Peer Relationship Experiences Of Deaf And Hard-Of-Hearing Adolescents.

Deaf and hard-of-hearing adolescents (DHH) experience more peer problems and lower levels of friendships than their hearing peers. This study used a qualitative approach to identify their experiences of peer problems and factors influencing them. A sample of 30, 13-19 year-old DHH adolescents with a moderate to profound hearing loss, drawn from a population-based cohort study in which their receptive language and social-emotional skills had been assessed, underwent semi-structured interviews. Interviews were analyzed using thematic analysis. Participants reported that, overall, they had developed positive and rewarding relationships with their peers, notwithstanding their earlier experience of being bullied. Conflicts and infrequency of interaction in their friendships were mainly reported by girls. Adolescents with moderate hearing loss were identified as facing the same or even more barriers than adolescents with severe to profound hearing loss in making new friends. Implications for educational practice are discussed.

Benign Intracranial Hypertension Necessitating Ventriculoperitoneal Shunt Insertion Secondary to Growth Hormone Therapy

Presentation Constant bilateral frontal headache associated with early morning awakenings, two episodes of vomiting and blurred vision. Diagnosis Benign Intracranial Hypertension. Treatment Repeat Lumbar Punctures were performed. GH was stopped and acetazolamide commenced. Later requiring VP shunt due to refractory symptoms with full resolution of symptoms. Conclusion Surgical management involving shunt procedures are reserved for refractory cases and are highly effective at resolving intractable symptoms.

An assessment of Irish farmers' knowledge of the risk of spread of infection from animals to humans and their transmission prevention practices.

The aim of this study was to ascertain farmers' knowledge of the risk of spread of infection from animals to humans, and their transmission prevention practices. This was a survey of farmers who submitted material to Ireland's Regional Veterinary Laboratories in 2015. There was an 84% response rate (1044 farmers). Ninety per cent of farmers were not aware that infection can be acquired from apparently healthy animals. Over half were not aware that disease could be contracted from sick poultry or pets. Conversely, the knowledge of the risk to pregnant women of infection from birthing animals was high (88%). Four-fifths of farmers sourced drinking water from a private well, and of these, 62% tested their water less frequently than once a year. Of dairy farmers, 39% drank unpasteurised milk once a week or more frequently. Veterinarians were the most commonly cited information source for diseases on farms. The survey findings indicate that the level of farmers' knowledge and awareness of the spread of infection from animals to humans is a concern. Further education of the farming community is needed to increase awareness of both the potential biohazards present on farms and the practical measures that can be taken to mitigate the risk of zoonoses.

Hydrophosphination using [GeCl{N(SiMe3)2}3] as a pre-catalyst.

Transformations catalyzed by germanium are scarce, with examples mainly limited to widely catalyzed processes such as polymerisation of lactide and hydroboration of carbonyls. Reported is the first example of hydrophosphination using a germanium pre-catalyst, yielding anti-Markovnikov products when diphenylphosphine is reacted with styrenes or internal alkynes at room temperature.

1,1-Diphosphines and divinylphosphines via base catalyzed hydrophosphination.

A catalytic hydrophosphination route to 1,1-diphosphines is yet to be reported: these narrow bite angle pro-ligands have been used to great effect as ligands in homogeneous catalysis. We herein demonstrate that terminal alkynes readily undergo double hydrophosphination with HPPh2 and catalytic potassium hexamethyldisilazane (KHMDS) to generate 1,1-diphosphines. A change to H2PPh leads to the formation of P,P-divinyl phosphines.

Neutrophil chemorepulsion in defined interleukin-8 gradients in vitro and in vivo.

We report for the first time that primary human neutrophils can undergo persistent, directionally biased movement away from a chemokine in vitro and in vivo, termed chemorepulsion or fugetaxis. Robust neutrophil chemorepulsion in microfluidic gradients of interleukin-8 (IL-8; CXC chemokine ligand 8) was dependent on the absolute concentration of chemokine, CXC chemokine receptor 2 (CXCR2), and was associated with polarization of cytoskeletal elements and signaling molecules involved in chemotaxis and leading edge formation. Like chemoattraction, chemorepulsion was pertussis toxin-sensitive and dependent on phosphoinositide-3 kinase, RhoGTPases, and associated proteins. Perturbation of neutrophil intracytoplasmic cyclic adenosine monophosphate concentrations and the activity of protein kinase C isoforms modulated directional bias and persistence of motility and could convert a chemorepellent to a chemoattractant response. Neutrophil chemorepulsion to an IL-8 ortholog was also demonstrated and quantified in a rat model of inflammation. The finding that neutrophils undergo chemorepulsion in response to continuous chemokine gradients expands the paradigm by which neutrophil migration is understood and may reveal a novel approach to our understanding of the homeostatic regulation of inflammation.

A comparison of breast muscle characteristics in three broiler great-grandparent lines.

Genetic selection of broiler chickens has led to a gross overdevelopment of the broiler breast muscle pectoralis major. This may have resulted in increased myopathy and detrimental effects on meat quality. The present study examined 3 commercial great-grandparent lines (lines A, B, and C). Lines A and B are female lines, and line C is a male line. The mean BW of line C (2.7 kg) was significantly greater than those of lines A and B (both 2.3 kg). However, the mean breast yield of both lines B and C (8.9 and 8.7%, respectively) was significantly greater than that of line A (6.9%). Line B therefore matched the meat yield of line A while maintaining a high reproductive capacity. The mean breast fillet weight of line A (169 g) was significantly lower than lines B (207 g) and C (235 g). No differences were observed between lines in either mean fiber size or amount of connective tissue. Therefore, additional fibers must provide the additional weight in the breast fillet of lines B and C, compared with A. Plasma creatine kinase activity, a commonly used marker of muscle damage, was significantly higher in line A (1368 IU/L) than in lines B (995 IU/L) and C (982 IU/L). However, qualitative evaluations of muscle pathology revealed no differences among lines. Selection for increased embryonic muscle fiber number, rather than for increased radial fiber growth, could improve growth potential and may also alleviate muscle damage.

Waterborne outbreak of cryptosporidiosis in the South East of Ireland: weighing up the evidence.

BACKGROUND: In late Spring 2012, 12 cases of cryptosporidiosis in a town in the South East of Ireland were notified to the regional Department of Public Health. AIM: The purpose of this paper is to describe the outbreak and the investigative process which led to the conclusion that the source was a public drinking water supply. METHODS: Outbreak and incident control teams were convened to investigate and control the outbreak. RESULTS: Eleven cases were speciated as Cryptosporidium parvum. GP60 analysis demonstrated that 10 were C. parvum IIaA20G3R1, indicating that the cases were linked. The public water supply was the only common risk factor identified. Increased water sampling identified Cryptosporidium muris/andersoni in the treated water at one of two water treatment plants (Water Treatment Plant, WTP A) for the supply, and on the network. C. parvum was subsequently identified in raw water from WTP A. CONCLUSIONS: The Health Service Executive (HSE) concluded that this outbreak was "probably associated with water" produced at WTP A based on (1) descriptive epidemiological evidence suggesting water-related illness and excluding other obvious explanations; and (2) water treatment failure at WTP A. WTP A was closed to facilitate an upgrade. No boil water notice was required as a supplementary supply was available. The upgrade was completed and the incident closed in 2013.

Aminopiperidine based complexes for lactide polymerisation.

Herein we report the synthesis and characterisation of a series of salalen and salan ligands derived from 2-(aminomethyl)piperidine. Depending on the choice of starting salicylaldehyde, a bicyclic salan type ligand (1-3H2) or imino salalen type ligand (4-6H, 7-9H2) were prepared. The ligands were successfully complexed to group 4 metals and aluminium; with hafnium and zirconium octahedral complexes, M(1-3)2, were realised; whilst with aluminium tetrahedral and trigonal bipyramidal complexes, Al(1-9)Mex (x = 1,2), were isolated. The complexes have been characterised in solution via(1)H and (13)C{(1)H} NMR spectroscopy and in the solid state by X-ray crystallography. The group 4 complexes were observed to have a fac-fac arrangement of ligands and there were two isomers present when 3H2 was ligated. The imino aluminium complexes Al(7-9)Me were isolated as a mixture of diastereoisomers. The resultant complexes were trialed in the ring opening polymerisation of rac-lactide with both heterotactic and isotactic PLA being demonstrated. Tacticity was found to be dependent on the nature of the ligand and metal used; the M(1-3)2 complexes were generally found to have a heterotactic preference (Pr = 0.67-0.76) and the aluminium polymerisation outcome was dictated more by the steric influence of the ligand, particularly for Al(4/6)Me2/Al(7/9)Me.

The aspartate aminotransferase-catalysed exchange of the alpha-protons of aspartate and glutamate: the effects of the R386A and R292V mutations on this exchange reaction.

1H-NMR was used to follow the aspartate aminotransferase-catalysed exchange of the alpha-protons of aspartate and glutamate. The effect of the concentrations of both the amino acids and the cognate keto acids on exchange rates was determined for wild-type and the R386A and R292V mutant forms of aspartate aminotransferase. The wild-type enzyme is found to be highly stereospecific for the exchange of the alpha-protons of L-aspartate and L-glutamate. The R386A mutation which removes the interaction of Arg-386 with the alpha-carboxylate group of aspartate causes an approximately 10,000-fold decrease in the first order exchange rate of the alpha-proton of L-aspartate. The R292V mutation which removes the interaction of Arg-292 with the beta-carboxylate group of L-aspartate and the gamma-carboxylate group of L-glutamate causes even larger decreases of 25,000- and 100,000-fold in the first order exchange rate of the alpha-proton of L-aspartate and L-glutamate respectively. Apparently both Arg-386 and Arg-292 must be present for optimal catalysis of the exchange of the alpha-protons of L-aspartate and L-glutamate, perhaps because the interaction of both these residues with the substrate is essential for inducing the closed conformation of the active site.

Two receptor interacting domains in the nuclear hormone receptor corepressor RIP13/N-CoR.

The thyroid hormone receptor (TR) and the retinoic acid receptor (RAR) act as transcriptional repressors when they are not occupied by their cognate ligands. This repressor function is mediated by proteins called corepressors. One of the nuclear hormone receptor corepressors, N-CoR, was originally isolated as a retinoid X receptor-interacting protein called RIP13. We have isolated a new potential variant of RIP13/N-CoR that is missing previously described transcriptional repressor domains but is similar in structure to the related corepressor termed SMRT or TRAC-2. Detailed analysis of the interaction with TR and RAR demonstrates that RIP13/N-CoR contains a new receptor interaction domain, termed ID-II, in addition to the previously described domain, referred to here as ID-I. Both ID-I and ID-II are capable of interacting independently with either TR or RAR, as assessed by the yeast two-hybrid system, by a mammalian two-hybrid system, or by direct in vitro binding. Results with all three approaches confirm that RIP13/N-CoR also interacts with retinoid X receptor, but this interaction is weaker than that with TR or RAR. Together, these results demonstrate that RIP13/N-CoR can interact with several different nuclear hormone receptors via two separate receptor interaction domains. Differences between the interactions observed in the different systems suggest that corepressor function may be modified by additional factors present in various cell types.

Copper malonamide complexes and their use in azide-alkyne cycloaddition reactions.

We report a rare example of the malonamide functionality being used as a ligand in copper catalysis. We have ligated a homologous series of these O,O-chelating architectures to copper, investigated their structure and exploited them in azide-alkyne cycloaddition reactions for the step-growth synthesis of oligo(triazoles) and in the synthesis of small organic azoles.

Effects of central muscarinic-1 receptor stimulation on blood pressure regulation.

Stimulation of central nervous system muscarinic-1 (M1) receptors in animals increases blood pressure, heart rate, and sympathetic outflow. In Alzheimer's disease, stimulation of central M1 receptors is reduced. When the oral formulation of the selective M1 agonist xanomeline was tested for the treatment of Alzheimer's disease, an increased incidence of syncope was observed. Therefore, we used Alzheimer's disease as a model of relative M1 deficiency to determine the effect of M1 receptor stimulation on blood pressure regulation in humans. Eight Alzheimer's patients and 6 healthy age- and sex-matched subjects underwent blood pressure, heart rate, forearm vascular resistance, plasma norepinephrine, and heart rate variability measurements during 90 minutes after ingestion of xanomeline or placebo, then during 45 minutes of head-up tilt. Alzheimer's patients were studied on three occasions: after placebo, the first dose of xanomeline, and 3 days of xanomeline. Normal subjects were studied after placebo and the first dose of xanomeline. A subset of 5 Alzheimer's patients was studied with the peripheral muscarinic antagonist methscopolamine. Oral xanomeline increased supine systolic and diastolic blood pressures in normal subjects and heart rate and plasma norepinephrine in all subjects. During the placebo tilt, 0 of 8 Alzheimer's patients and 2 of 6 healthy subjects developed near-syncope, and during the first-dose xanomeline tilt, 4 of 8 Alzheimer's patients and 3 of 6 healthy subjects had near-syncope. The maximal decrease in systolic blood pressure during tilt was greater with xanomeline than placebo in both groups (P<.03). Methscopolamine did not prevent xanomeline-induced hypotension. Central M1 receptor stimulation with the oral formulation of xanomeline in humans is associated with sympathetic stimulation under supine conditions and impaired baroreflex compensation during tilt. Alzheimer's patients, who presumably lack M1 receptor activity, may have a reduced risk of tilt-induced syncope compared with normal subjects. Both groups, however, have enhanced susceptibility to hypotension and syncope when M1 receptor activity is pharmacologically increased.

Influence of LDL oxidation on the proliferation of human breast cancer cells.

The effects of lipid peroxidation and the antioxidant vitamin E contained in LDL isolated from control plasma (LDL--) and from plasma preincubated with 0.5 mmol/ml alpha-tocopherol (LDL+) on the proliferation of estrogen-receptor positive (ER+ : ZR-75, T-47-D, MCF-7) and negative (ER--: HBL-100, MDA-MB-231) human breast cancer cells were studied. Human skin fibroblasts served as controls. Incubation of plasma with 0.5 mmol/ml alpha-tocopherol resulted in a 3-fold increase of its content and a significant reduction in lipid hydroperoxides and conjugated dienes in LDL. Incubation of fibroblasts or ER+ tumor cells with LDL- or LDL+ had an effect on neither cell proliferation nor on the cellular levels of peroxidation products as compared to control incubations in the absence of LDL. In ER- cells, however, LDL+ stimulated the proliferation, whereas LDL- yielded a cytotoxic effect. Moreover, LDL- supplementation resulted in an increase in the content of hydroperoxides and conjugated dienes. LDL+ supplemented cells exhibited hydroperoxide levels in these tumor cells comparable to the basal levels measured in the absence of LDL. Our data suggested that peroxidation products in LDL are cytotoxic to estrogen-receptor negative breast tumor cells and vitamin E counteracts this effect.

The pyridoxal-5'-phosphate-dependent catalytic antibody 15A9: its efficiency and stereospecificity in catalysing the exchange of the alpha-protons of glycine.

13C-NMR has been used to follow the exchange of the alpha-protons of [2-(13)C]glycine in the presence of pyridoxal-5'-phosphate and the catalytic antibody 15A9. In the presence of antibody 15A9 the 1st order exchange rates for the rapidly exchanged proton of [2-(13)C]glycine were only 25 and 150 times slower than those observed with tryptophan synthase (EC 4.2.1.20) and serine hydroxymethyltransferase (EC 2.1.2.1). The catalytic antibody increases the 1st order exchange rates of the alpha-protons of [2-(13)C]glycine by at least three orders of magnitude. We propose that this increase is largely due to an entropic mechanism which results from binding the glycine-pyridoxal-5'-phosphate Schiff base. The 1st and 2nd order exchange rates of the pro-2S proton have been determined but we were only able to determine the 2nd order exchange rate for the pro-2R proton of glycine. In the presence of 50 mM glycine the antibody preferentially catalyses the exchange of the pro-2S proton of glycine. The stereospecificity of the 2nd order exchange reaction was quantified and we discuss mechanisms which could account for the observed stereospecificity.

Synthesis and biological activity of the superestrogen (E)-17-oximino-3-O-sulfamoyl-1,3,5(10)-estratriene: x-ray crystal structure of (E)-17-oximino-3-hydroxy-1,3,5(10)-estratriene.

Steroid sulfatases regulate the formation of estrogenic steroids which can support the growth of endocrine-dependent breast tumors. Therefore, the development of potent steroid sulfatase inhibitors could have considerable therapeutic potential. Several such inhibitors have now been developed including estrone 3-O-sulfamate (EMATE, 1), which shows potent active site-directed inhibition. However, EMATE was subsequently shown to be also a potent estrogen. In an attempt to reduce the estrogenicity while retaining the potent sulfatase inhibitory properties associated with this type of molecule, (E)-17-oximino-3-O-sulfamoyl-1,3,5(10)-estratriene (5) (estrone oxime 3-O-sulfamate, OMATE) was synthesized. The X-ray crystal structure of (E)-17-oximino-3-hydroxy-1,3,5(10)-estratriene (4) (estrone oxime) demonstrated the presence of only one geometrical isomer [anti-isomer, (E)]. OMATE potently inhibited estrone sulfatase (E1-STS) activity and was similar to EMATE (>99% inhibition at 0.1 microM in MCF-7 breast cancer cells). It was also evaluated in vivo for its estrogenicity and ability to inhibit sulfatase activity. While it was equipotent with EMATE in vivo as a sulfatase inhibitor, it surprisingly had a stimulatory effect on uterine growth in ovariectomized rats about 1.5-fold greater than that of EMATE. Thus, OMATE possesses potential as a superestrogen and modification at C-17 is identified as a useful route for enhancement of estrogenicity in sulfamate-based estrogens.

Bicyclic analogues of D-myo-inositol 1,4,5-trisphosphate related to adenophostin A: synthesis and biological activity.

The high affinity of adenophostin A for 1D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] receptors may be related to an alteration in the position of its 2'-phosphate group relative to the corresponding 1-phosphate group in Ins(1,4,5)P(3). To investigate this possibility, two bicyclic trisphosphates 9 and 10, designed to explore the effect of relocating the 1-phosphate group of Ins(1,4,5)P(3) using a novel fused-ring system, were synthesized from myo-inositol. Biological evaluation of 9 and 10 at the Ins(1,4,5)P(3) receptors of hepatocytes showed that both were recognized by hepatic Ins(1,4,5)P(3) receptors and both stimulated release of Ca(2+) from intracellular stores, but they had lower affinity than Ins(1,4,5)P(3). This finding may be explained by considering the three-dimensional structures of 9 and 10 in light of recent studies on the conformation of adenophostin A.

A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients.

BACKGROUND: The aim of this study was to compare the efficacy and safety of Thymoglobulin (a rabbit-derived polyclonal antibody) to Atgam (a horse-derived polyclonal antibody) for induction in adult renal transplant recipients. METHODS: Transplant recipients (n=72) were randomized 2:1 in a double-blinded fashion to receive Thymoglobulin (n=48) at 1.5 mg/kg intravenously or Atgam (n=24) at 15 mg/kg intravenously, intraoperatively, then daily for at least 6 days. Recipients were observed for at least 1 year of follow-up. RESULTS: By 1 year after transplantation, 4% of Thymoglobulin-treated patients experienced acute rejection compared with 25% of Atgam-treated patients (P=0.014). The rate of acute rejection was lower with Thymoglobulin than Atgam (relative risk=0.09; P=0.009). Rejection was less severe with Thymoglobulin than Atgam (P=0.02). No recurrent rejection occurred with Thymoglobulin compared with 33% with Atgam (P=NS). Patient survival was not different, but the composite end point of freedom from death, graft loss, or rejection, the "event-free survival," was superior with Thymoglobulin (94%) compared with Atgam (63%; P=0.0005). Fewer adverse events occurred with Thymoglobulin (P=0.013). Leukopenia was more common with Thymoglobulin than Atgam (56% vs. 4%; P<0.0001) during induction. The mean absolute lymphocyte count remained below baseline with Thymoglobulin throughout the study (P<0.007), but with Atgam, significant lymphocyte reductions occurred only at day 7. The incidence of cytomegalovirus disease was less with Thymoglobulin than Atgam at 6 months (10% vs. 33%; P=0.025). CONCLUSIONS: Brief (7-day) induction with Thymoglobulin resulted in less frequent and less severe rejection, a better event-free survival, less cytomegalovirus disease, fewer serious adverse events, but more frequent early leukopenia than induction with Atgam. These results may in fact be explained by a more profound and durable beneficial lymphopenia.

Suppression of tumorigenicity of rat liver epithelial tumor cell lines by a putative human 11p11.2-p12 liver tumor suppressor locus.

We have previously identified and mapped a locus within human chromosome 11p11.2-p12 that suppresses the tumorigenic potential of a rat liver tumor cell line (termed GN6TF) which contains well defined chromosomal aberrations involving rat chromosomes 1, 4, 7, and 10. In the present study, we investigated the potential of this human 11p11.2-p12 liver tumor suppressor locus to suppress the tumorigenic potential of two other rat liver tumor cell lines (GN3TG and GP10TA) following microcell-mediated introduction of human chromosome 11. These tumor cell lines are aneuploid and contain chromosomal abnormalities that are similar to the GN6TF tumor line. The tumorigenic potential and other phenotypic characteristics of GN3TG-11neo and GP10TA-11neo microcell hybrid (MCH) cell lines were variable, and dependent upon the status of the introduced human chromosome 11. MCH cell lines that retained the region of 11p11. 2-p12 delineated by microsatellite markers D11S1385 and D11S903 exhibited suppression of tumorigenicity in vivo (decrease in tumorigenicity and/or elongation of latency), whereas, the tumorigenic potential of one MCH line that lacked markers in this region of human 11p11.2-p12, but retained flanking markers, was not changed from that of the parental tumor cell line. The chromosomal interval between microsatellite markers D11S1385 and D11S903 encompasses the previously localized minimal liver tumor suppressor region, suggesting that a common locus is responsible for tumor suppression among the rat liver tumor cell lines examined. The results of the present study have verified the presence of a liver tumor suppressor locus within human 11p11.2-p12, and have identified a substantial number of microsatellite markers that are closely linked to this tumor suppressor region. These chromosomal markers will facilitate positional cloning of candidate genes from this region, and may prove useful for determining the involvement of this locus in the pathogenesis of human liver cancer.

Germ cell-somatic cell dichotomy of a low-density lipoprotein receptor gene family member in testis.

Members of the low-density lipoprotein receptor (LDLR) supergene family interact with a large number of diverse ligands. One of the relevant receptors is the recently characterized LDLR relative with eight ligand-binding repeats, termed LR8, which exists in two splice variant forms. The gonads, relying on receptor-mediated lipoprotein supply for steroidogenesis, and on interplay of germ cells with somatic cells, provide a particularly attractive setting to study details of the expression of LR8. Here we show by polymerase chain reactions and Northern analysis, as well as by in situ hybridization, that the longer of the two splice variants (LR8+), containing an additional region defining an O-linked sugar domain, is produced in the somatic cells of chicken testis, whereas the shorter form lacking this domain (LR8-) is expressed in the male germ cells. Interestingly, as shown by transcript analysis and at the functional level by ligand blotting, LR8- expression in the spermatoids increases with germ cell maturation, but is absent from ejaculated sperm. This constitutes a scenario reminiscent of the situation in growing vitellogenic oocytes, which express very high levels of LR8-, but lack the receptor following ovulation. Thus, the cell-specific expression of different LR8 splice variants may relate to the requirements of extensive communication and cooperation between germ cells and somatic cells in the gonads.