SFDHFR II) are both biphasic and give similar apparent rate constants for both phases. The faster phase has an apparent rate constant that is dependent on MTX concentration and therefore corresponds to the initial binding reaction. From the concentration dependence it has been calculated that the association rate constant is 3.0 X 10(5) M-1 s-1 at 20 degrees C and pH 7.3, and the association constant (equilibrium constant) under these conditions is 5.8 X 10(5) M-1. By examination of the amplitude of the fast-phase absorbance change at various wavelengths, it has been determined that the absorbance change occurring in the fast phase is due to MTX protonation. Within the limits of the method it was thus not possible to detect a difference in the rates of binding and of protonation of MTX. The MTX association rate constant is pH dependent, decreasing 330-fold as the pH is decreased from 5.0 to 9.0. The data fit well to a curve generated by assuming a single ionization with a pKa of 6.0 and a pH-independent association rate constant 1000-fold greater for binding of protonated MTX to SFDHFR II than for binding of unprotonated MTX.(ABSTRACT TRUNCATED AT 250 WORDS)


[Acute transverse myelitis in patients with systemic lupus erythematosus].
The authors provide disease histories of 4 patients afflicted with genuine systemic lupus erythematosus (SLE). There were 2 men and 2 women who developed acute transverse myelitis (ATM) at an age of 24 to 31 years. Before ATM developed, SLE standing was from 3 to 10 years. Based on the authors' and reported data, the problems of the pathogenesis, clinical picture, diagnosis and prognosis in that grave complication of SLE are discussed. As for the mechanisms of ATM development, the role of antiphospholipid antibodies is reviewed. The data on familial aggravation of the patients are presented in terms of the development of the antiphospholipid syndrome in their relatives. Emphasis is laid on the necessity of early intensive care with glucocorticoid hormones and cyclophosphamide of patients with associated SLE and ATM in order to improve their prognosis.


Binding of Ni2+ and Cu2+ ions to peptides with a Cys-His motif.
Waglerin I is a 22 amino acid snake venom toxin. Its three fragments (GGKPDLRPCHP-NH2, PCHYIPRPKPR-NH2, PCHPPCHYIPR-NH2), due to the presence of two Cys and His residues, are potentially very attractive ligands for transition metal ions. The main aim of this work was to establish the impact of these two adjacent residues on Ni2+ ion binding, especially because this kind of motif is very common in nature, and the study of low molecular weight models could be helpful in understanding larger systems. In this work waglerin fragments and their N-protected analogues were studied with Ni2+ (and Cu2+ for peptides with disulfide bridges) ions using combined potentiometric and spectroscopic measurements (UV-Vis, CD, EPR and NMR). In all peptides, except PCHPPCHYIPR-NH2 with a disulfide bridge, the Cys-His motif was found to be crucial for the coordination of Ni2+ ions. In the case of the N-unprotected analogues, the N-terminal amino group participates in the coordination as well.


Fibroblast growth factor-23 and incident coronary heart disease, heart failure, and cardiovascular mortality: the Atherosclerosis Risk in Communities study.
Fibroblast growth factor-23 (FGF-23) is a hormone involved in phosphorous regulation and vitamin D metabolism that may be associated with cardiovascular risk, and it is a potential target for intervention. We tested whether elevated FGF-23 is associated with incident coronary heart disease, heart failure, and cardiovascular mortality, even at normal kidney function. A total of 11 638 Atherosclerosis Risk In Communities study participants, median age 57 at baseline (1990-1992), were followed through 2010. Cox regression was used to evaluate the independent association of baseline serum active FGF-23 with incident outcomes. Models were adjusted for traditional cardiovascular risk factors and estimated glomerular filtration rate. During a median follow-up of 18.6 years, 1125 participants developed coronary heart disease, 1515 developed heart failure, and 802 died of cardiovascular causes. For all 3 outcomes, there was a threshold, whereby FGF-23 was not associated with risk at <40 pg/mL but was positively associated with risk at >40 pg/mL. Compared with those with FGF-23 <40 pg/mL, those in the highest FGF-23 category (≥ 58.8 pg/mL) had a higher risk of incident coronary heart disease (adjusted hazard ratio, 95% CIs: 1.65, 1.40 to 1.94), heart failure (1.75, 1.52 to 2.01), and cardiovascular mortality (1.65, 1.36 to 2.01). Associations were modestly attenuated but remained statistically significant after further adjustment for estimated glomerular filtration rate. In stratified analyses, similar results were observed in African Americans and among persons with normal kidney function. High levels of serum FGF-23 were associated with increased risk of coronary heart disease, heart failure, and cardiovascular mortality in this large, biracial, population-based cohort. This association was independent of traditional cardiovascular risk factors and kidney function.


Comparing the Performance of Indoor Localization Systems through the EvAAL Framework.
In recent years, indoor localization systems have been the object of significant research activity and of growing interest for their great expected social impact and their impressive business potential. Application areas include tracking and navigation, activity monitoring, personalized advertising, Active and Assisted Living (AAL), traceability, Internet of Things (IoT) networks, and Home-land Security. In spite of the numerous research advances and the great industrial interest, no canned solutions have yet been defined. The diversity and heterogeneity of applications, scenarios, sensor and user requirements, make it difficult to create uniform solutions. From that diverse reality, a main problem is derived that consists in the lack of a consensus both in terms of the metrics and the procedures used to measure the performance of the different indoor localization and navigation proposals. This paper introduces the general lines of the EvAAL benchmarking framework, which is aimed at a fair comparison of indoor positioning systems through a challenging competition under complex, realistic conditions. To evaluate the framework capabilities, we show how it was used in the 2016 Indoor Positioning and Indoor Navigation (IPIN) Competition. The 2016 IPIN competition considered three different scenario dimensions, with a variety of use cases: (1) pedestrian versus robotic navigation, (2) smartphones versus custom hardware usage and (3) real-time positioning versus off-line post-processing. A total of four competition tracks were evaluated under the same EvAAL benchmark framework in order to validate its potential to become a standard for evaluating indoor localization solutions. The experience gained during the competition and feedback from track organizers and competitors showed that the EvAAL framework is flexible enough to successfully fit the very different tracks and appears adequate to compare indoor positioning systems.


A high physical workload and high job demands hamper the good prognosis in physical functioning in persons with early inflammatory joint conditions.
To determine the influence of job characteristics on the prognosis of patients with early inflammatory joint conditions. In a prospective cohort study of 210 workers with inflammatory joint conditions present for <12 months, data were collected by questionnaires and medical examination at baseline and after 6 and 12 months. Outcomes were self-reported pain and physical functioning, and the presence of at least one swollen joint. Generalized estimation equations were used to study the influence of job characteristics on prognosis in pain and function, and logistic regression analysis to study prognosis in swollen joints. Pain and physical functioning strongly improved during the first 6-month period (40 and 14%, respectively), and improvement slowed considerably in the second 6-month period. The proportion of workers with swollen joints dramatically decreased from 58 to 20 then 7%. The good prognosis in pain and physical functioning in the first 6 months was hampered by persistent high levels of inflammation, older age, low perceived health control and low social support. Job characteristics had no influence on the prognosis of pain and swollen joints, whereas workers with frequent manual material handling or high job demands improved ∼50% less in physical functioning. Job characteristics had no influence on the disease characteristics pain and swollen joints, but strongly affected the consequences of disease in physical functioning. Among patients with early inflammatory joint conditions, who do not recover in functional abilities, adjustments in working conditions may be imperative.


Cardiac pacing--from then to now.
Progress in both the health sciences and engineering sciences has been necessary for the development of the cardiac pacemaker. From the invention of the vacuum tube triode amplifier in 1906 to that of the oscillator just a few years later; from the early electrocardiograph in 1906 and the first stimulation of a dog's heart in 1927 to the application of electricity to the heart of a stillborn infant only 2 years later, engineering and medicine have progressed together to solve problems in pacemakers. The semiconductor transistor emerged in 1948, and in 1950 work was published on the open heart resuscitation of dogs with voltage pulses to the heart, work whose principle was applied soon after in a human patient with complete heart block. The development of the modern pacemaker has run an exciting course, including such phenomena as one engineer helping to design his own pacemaker. In the past 20 years, science has change the package, the power source, pacing mode, electrodes, and leads of pacemakers; it has improved their reliability and longevity, their programming, telemetry, and instrumentation.


Effects of acute exercise on endothelial function in patients with abdominal aortic aneurysm.
Endothelial dysfunction is observed in patients with abdominal aortic aneurysm (AAA), who have increased risk of cardiovascular events and mortality. This study aimed to assess the acute effects of moderate- and higher-intensity exercise on endothelial function, as assessed by flow-mediated dilation (FMD), in AAA patients (74 ± 6 yr old, n = 22) and healthy adults (72 ± 5 yr old, n = 22). Participants undertook three randomized visits, including moderate-intensity continuous exercise [40% peak power output (PPO)], higher-intensity interval exercise (70% PPO), and a no-exercise control. Brachial artery FMD was assessed at baseline and at 10 and 60 min after each condition. Baseline FMD was lower [by 1.10% (95% confidence interval: 0.72-.81), P = 0.044] in AAA patients than in healthy adults. There were no group differences in FMD responses after each condition ( P = 0.397). FMD did not change after no-exercise control but increased by 1.21% (95% confidence interval: 0.69-1.73, P < 0.001) 10 min after moderate-intensity continuous exercise in both groups and returned to baseline after 60 min. Conversely, FMD decreased by 0.93% (95% confidence interval: 0.41-1.44, P < 0.001) 10 min after higher-intensity interval exercise in both groups and remained decreased after 60 min. We found that the acute response of endothelial function to exercise is intensity-dependent and similar between AAA patients and healthy adults. Our findings provide evidence that regular exercise may improve vascular function in AAA patients, as it does in healthy adults. Improved FMD after moderate-intensity exercise may provide short-term benefit. Whether the decrease in FMD after higher-intensity exercise represents an additional risk and/or a greater stimulus for vascular adaptation remains to be elucidated. NEW & NOTEWORTHY Abdominal aortic aneurysm patients have vascular dysfunction. We observed a short-term increase in vascular function after moderate-intensity exercise. Conversely, higher-intensity exercise induced a prolonged reduction in vascular function, which may be associated with both short-term increases in cardiovascular risk and signaling for longer-term vascular adaptation in abdominal aortic aneurysm patients.


Impact of introducer sheath coating on endothelial function in humans after transradial coronary procedures.
The aim of this study was to compare the impact of transradial catheterization with hydrophilic-coated catheter sheaths versus uncoated sheaths on NO-mediated endothelial-dependent and -independent vasodilator function. Thirty-five subjects undergoing transradial catheterization were recruited and assessed before and the day after catheterization. A subgroup was also assessed 3 to 4 months after catheterization. Subjects received hydrophilic-coated sheaths (n=15) or uncoated sheaths (n=20). Radial artery flow-mediated dilatation and endothelium- and NO-dependent arterial dilatation were assessed within the region of sheath placement. Glyceryl trinitrate endothelium-independent NO-mediated function was also assessed. The noncatheterized arm provided an internal control. Flow-mediated dilatation in the catheterized arm decreased from 10.3+/-3.8% to 5.3+/-3.3% and 8.1+/-2.4% to 5.2+/-3.7% in the coated and uncoated groups, respectively (P<0.01). These values returned toward baseline levels approximately 3 months later (coated, 6.4+/-1.4%; uncoated, 9.4+/-4.1%; P<0.05) versus postprocedure. Glyceryl trinitrate decreased from 14.8+/-7.2% to 9.5+/-4.1% (P<0.05) in the coated group and from 12.2+/-4.6% to 7.5+/-4.2% (P<0.01) in the uncoated group. Values returned to baseline at approximately 3 months (coated, 16.6+/-5.6%; uncoated, 12.1+/-3.9%; P<0.05). There was no difference in the magnitude of decrease in flow-mediated dilatation or glyceryl trinitrate between coated and uncoated groups. No changes in function occurred in the noncatheterized arm. Placement of a catheter sheath inside the radial artery disrupts vasodilator function, which recovers after 3 months. No differences were evident between hydrophilic-coated and uncoated sheaths.


Inflammatory abdominal aortic aneurysm.
The inflammatory abdominal aortic aneurysm has received little attention in the literature. To date only four reports have addressed the subject specifically. Controversy remains as to whether this is a variant of the usual atherosclerotic aneurysm or a separate entity. The operative reports of 24 patients with inflammatory abdominal aortic aneurysms are reviewed; 21 were intact and 3 ruptured. Intact aneurysms ranged in diameter from 5 to 12 cm and the ruptured ones from 5 to 10 cm. Nine patients with intact aneurysms had symptoms of abdominal or back pain. Of 13 patients who underwent excretory pyelography before operation, only 3 had evidence of obstruction. Nine patients had tube grafts placed, 10 had aortoiliac grafts and 5 aortofemoral grafts. There was one intraoperative duodenal injury and in another patient it was necessary to divide the left renal vein for proximal exposure. No attempt was made to expose the ureters at operation. All patients were discharged from hospital. The authors believe that the inflammatory aneurysm is a variant of the abdominal aortic arteriosclerotic aneurysm. Intraoperative complications can be avoided by the recognition of the pathological features.


An alternative to synthetic aortic grafts using jejunum.
Synthetic materials currently used for arterial grafts can provoke serious complications such as infection, rejection, and incomplete reendothelialization. Porcine small intestinal submucosa (SIS) allografts (homografts) may not share these disadvantages yet still may provide an effective graft alternative. This study was designed to provide additional information concerning the performance of this material when used as an allo-patch graft. A porcine model was selected to enable hemodynamic comparisons to the adult human physiology. Slaughterhouse small intestine was used to prepare the SIS graft material. A well-vascularized section ofjejunum was resected, rinsed, and maintained in 0.9% NaCl solution containing 10% gentamicin. The graft was prepared by removing the serosal layer, inverting the material, and discarding the mucosal surface in a similar manner. The remaining submucosa and stratum compactum constituted the graft material and was subdivided into sizes from 1.5 to 3.0 cm2 tacked to foil for manageability, and was returned to the gentamicin solution. The surgery was initiated with a femoral arterial line in the anesthetized swine, followed by isolation and preparation of the infrarenal aorta for grafting. Cross-clamps were applied and a 1.0 x 1.5-cm section of aortic wall was resected. Two sides of allograft were freed from the foil and sewn into the aorta. Then the remaining sides were removed from the foil and final graft placement was completed. The graft was harvested at postoperative day 28 and presented for microscopic examination. Results confirmed that reendothelialization with neovascularization had occurred during this interval.


New application of in silico methods in identifying mechanisms of action and key components of anti-cancer herbal formulation YIV-906 (PHY906).
YIV-906 (formally PHY906, KD018) is a four-herb formulation that is currently being developed to improve the therapeutic index and ameliorate the side effects of many chemotherapeutic drugs including sorafenib, irinotecan, and capecitabine. However, as a promising anti-cancer adjuvant, the molecular mechanism of action of YIV-906 remains unrevealed due to its multi-component and multi-target features. Since YIV-906 has been shown to induce apoptosis and autophagy in cancer cells through modulating the negative regulators of ERK1/2, namely DUSPs, it is of great interest to elucidate the key components that cause the therapeutic effect of YIV-906. In this work, we investigated the mechanism of YIV-906 inhibiting DUSPs, using a broad spectrum of molecular modelling techniques, including molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations. In total, MD simulations and binding free energy calculations were performed for 99 DUSP-ligand complexes. We found that some herbal components or their metabolites could inhibit DUSPs. Based on the docking scores and binding free energies, the sulfation and glucuronidation metabolites of the S ingredient in YIV-906 play a leading role in inhibiting DUSPs, although several original herbal chemicals with carboxyl groups from the P and Z ingredients also make contributions to this inhibitory effect. It is not a surprise that the electrostatic interaction plays the dominant role in the ligand binding process, given the fact that several charged residues reside in the binding pockets of DUSPs. Our MD simulation results demonstrate that the sulfate moieties and carboxyl moieties of the advantageous ligands from YIV-906 can occupy the enzymes' catalytic sites, mimicking the endogenous phosphate substrates of DUSPs. As such, the ligand binding can inhibit the association of DUSPs and ERK1/2, which in turn reduces the dephosphorylation of ERK1/2 and causes cell cycle arrest in the tumor. Our modelling study provides useful insights into the rational design of highly potent anti-cancer drugs targeting DUSPs. Finally, we have demonstrated that multi-scale molecular modelling techniques are able to elucidate molecular mechanisms involving complex molecular systems.


Astrocytic Glutamatergic Transmission and Its Implications in Neurodegenerative Disorders.
Several neurodegenerative disorders involve impaired neurotransmission, and glutamatergic neurotransmission sets a prototypical example. Glutamate is a predominant excitatory neurotransmitter where the astrocytes play a pivotal role in maintaining the extracellular levels through release and uptake mechanisms. Astrocytes modulate calcium-mediated excitability and release several neurotransmitters and neuromodulators, including glutamate, and significantly modulate neurotransmission. Accumulating evidence supports the concept of excitotoxicity caused by astrocytic glutamatergic release in pathological conditions. Thus, the current review highlights different vesicular and non-vesicular mechanisms of astrocytic glutamate release and their implication in neurodegenerative diseases. As in presynaptic neurons, the vesicular release of astrocytic glutamate is also primarily meditated by calcium-mediated exocytosis. V-ATPase is crucial in the acidification and maintenance of the gradient that facilitates the vesicular storage of glutamate. Along with these, several other components, such as cystine/glutamate antiporter, hemichannels, BEST-1, TREK-1, purinergic receptors and so forth, also contribute to glutamate release under physiological and pathological conditions. Events of hampered glutamate uptake could promote inflamed astrocytes to trigger repetitive release of glutamate. This could be favorable towards the development and worsening of neurodegenerative diseases. Therefore, across neurodegenerative diseases, we review the relations between defective glutamatergic signaling and astrocytic vesicular and non-vesicular events in glutamate homeostasis. The optimum regulation of astrocytic glutamatergic transmission could pave the way for the management of these diseases and add to their therapeutic value.


Application of the boron center for the design of a covalently bonded closely spaced triad of porphyrin-fullerene mediated by dipyrromethane.
Two novel triads had been designed through covalent bond connection of the boron dipyrromethane (BODIPY), free base porphyrin (H2P) or zinc(ii) porphyrin (ZnP) and N-methyl-2-phenyl-3,4-fulleropyrrolidine (C60) mediated by BODIPY. This closely spaced triad arrangement where porphyrin and fullerene are placed apart is anticipated to stabilize charge separation by separating the two radicals from each other. Two model polyads were synthesized with BODIPY and H2P or ZnP to investigate interaction between the two chromophores. Photo-excitation of the BODIPY triggered an efficient singlet energy transfer where the rates are found to be ∼1010-1011 s-1. For triads with C60 fast electron transfer was confirmed by the detection of the C60˙- signature from femtosecond transient absorption (fs-TA) in ∼0.4-3 ps. The charge recombination is estimated to be in the nanosecond window. This indicates the convenience of this arrangement for stabilizing the charge-separated state.


[The nurse--construction of a behavior model, based on the medical discourse at the beginning of the century].
The purpose of this study is to trace a parallel between the medical discourse content and the expected and stereotyped nurses behavior at the beginning of the twentieth century. It is a historic-social approach in which authors analysed the speeches used by nurses and physicians at nursing and medicine schools. The analysis of the physicians discourse compared to nurses discourse revealed the formation of a mentality shaped by the medical power that wanted them "holy" and servile.


Gender, religion, and adolescent patterns of self-disclosure in the divided society of Northern Ireland.
Adolescence is a period when levels of self-disclosure are often lowest. While studies have revealed a clear preference for female targets of disclosure, little research has been carried out on the effects of religion upon disclosure. The impact of religion was of importance in this investigation, given that it was conducted in Northern Ireland, where religion affects almost every aspect of social life. The aim was to ascertain the effects of gender and religious affiliation on adolescent disclosure to friends and strangers. Results revealed that while females were significantly higher disclosers than were males, religion per se did not play a key role. This suggests that even in a highly polarized society, gender is the central determinant of disclosure and is even more important than political identity. The implications of these findings are discussed, particularly with regard to the difficulty young males have in terms of revealing personal information.


The adaptive response modifies latency for radiation-induced myeloid leukemia in CBA/H mice.
We have investigated the effect of the adaptive response on acute myeloid leukemia (AML) induced in CBA/Harwell mice by a chronic radiation exposure. Groups of mice irradiated with a total dose of 1. 0 Gy at two different chronic dose rates (0.5, 0.004 Gy/h) had similar frequencies of AML. Compared to control animals that did not develop AML, irradiation at either of these dose rates did not change the longevity of the mice that did not die of leukemia. The survival rates of irradiated mice that did develop leukemia in the two groups were not different from each other, indicating that the dose rates produced similar responses and therefore were both chronic exposures. We then tested the ability of a chronic 10-cGy (0. 5 Gy/h) exposure to ionizing radiation, mild hyperthermia (40.5 degrees C whole-body, 60 min) or treatment with interleukin-1 (1500 U i.p.) to induce an adaptive response and modify the frequency or latency of AML which resulted from a subsequent (24 h later) 1.0-Gy (0.5 Gy/h) chronic radiation exposure. The frequency of radiation-induced leukemia was not changed in mice given any of the three adapting treatments 24 h prior to the chronic 1.0-Gy dose that induced leukemia. However, the latent period for development of AML was significantly increased by both the prior low radiation dose and mild hyperthermia treatment. Injection of interleukin-1, in contrast, may have reduced the latent period. Similar to the single 1.0-Gy chronic exposure alone, none of the adapting treatments prior to that exposure influenced the survival of animals that did not develop AML. These results indicate that an earlier exposure to a small adapting dose of radiation or to a mild heat stress can influence secondary steps in radiation-induced carcinogenesis.


The impact of zero-valent iron nanoparticles on a river water bacterial community.
Zero-valent iron (ZVI) nanoparticles are of interest because of their many potential biomedical and environmental applications. However, these particles have recently been reported to be cytotoxic to bacterial cells. The overall objective of this study was to determine the impact of 100mg/L ZVI nanoparticles on the diversity and structure of an indigenous river water bacterial community. Response during exposure for 36 days was determined by denaturing gel gradient electrophoresis (DGGE) analysis of bacterial 16S rRNA genes, amplified from extracted DNA, and viable and total cell abundances were determined by plate counting and fluorescent microscopy of DAPI-stained cells. Changes in river water chemistry were also monitored. Addition of ZVI nanoparticles led to a rapid decrease in oxidation-reduction potential (ORP) (+196 to -281 mV) and dissolved oxygen (DO) concentration (8.2-0.6 mg/L), both of which stabilized during the experiment. Interestingly, both viable and total bacterial cell abundances increased and pH decreased, characteristic of an active microbial community. Total community structure was visualized using rank-abundance plots fitted with linear regression models. The slopes of the regression models were used as a descriptive statistic of changes in evenness over time. Importantly, despite bacterial growth, addition of ZVI nanoparticles did not influence bacterial community structure.


Assembly of monomeric acetylcholinesterase into tetrameric and asymmetric forms.
A pulse-chase experiment was performed in embryonic rat myotube cultures to examine possible precursor-product relationships among the various molecular forms of acetylcholinesterase (AChE). AChE was labeled with paraoxon, a compound which diethylphosphorylates AChE at its active site. Diethylphosphorylated (labeled) AChE is inactive but can be reactivated by treatment with 1-methyl-2-hydroxyiminomethyl-pyridinium. Thus labeled enzyme could be followed as AChE that regained activity following treatment with 1-methyl-2-hydroxyiminomethylpyridium. To selectively label monomeric AChE (the hypothesized precursor form), cultures were treated with methanesulfonylfluoride which irreversibly inactivated more than 97% of total cellular AChE. Methylsulfonylfluoride was then washed from the cultures, and they were labeled with paraoxon during a 40-55-min recovery period. AChE appearing in the cultures during this recovery period is newly synthesized and consists almost entirely (92%) of the monomeric form. Immediately and 120-130 min after labeling, cultures were subjected to a sequential extraction procedure to separate globular from asymmetric forms. Individual forms were then separated by velocity sedimentation on sucrose gradients. In our first series of experiments, we observed a 55% decrease in labeled monomers during the chase, a 36% increase in labeled tetramers, and a 36% increase in labeled asymmetric forms. In a second series of experiments focused on individual asymmetric forms, we observed a 55% decrease in labeled monomers, a 58% increase in labeled tetramers, an overall increase of 81% in labeled asymmetric forms, and a 380% increase in labeled A12 AChE. These data provide the first uniequivocal proof that complex forms of AChE are assembled from active monomeric precursors.


Sexual differences in dental development and prediction of emergence.
The dental development of a genetically homogeneous French-Canadian group of children ranging in age from 2.5 to 19 years was evaluated from 5,437 panoramic radiographs by the method of Demirjian et al. The maturity of each mandibular tooth was evaluated individually. For each stage of each tooth, the developmental curves of boys and girls were compared. A common pattern was found for each tooth, namely the chronological similarity between boys and girls in the early stages of development and the advancement of girls over boys for the later stages. Development scores were given to the seven mandibular teeth. Up to five to six years of age, no difference was found in the timing of dental development between boys and girls, in contrast to the older ages where girls were always more developed than boys. When the emergence curve was plotted with developmental curves, a close relation was established between the stage of formation of all teeth and their emergence, hence the predictive value of the use of dental maturity curves in clinics.


Stepwise asynchronous telehealth assessment of patients with suspected axial spondyloarthritis: results from a pilot study.
Patients with axial spondyloarthritis (axSpA) suffer from one of the longest diagnostic delays among all rheumatic diseases. Telemedicine (TM) may reduce this diagnostic delay by providing easy access to care. Diagnostic rheumatology telehealth studies are scarce and largely limited to traditional synchronous approaches such as resource-intensive video and telephone consultations. The aim of this study was to investigate a stepwise asynchronous telemedicine-based diagnostic approach in patients with suspected axSpA. Patients with suspected axSpA completed a fully automated digital symptom assessment using two symptom checkers (SC) (bechterew-check and Ada). Secondly, a hybrid stepwise asynchronous TM approach was investigated. Three physicians and two medical students were given sequential access to SC symptom reports, laboratory and imaging results. After each step, participants had to state if axSpA was present or not (yes/no) and had to rate their perceived decision confidence. Results were compared to the final diagnosis of the treating rheumatologist. 17 (47.2%) of 36 included patients were diagnosed with axSpA. Diagnostic accuracy of bechterew-check, Ada, TM students and TM physicians was 47.2%, 58.3%, 76.4% and 88.9% respectively. Access to imaging results significantly increased sensitivity of TM-physicians (p < 0.05). Mean diagnostic confidence of false axSpA classification was not significantly lower compared to correct axSpA classification for both students and physicians. This study underpins the potential of asynchronous physician-based telemedicine for patients with suspected axSpA. Similarly, the results highlight the need for sufficient information, especially imaging results to ensure a correct diagnosis. Further studies are needed to investigate other rheumatic diseases and telediagnostic approaches.


Preclinical Models of Visceral Sarcomas.
Visceral sarcomas are a rare malignant subgroup of soft tissue sarcomas (STSs). STSs, accounting for 1% of all adult tumors, are derived from mesenchymal tissues and exhibit a wide heterogeneity. Their rarity and the high number of histotypes hinder the understanding of tumor development mechanisms and negatively influence clinical outcomes and treatment approaches. Although some STSs (~20%) have identifiable genetic markers, as specific mutations or translocations, most are characterized by complex genomic profiles. Thus, identification of new therapeutic targets and development of personalized therapies are urgent clinical needs. Although cell lines are useful for preclinical investigations, more reliable preclinical models are required to develop and test new potential therapies. Here, we provide an overview of the available in vitro and in vivo models of visceral sarcomas, whose gene signatures are still not well characterized, to highlight current challenges and provide insights for future studies.


Complete percutaneous treatment of vertebral body tumors causing spinal canal compromise using a transpedicular cavitation, cement augmentation, and radiosurgical technique.
Patients with symptomatic pathological compression fractures require spinal stabilization surgery for mechanical back pain control and radiation therapy for the underlying malignant process. Spinal radiosurgery provides excellent long-term radiographic control for vertebral metastases. Percutaneous cement augmentation using polymethylmethacrylate (PMMA) may be contraindicated in lesions with spinal canal compromise due to the risk of displacement of tumor resulting in spinal cord or cauda equina injury. However, there is also significant morbidity associated with open corpectomy procedures in patients with metastatic cancer, especially in those who subsequently require adjuvant radiotherapy. This study evaluated a treatment paradigm for malignant vertebral compression fractures consisting of transpedicular coblation corpectomy combined with closed fracture reduction and fixation, followed by spinal radiosurgery. Eleven patients (6 men and 5 women, mean age 58 years) with symptomatic vertebral body metastatic tumors associated with moderate spinal canal compromise were included in this study (8 thoracic levels, 3 lumbar levels). Primary histologies included 4 lung, 2 breast, 2 renal, and 1 each of thyroid, bladder, and hepatocellular carcinomas. All patients underwent percutaneous transpedicular coblation corpectomy immediately followed by balloon kyphoplasty through the same 8-gauge cannula under fluoroscopic guidance. Patients subsequently underwent radiosurgery to the affected vertebral body (mean time to treatment 14 days). Postoperatively, patients were assessed for pain reduction and neurological morbidity. There were no complications associated with any part of the procedure. Adequate cement augmentation within the vertebral body was achieved in all cases. The mean radiosurgical tumor dose was 19 Gy covering the entire vertebral body. The procedure provided long-term pain improvement and radiographic tumor control in all patients (follow-up range 7-44 months). No patient later required open surgery. No radiation-induced toxicity or new neurological deficit occurred during the follow-up period. CONCLUSIONS This treatment paradigm for pathological fractures of percutaneous transpedicular corpectomy combined with cement augmentation followed by radiosurgery was found to be safe and clinically effective. This technique combines minimally invasive procedures that avoid the morbidity associated with open surgery while providing spinal canal decompression and immediate fracture stabilization, and then administering a single-fraction tumoricidal radiation dose.


Bioanalytical method validation: An updated review.
The development of sound bioanalytical method(s) is of paramount importance during the process of drug discovery and development, culminating in a marketing approval. The objective of this paper is to review the sample preparation of drug in biological matrix and to provide practical approaches for determining selectivity, specificity, limit of detection, lower limit of quantitation, linearity, range, accuracy, precision, recovery, stability, ruggedness, and robustness of liquid chromatographic methods to support pharmacokinetic (PK), toxicokinetic, bioavailability, and bioequivalence studies. Bioanalysis, employed for the quantitative determination of drugs and their metabolites in biological fluids, plays a significant role in the evaluation and interpretation of bioequivalence, PK, and toxicokinetic studies. Selective and sensitive analytical methods for quantitative evaluation of drugs and their metabolites are critical for the successful conduct of pre-clinical and/or biopharmaceutics and clinical pharmacology studies.


Study of Red Cell Fragility in Different Stages of Chronic Kidney Disease in Relation to Parathyroid Hormone.
Anaemia is one of the common complications associated with Chronic Kidney Disease (CKD) responsible for the increase in the morbidity and mortality in such patients. Several factors have been attributed to cause renal anaemia, amongst which hyperparathyroidism is one of the less recognised reasons. Most studies have been conducted in this regard in CKD patients undergoing haemodialysis. The level of PTH in early stages of chronic kidney disease has not been much studied. The excess amount of Parathyroid Hormone (PTH) secondary to CKD has been suggested to be a causative factor for anaemia. To evaluate the serum PTH level in CKD patients before haemodialysis and to study the association of the haemoglobin status with the parathyroid hormone. Forty CKD patients above 18 years of age before haemodialysis and 25 age and sex matched healthy controls were included in the study. Routine biochemical and haematological parameters such as Routine Blood Sugar (RBS), urea, creatinine, Na+, K+, Ca2+, PTH and Hb% were perfomed. Red cell osmotic fragility was measured by serial dilutions of whole blood with varying concentrations of sodium chloride ranging from 0.1% to 0.9%. The study revealed a significant fall in Hb%, along with a rise in Median Osmotic Fragility (MOF) and PTH in the CKD patients when compared to the control group. Linear regression of PTH with Hb% revealed significant negative association between both the parameters with a R2 value of 0.677. Multilinear regression analysis of MOF and other independent variables such as Hb%, Na+, K+, Ca2+, urea, PTH and creatinine highlighted the variance of MOF by 72%, maximal variance contributed by PTH. Receiver Operating Curve (ROC) analysis revealed an area under the curve of 0.980 with a sensitivity of 100% and specificity of 87% in detecting osmotic fragility at a cut off value of PTH ≥100 pg/ml. The underlying cause of anaemia should be identified early in the CKD patients before haemodialysis. Secondary hyperparathyroidism should be ruled out as a causative factor of anaemia to slow down the progression of the disease process.


Ethylene receptor degradation controls the timing of ripening in tomato fruit.
Fruit ripening in tomato requires the coordination of both developmental cues and the phytohormone ethylene. The multigene ethylene receptor family has been shown to negatively regulate ethylene signal transduction and suppress ethylene responses. Here we demonstrate that reduction in the levels of either of two family members, LeETR4 or LeETR6, causes an early-ripening phenotype. We provide evidence that the receptors are rapidly degraded in the presence of ethylene, and that degradation probably occurs through the 26S proteasome-dependent pathway. Ethylene exposure of immature fruits causes a reduction in the amount of receptor protein and earlier ripening. The results are consistent with a model in which receptor levels modulate timing of the onset of fruit ripening by measuring cumulative ethylene exposure.


Conversion of linoleic acid into arachidonic acid by cultured murine and human keratinocytes.
The origin of arachidonic acid (AA) found in the epidermis is not known. Two possibilities exist: either de novo synthesis within the epidermal keratinocyte, or transport of AA formed at distant tissue sites. The current study examined the ability of cultured murine and human keratinocytes to metabolize exogenously added linoleic acid (LA). Conversion of radiolabeled substrate (14C-LA) into 18:3(n-6), 20:2(n-6), 20:3(n-6), and 20:4(n-6) (AA) was noted. The conversion of non-radiolabeled 18:3(n-6) or 20:2(n-6) was also examined and the pattern of metabolites synthesized suggests that the preferred metabolic pathway for conversion of linoleic acid into arachidonic acid is via the classically described pathway in which a delta 6 desaturase constitutes the initial reaction. Although cultured skin fibroblasts are known to convert linoleic acid into arachidonic acid, the current study demonstrates that cultured epidermal keratinocytes can also avidly metabolize exogenous linoleic acid. The ability of cultured keratinocytes, and not of whole epidermis in vivo, to convert linoleic acid into arachidonic acid suggests that specific enzymatic activities may be induced by the tissue culture system itself. Hence, findings of metabolic capabilities in cultured cells may not necessarily be extrapolated to the in vivo situation.


The Gastroprotective Effect of Walnut Peptides: Mechanisms and Impact on Ethanol-Induced Acute Gastric Mucosal Injury in Mice.
The objective of this research was to explore the protective impact of walnut peptides (WP) against ethanol-induced acute gastric mucosal injury in mice and to investigate the underlying defense mechanisms. Sixty male BALB-c mice were divided into five groups, and they were orally administered distilled water, walnut peptides (200 and 400 mg/kg bw), and omeprazole (20 mg/kg bw) for 24 days. Acute gastric mucosal injury was then induced with 75% ethanol in all groups of mice except the blank control group. Walnut peptides had significant protective and restorative effects on tissue indices of ethanol-induced gastric mucosal damage, with potential gastric anti-ulcer effects. Walnut peptides significantly inhibited the excessive accumulation of alanine aminotransferase (ALT), aspartate transferase (AST), and malondialdehyde (MDA), while promoting the expression of reduced glutathione (GSH), total antioxidant capacity (T-AOC), glutathione disulfide (GSSG), and mouse epidermal growth factor (EGF). Furthermore, the Western blot analysis results revealed that walnut peptides significantly upregulated the expression of HO-1 and NQO1 proteins in the Nrf2 signaling pathway. The defensive impact of walnut peptides on the gastric mucosa may be achieved by mitigating the excessive generation of lipid peroxides and by boosting cellular antioxidant activity.


Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study.
Results of intervention studies in patients with type 2 diabetes have led to concerns about the safety of aiming for normal blood glucose concentrations. We assessed survival as a function of HbA(1c) in people with type 2 diabetes. Two cohorts of patients aged 50 years and older with type 2 diabetes were generated from the UK General Practice Research Database from November 1986 to November 2008. We identified 27 965 patients whose treatment had been intensified from oral monotherapy to combination therapy with oral blood-glucose lowering agents, and 20 005 who had changed to regimens that included insulin. Those with diabetes secondary to other causes were excluded. All-cause mortality was the primary outcome. Age, sex, smoking status, cholesterol, cardiovascular risk, and general morbidity were identified as important confounding factors, and Cox survival models were adjusted for these factors accordingly. For combined cohorts, compared with the glycated haemoglobin (HbA(1c)) decile with the lowest hazard (median HbA(1c) 7.5%, IQR 7.5-7.6%), the adjusted hazard ratio (HR) of all-cause mortality in the lowest HbA(1c) decile (6.4%, 6.1-6.6) was 1.52 (95% CI 1.32-1.76), and in the highest HbA(1c) decile (median 10.5%, IQR 10.1-11.2%) was 1.79 (95% CI 1.56-2.06). Results showed a general U-shaped association, with the lowest HR at an HbA(1c) of about 7.5%. HR for all-cause mortality in people given insulin-based regimens (2834 deaths) versus those given combination oral agents (2035) was 1.49 (95% CI 1.39-1.59). Low and high mean HbA(1c) values were associated with increased all-cause mortality and cardiac events. If confirmed, diabetes guidelines might need revision to include a minimum HbA(1c) value. Eli Lilly and Company.


Detection limits of the strip test and PCR for genetically modified corn in Brazil.
Brazilian legislation establishes a labeling limit for products that contain more than 1% material from genetically modified organisms (GMOs). We assessed the sensitivity of the lateral flow strip test in detection of the GMO corn varieties Bt11 and MON810 and the specificity and sensitivity of PCR techniques for their detection. For the strip test, the GMO seeds were mixed with conventional seeds at levels of 0.2, 0.4 and 0.8% for Bt11, and 0.4, 0.8 and 1.6% for MON810. Three different methodologies were assessed and whole seeds, their endosperm and embryonic axis were used. For the PCR technique, the GMO seeds of each of the two varieties were mixed with conventional seeds at levels of 20, 10, 5, 2, 1, and 0.5%. The seeds were ground and the DNA extracted. For detection of the GMO material, specific primers were used for MON810 and Bt11 and maize zein as an endogenous control. The sensitivity of the strip test varied for both maize varieties and methodologies. The test was positive for Bt11 only at 0.8%, in contrast with the detection limit of 0.4% indicated by the manufacturer. In the multiplex PCR, the primers proved to be specific for the different varieties. These varieties were detected in samples with one GMO seed in 100. Thus, this technique proved to be efficient in detecting contaminations equal to or greater than 1%.


Morphine versus clonidine for neonatal abstinence syndrome.
The study goal was to determine whether clonidine treatment of neonatal abstinence syndrome (NAS) would result in a better neurobehavioral performance compared with morphine. This pilot study prospectively enrolled infants ≥ 35 weeks' gestational age admitted for treatment of NAS. After informed consent was obtained, infants were randomized to receive morphine (0.4 mg/kg per day) or clonidine (5 μg/kg per day) divided into 8 doses. A 25% dose escalation every 24 hours was possible per protocol (maximum of 1 mg/kg per day for morphine and 12 μg/kg per day for clonidine). After control of symptoms, the dose was tapered by 10% every other day. Clinical staff monitored infants by using Finnegan scoring. Masked research staff administered the NICU Network Neurobehavioral Scale (NNNS) at 1 week and at 2 to 4 weeks after initiation of treatment and the Bayley Scales III, and Preschool Language Scale IV, at 1-year adjusted age. Analyses included descriptive statistics, repeated measures analysis of variance, and Wilcoxon tests. Infants treated with morphine (n = 15) versus clonidine (n = 16) did not differ in birth weight or age at treatment. Treatment duration was significantly longer for morphine (median 39 days) than for clonidine (median 28 days; P = .02). NNNS summary scores improved significantly with clonidine but not with morphine. On subsequent assessment, those receiving clonidine had lower height of arousal and excitability (P < .05). One-year motor, cognitive, and language scores did not differ between groups. Clonidine may be a favorable alternative to morphine as a single-drug therapy for NAS. A multicenter randomized trial is warranted.


Selective effects of dopamine depletion and L-DOPA therapy on learning-related firing dynamics of striatal neurons.
Despite evidence that dopamine neurotransmission in the striatum is critical for learning as well as for movement control, little is yet known about how the learning-related dynamics of striatal activity are affected by dopamine depletion, a condition faced in Parkinson's disease. We made localized intrastriatal 6-hydroxydopamine lesions in rats and recorded within the dopamine-depleted sensorimotor striatal zone and its contralateral correspondent as the animals learned a conditional maze task. Rather than producing global, nonspecific elevations in firing rate across the task, the dopamine depletion altered striatal projection neuron activity and fast-spiking interneuron activity selectively, with sharply task-specific and cell type-specific effects, and often, with learning-stage selective effects as well. Striatal projection neurons with strong responses during the maze runs had especially elevated responsiveness during the maze runs. Projection neurons that, instead, fired most strongly before maze running showed elevated pre-start firing rates, but not during maze running, as learning progressed. The intrastriatal dopamine depletion severely affected the learning-related patterning of fast-spiking interneuron ensembles, especially during maze running and after extended training. Remarkably, L-DOPA treatment almost entirely reversed the depletion-induced elevations in pre-run firing of the projection neurons, and elevated their responses around start and end of maze runs. By contrast, L-DOPA failed to normalize fast-spiking interneuron activity. Thus the effects of striatal dopamine depletion and restoration on striatal activity are highly dependent not only on cell type, as previously shown, but also on the behavioral activity called for and the state of behavioral learning achieved.