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The notion that student teachers are less accepting of mentally ill than of normal students was investigated. The hypothesis was supported. Implications for revealing potentially stigmatizing information about mental illness to teachers were discussed. (Author)

RATIONALE Human genetics studies in African Americans have shown a strong correlation between polymorphisms in the ApoL1 gene and chronic kidney disease (CKD). To gain further insight into the etiology of ApoL1-associated kidney diseases, the determination of circulating levels of both wild type as well as ApoL1 variants could be of significant use. To date, antibodies that discriminate between all three ApoL1variant forms (wild type, G1 and G2) are not available. We aimed to develop a rapid method for detecting and quantifying ApoL1 variants and total levels in plasma. METHODS Ultra-performance liquid chromatography (UPLC) and tandem mass spectrometry (MS/MS) in multiple-reaction monitoring acquisition mode was used to quantify ApoL1. RESULTS We demonstrated that it is feasible to detect and quantify ApoL1 variants (wild type, G1 and G2), and total ApoL1 concentrations in plasma. ApoL1 genotypes determined by LC/MS agreed perfectly with the traditional method DNA sequencing for 74 human subjects. The method exhibited at least three orders of linearity with a lower limit of quantification of 10 nM. Moreover, the method can readily be multiplexed for the quantification of a panel of protein markers in a single sample. CONCLUSIONS The method reported herein obviates the need to perform DNA genotyping of ApoL1 variants, which is of significant value in cases where stored samples are unsuitable for DNA analysis. More importantly, the method could potentially be of use in the early identification of individuals at risk of developing CKD, and for the stratification of patients for treatment with future ApoL1-modifying therapies. Copyright © 2013 John Wiley & Sons, Ltd.

An interprofessional educational approach was used to provide five in-service training sessions for all direct health care providers in a long-term care facility, and one half-day seminar/live webinar for community-licensed health care professionals. Content included presentations by five disciplines: (a) periodontist: oral-systemic relationship, (b) oral pathologist: oral pathology, (c) pharmacist: oral health-pharmacological link, (d) dietitian: oral health-dietary link, and (e) occupational therapist: providing and practicing proper oral hygiene. Significant improvement in posttest scores for the five in-service training sessions and the half-day seminar/live webinar was revealed in t-test results, representing an increase in knowledge gained. Approximately 80% of the 145 participants indicated that they would make a change in patient care. Findings indicate that the in-service training sessions and half-day seminar/live webinar supported development of the geriatric work force by utilizing an interprofessional educational approach which will assist in meeting the oral health care needs of the geriatric population.

Acquisition of enemy-free-space has been suggested to reduce selective pressure against host range expansion in phytophagous insects. The gall midge, Asphondylia borrichiae Rossi and Strong (Diptera: Cecidomyiidae), which attacks the stem tips of its 3 host plants produces a spherical tumor-like growth (= gall). Juvenile stages (larvae and pupae) of A. borrichiae develop inside the gall; the midge spends approximately 95–98% of its life cycle embedded within the gall. During these juvenile stages, A. borrichiae are parasitized by 4 species of hymenopterans. Previous studies have found that one of the most common and the largest parasitoid, Torymus umbilicatus (Gahan), tends to dominate large galls owing to its significantly longer ovipositor, which enables it to penetrate the biggest galls and reach larvae and pupae that become unavailable to the other 3 parasitoids, which have much shorter ovipositors. Moreover, previous studies suggest that the gall midge is diverging both morphologically and genetically in sympatry. The current study is the first to provide morphological evidence that T. umbilicatus, which is a dominant member of the parasitoid guild that attacks A. borrichiae, may also be diverging in sympatry along with its host. Female T. umbilicatus from sea oxeye daisy (Borrichia frutescens [L.] DC) were significantly larger than those from alternative host plants of the gall midge, dune elder (Iva imbricata Walter) and marsh elder (I. frutescens L). Additionally, size of female T. umbilicatus collected from 2 geographically distant sites were significantly different and these differences were consistent with a latitudinal gradient in size between plant species. Although T. umbilicatus were larger from galls collected from B. frutescens compared to I. frutescens at both sites, gall diameter demonstrated a significant decline along a south-north latitudinal gradient. However, a significant interaction between plant species and site suggests that differences in T. umbilicatus size (and most likely their gall midge host) is caused either by phenotypic plasticity of the species at the 2 sites, or these insects (T umbilicatus and gall midges) tend to be smaller with increasing latitude. Moreover, galls on I, frutescens, owing to their smaller size and increased crowding, decline in size at a greater rate than those from B. frutescens which produces significantly larger and less crowded galls.

Objective:To specify the presenting symptoms and clinical course of patients with frontotemporal dementia (FTD) and chromosome 9 open reading frame 72 (C9ORF72) repeat expansion.Background:The 2011 discovery of the C9ORF72 repeat expansion causing familial FTD and amyotrophic lateral sclerosis has permitted retrospective evaluation of potential defining clinical characteristics that may distinguish carriers of the C9ORF72 mutation from other patients with FTD. Prior reports identified a subset of patients with FTD who had an unusually high prevalence of psychosis, although their specific symptoms had not yet been fully described.Methods:From a cohort of 62 patients with FTD, we conducted a retrospective chart review of 7 patients who had C9ORF72 mutations on genetic testing, and 1 untested sibling of a C9ORF72 carrier.Results:Detailed histories revealed a higher prevalence of psychosis, including visual and auditory hallucinations and delusions, in the 8 C9ORF72 carriers than in our patients with sporadic FTD.Conclusions:This cohort confirms and adds clinical details to the reports of a high prevalence of psychotic phenomena in patients who have C9ORF72 mutations as well as FTD or amyotrophic lateral sclerosis.

Novel oxazolidinedione analogs were discovered as potent and selective mineralocorticoid receptor (MR) antagonists. Structure–activity relationship (SAR) studies were focused on improving the potency and microsomal stability. Selected compounds demonstrated excellent MR activity, reasonable nuclear hormone receptor selectivity, and acceptable rat pharmacokinetics.

To evaluate the difference in 10-year neurocognitive outcomes between extremely low gestational age newborns without bacteremia and those with suspected or confirmed late-onset bacteremia.Neurocognitive function was evaluated at 10 years of age in 889 children born at28 weeks of gestation and followed from birth. Definite (culture-positive) late-onset bacteremia during postnatal weeks 2-4 was identified in 223 children, and 129 children had suspected bacteremia.Infants with the lowest gestational age and birth weight z-score had the highest prevalence of definite and suspected late-onset bacteremia. Compared with peers with no or suspected bacteremia, infants with definite bacteremia performed worse on tests of general cognitive ability, language, academic achievement, and executive function, even after adjustment for potential confounders. Adjustment for low IQ attenuated the associations between bacteremia and all dysfunctions at age 10 years. Children with suspected bacteremia did not differ appreciably from those with no evidence of bacteremia. The motor domain was unaffected.Extremely low gestational age newborns who had definite late bacteremia during postnatal weeks 2-4 are at heightened risk of neurocognitive limitations at age 10 years.

OBJECTIVE: To assess the association between maternal prepregnancy body mass index and adequacy of pregnancy weight gain in relation to neurocognitive function in school-aged children born extremely preterm.STUDY DESIGN: Study participants were 535 ten-year-old children enrolled previously in the prospective multicenter Extremely Low Gestational Age Newborns cohort study who were products of singleton pregnancies. Soon after delivery, mothers provided information about prepregnancy weight. Prepregnancy body mass index and adequacy of weight gain were characterized based on this information. Children underwent a neurocognitive evaluation at 10 years of age.RESULTS: Maternal prepregnancy obesity was associated with increased odds of a lower score for Differential Ability Scales-II Verbal IQ, for Developmental Neuropsychological Assessment-II measures of processing speed and visual fine motor control, and for Wechsler Individual Achievement Test-III Spelling. Children born to mothers who gained an excessive amount of weight were at increased odds of a low score on the Oral and Written Language Scales Oral Expression assessment. Conversely, children whose mother did not gain an adequate amount of weight were at increased odds of a lower score on the Oral and Written Language Scales Oral Expression and Wechsler Individual Achievement Test-III Word Reading assessments.CONCLUSION: In this cohort of infants born extremely preterm, maternal obesity was associated with poorer performance on some assessments of neurocognitive function. Our findings are consistent with the observational and experimental literature and suggest that opportunities may exist to mitigate risk through education and behavioral intervention before pregnancy.

No prospective cohort study of high-risk children has used rigorous exposure assessment and optimal diagnostic procedures to examine the perinatal antecedents of autism spectrum disorder separately among those with and without cognitive impairment.We sought to identify perinatal factors associated with increased risk for autism spectrum disorder with and without intellectual disability (intelligence quotient70) in children born extremely preterm.This prospective multicenter (14 institutions in 5 states) birth cohort study included children born at 23-27 weeks' gestation in 2002 through 2004 who were evaluated for autism spectrum disorder and intellectual disability at age 10 years. Pregnancy information was obtained from medical records and by structured maternal interview. Cervical-vaginal "infection" refers to maternal report of bacterial infection (n = 4), bacterial vaginosis (n = 30), yeast infection (n = 62), mixed infection (n = 4), or other/unspecified infection (n = 43; eg, chlamydia, trichomonas, or herpes). We do not know the extent to which infection per se was confirmed by microbial colonization. We use the terms "fetal growth restriction" and "small for gestational age" interchangeably in light of the ongoing challenge to discern pathologically from constitutionally small newborns. Severe fetal growth restriction was defined as a birthweight Z-score for gestational age at delivery-2 (ie, ≥2 SD below the median birthweight in a referent sample that excluded pregnancies delivered for preeclampsia or fetal indications). Participants were classified into 4 groups based on whether or not they met rigorous diagnostic criteria for autism spectrum disorder and intellectual disability (autism spectrum disorder+/intellectual disability-, autism spectrum disorder+/intellectual disability+, autism spectrum disorder-/intellectual disability+, and autism spectrum disorder-/intellectual disability-). Temporally ordered multinomial logistic regression models were used to examine the information conveyed by perinatal factors about increased risk for autism spectrum disorder and/or intellectual disability (autism spectrum disorder+/intellectual disability-, autism spectrum disorder+/intellectual disability+, and autism spectrum disorder-/intellectual disability+).In all, 889 of 966 (92%) children recruited were assessed at age 10 years, of whom 857 (96%) were assessed for autism spectrum disorder; of these, 840 (98%) children were assessed for intellectual disability. Autism spectrum disorder+/intellectual disability- was diagnosed in 3.2% (27/840), autism spectrum disorder+/intellectual disability+ in 3.8% (32/840), and autism spectrum disorder-/intellectual disability+ in 8.5% (71/840). Maternal report of presumed cervical-vaginal infection during pregnancy was associated with increased risk of autism spectrum disorder+/intellectual disability+ (odds ratio, 2.7; 95% confidence interval, 1.2-6.4). The lowest gestational age category (23-24 weeks) was associated with increased risk of autism spectrum disorder+/intellectual disability+ (odds ratio, 2.9; 95% confidence interval, 1.3-6.6) and autism spectrum disorder+/intellectual disability- (odds ratio, 4.4; 95% confidence interval, 1.7-11). Severe fetal growth restriction was strongly associated with increased risk for autism spectrum disorder+/intellectual disability- (odds ratio, 9.9; 95% confidence interval, 3.3-30), whereas peripartum maternal fever was uniquely associated with increased risk of autism spectrum disorder-/intellectual disability+ (odds ratio, 2.9; 95% confidence interval, 1.2-6.7).Our study confirms that low gestational age is associated with increased risk for autism spectrum disorder irrespective of intellectual ability, whereas severe fetal growth restriction is strongly associated with autism spectrum disorder without intellectual disability. Maternal report of cervical-vaginal infection is associated with increased risk of autism spectrum disorder with intellectual disability, and peripartum maternal fever is associated with increased risk for intellectual disability without autism spectrum disorder.

Reported herein are a series of reverse indoles that represent novel non-steroidal mineralocorticoid receptor (MR) antagonists. The key structure–activity relationships (SAR) are presented below. This reverse indole series is exemplified by a compound that demonstrated efficacy in an acute natriuresis rodent model comparable to marketed MR antagonists, spironolactone and eplerenone.

Objectives To test the hypothesis that higher blood levels of neurotrophic proteins (proteins that support neuronal survival and function) in the first 2 weeks of life are associated with a lower risk of cognitive impairment at 10 years. Study design We evaluated 812 10-year-old children with neonatal blood specimens enrolled in the multicenter prospective Extremely Low Gestational Age Newborn Study, assessing 22 blood proteins collected on 3 days over the first 2 weeks of life. Using latent profile analysis, we derived a cognitive function level based on standardized cognitive and executive function tests. We defined high exposure as the top quartile neurotrophic protein blood level on ≥2 days either for ≥4 proteins or for a specific cluster of neurotrophic proteins (defined by latent class analysis). Multinomial logistic regression analyzed associations between high exposures and cognitive impairment. Results Controlling for the effects of inflammatory proteins, persistently elevated blood levels of ≥4 neurotrophic proteins were associated with reduced risk of moderate (OR, 0.35; 95% CI, 0.18-0.67) and severe cognitive impairment (OR, 0.22; 95% CI, 0.09-0.53). Children with a cluster of elevated proteins including angiopoietin 1, brain-derived neurotrophic factor, and regulated upon activation, normal T-cell expressed, and secreted had a reduced risk of adverse cognitive outcomes (OR range, 0.31-0.6). The risk for moderate to severe cognitive impairment was least with 0-1 inflammatory and >4 neurotrophic proteins. Conclusions Persisting elevations of circulating neurotrophic proteins during the first 2 weeks of life are associated with lowered risk of impaired cognition at 10 years of age, controlling for increases in inflammatory proteins.

In response to the issues posed in this scenario, the National Institutes of Health - Office of Laboratory Animal Welfare (NIH-OLAW) provides the following clarification

Background and purpose: Inhibition of cholesteryl ester transfer protein (CETP) with torcetrapib in humans increases plasma high density lipoprotein (HDL) cholesterol levels but is associated with increased blood pressure. In a phase 3 clinical study, evaluating the effects of torcetrapib in atherosclerosis, there was an excess of deaths and adverse cardiovascular events in patients taking torcetrapib. The studies reported herein sought to evaluate off-target effects of torcetrapib.

The term BID – standing for Business Improvement Districts – is now so well established in the UK's regeneration and property vocabulary it is hard to believe it is only a few years ago that the co...

To address the challenging health care needs of the population served by an urban academic medical center, we developed the Johns Hopkins Community Health Partnership (J-CHiP), a novel care coordination program that provides services in homes, community clinics, acute care hospitals, emergency departments, and skilled nursing facilities. This case study describes a comprehensive program that includes: a community-based intervention using multidisciplinary care teams that work closely with the patient's primary care provider; an acute care intervention bundle with collaborative team-based care; and a skilled nursing facility intervention emphasizing standardized transitions and targeted use of care pathways. The program seeks to improve clinical care within and across settings, to address the non-clinical determinants of health, and to ultimately improve healthcare utilization and costs. The case study introduces: a) main program features including rationale, goals, intervention design, and partnership development; b) illness burden and social barriers of the population contributing to care challenges and opportunities; and c) lessons learned with steps that have been taken to engage both patients and providers more actively in the care model. Urban health systems, including academic medical centers, must continue to innovate in care delivery through programs like J-CHiP to meet the needs of their patients and communities.

A sensitive method has been developed for the identification and assessment of phosphorothioate oligonucleotide accumulation in dosed animal tissues using an in situ hybridization approach, which is both sequence specific yet adaptable to every antisense oligonucleotide (ASO), which has been tested to date. Hybridization is accomplished using a digoxigenin-tailed oligonucleotide probe complementary to the ASO target sequence on routinely processed paraffin sections which have been pretreated with a mild target retrieval solution. The DIG-labeled probe is amplified first with an anti-DIG:FITC antibody conjugate followed by an anti:FITC Alexa 488 antibody, then visualized using FITC epifluorescence microscopy. Fluorescent labeling of ASO drug in tissue sections by this method confirms that H&E basophilia previously observed in dosed tissues represents largely intact ASO. However, the fluorescent method enables a wider assessment of tissue distribution in a variety of tissue types due to increased sensitivity and lower signal to noise than can be obtained through an examination of H&E stained tissue sections alone.

The 2015 9th Workshop on Recent Issues in Bioanalysis (9th WRIB) took place in Miami, Florida with participation of over 600 professionals from pharmaceutical and biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. It is once again a 5-day week long event – a full immersion bioanalytical week – specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches including the focus on biomarkers and immunogenicity. This 2015 White Paper encompasses recommendations that emerged from the extensive discussions held during the workshop, and is aimed at providing the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to advance scientific excellence, improve quality and deliver better regulatory compliance. Due to its length, the 2015 edition of this comprehensive White Paper has been divided into three parts. Part 2 covers the recommendations for hybrid LBA/LCMS and regulatory agencies’ inputs. Part 1 (small molecule bioanalysis using LCMS) and Part 3 (large molecule bioanalysis using LBA, biomarkers and immunogenicity) will be published in volume 7 of Bioanalysis, issues 22 and 24, respectively.

Two common missense variants in APOL1 (G1 and G2) have been definitively linked to CKD in black Americans. However, not all individuals with the renal-risk genotype develop CKD, and little is known about how APOL1 variants drive disease. Given the association of APOL1 with HDL particles, which are cleared by the kidney, differences in the level or quality of mutant APOL1‑HDL particles could be causal for disease and might serve as a useful risk stratification marker. We measured plasma levels of G0 (low risk), G1, and G2 APOL1 in 3450 individuals in the Dallas Heart Study using a liquid chromatography-MS method that enabled quantitation of the different variants. Additionally, we characterized native APOL1‑HDL from donors with no or two APOL1 risk alleles by size-exclusion chromatography and analysis of immunopurified APOL1‑HDL particles. Finally, we identified genetic loci associated with plasma APOL1 levels and tested for APOL1-dependent association with renal function. Although we replicated the previous association between APOL1 variant status and renal function in nondiabetic individuals, levels of circulating APOL1 did not associate with microalbuminuria or GFR. Furthermore, the size or known components of APOL1‑HDL did not consistently differ in subjects with the renal-risk genotype. Genetic association studies implicated variants in loci harboring haptoglobin-related protein (HPR), APOL1, and ubiquitin D (UBD) in the regulation of plasma APOL1 levels, but these variants did not associate with renal function. Collectively, these data demonstrate that the risk of renal disease associated with APOL1 is probably not related to circulating levels of the mutant protein.

Burn injury can be detrimental to the health of individuals, meanwhile victims lose proteins and micronutrients in wound exudates. Victims also experience extensive protein catabolism. These make them prone to malnutrition. Burn patients also suffer a lot of emotional trauma that reduce nutrient intake. The aim of this paper was to review primary evidence on the effect of antioxidant micronutrients on the recovery rate of burn patients. Electronic databases such as PubMed, BioMed, and Cochrane were systematically searched between January 1, 2014, and January 30, 2014. Keywords include vitamin A, vitamin C, vitamin E, ascorbic acid, zinc, copper, selenium, tocopherol, carotenoids, dietary intake, supplementation, wound healing, infection, recovery rate, and burn patients. The systematic search was done to retrieve all published data from 1990 to 2013. A total of 518 journal articles were obtained, and after the removal of duplicates, reviews, commentaries, and studies with non-human subjects, 11 papers were accepted for review. The review considered only papers that were published, and there might be some unpublished data that may have been omitted. Generally, the wound healing time and infection rates were reduced by the administration of the antioxidant micronutrients. The review revealed that there was no such published work in developing countries and children were excluded from most studies. It was also stated clearly that there was no uniformity in burn management; hence, there is a need for more studies on burn management in various populations.

Contains fulltext : 154461.pdf (Publisher’s version ) (Closed access) Frontotemporal lobar degeneration with TAR DNA-binding protein 43 inclusions (FTLD-TDP) is the most common pathology associated with frontotemporal dementia (FTD). Repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) and mutations in progranulin (GRN) are the major known genetic causes of FTLD-TDP; however, the genetic etiology in the majority of FTLD-TDP remains unexplained. In this study, we performed whole-genome sequencing in 104 pathologically confirmed FTLD-TDP patients from the Mayo Clinic brain bank negative for C9ORF72 and GRN mutations and report on the contribution of rare single nucleotide and copy number variants in 21 known neurodegenerative disease genes. Interestingly, we identified 5 patients (4.8 %) with variants in optineurin (OPTN) and TANK-binding kinase 1 (TBK1) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the p.Q235* nonsense and p.A481V missense mutation in trans, while case B carried a deletion of OPTN exons 13-15 (p.Gly538Glufs*27) and a loss-of-function mutation (p.Arg117*) in TBK1. Cases C-E carried heterozygous missense mutations in TBK1, including the p.Glu696Lys mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain. Quantitative mRNA expression and protein analysis in cerebellar tissue showed a striking reduction of OPTN and/or TBK1 expression in 4 out of 5 patients supporting pathogenicity in these specific patients and suggesting a loss-of-function disease mechanism. Importantly, neuropathologic examination showed FTLD-TDP type A in the absence of motor neuron disease in 3 pathogenic mutation carriers. In conclusion, we highlight TBK1 as an important cause of pure FTLD-TDP, identify the first OPTN mutations in FTLD-TDP, and suggest a potential oligogenic basis for at least a subset of FTLD-TDP patients. Our data further add to the growing body of evidence linking ALS and FTD and suggest a key role for the OPTN/TBK1 pathway in these diseases.

A quantitative method for the determination of a partially modified, 2′-ribose alkoxy 18-mer phosphorothioate oligonucleotide in liver tissue has been developed. A liquid:liquid extraction, ion-pair reverse phase chromatographic separation and tandem mass spectrometry were used to achieve a quantitation range of 125 to 10,000 ng g−1 mouse liver tissue. A total cycle time of 5 min was obtained while maintaining separation of three potential impurities. Separations were performed using a Discovery RP-Amide C16, 100 × 2 mm column packed with 5 μm particles. The separation was facilitated by the use of triethylamine (TEA) and hexafluoroisopropanol (HFIP) as ion-pair agents. The method has subsequently been used for the determination of other phosphorothioate oligonucleotides in support of discovery research.

Ribozymes are RNA or modified RNA polymers capable of catalyzing cleavage reactions in target strands RNA, and are under development as human therapeutics. Previous methods used for quantitation of nucleic acid polymers in serum or plasma required extraction of the polymer followed by capillary electrophoresis, HPLC, or gel electrophoresis. These methods are time consuming and lack sensitivity. A bioanalytical method has been developed that does not require extraction of the ribozyme analyte from serum. This technique relies on hybridization of the ribozyme molecule to two complementary biotin and digoxigenin labeled oligonucleotide probes. Serum containing the ribozyme is mixed with the labeled probes, and the mixture is heated at 75 °C for 5 min to disrupt the ribozyme secondary structure. Samples are then cooled to permit probe annealing and are added to a streptavidin-coated 96-well plate. The bound complex is detected with an anti-digoxigenin alkaline phosphatase (AP) conjugate using PNPP ( p -nitrophenyl phosphate) as a substrate. The amount of colored product is measured on a microtiter plate reader at a wavelength of 405 nm. Concentrations of unknown ribozyme samples are estimated based on a standard curve (0.37–270 ng/ml) prepared in serum. The validated lower and upper limits of quantification are 5.0 and 120 ng/ml, respectively. The assay can be completed in approximately 5 h and does not require extraction procedures or electrophoretic/chromatographic separation. It is therefore a simple, sensitive and rapid technique. This assay has been validated and has been used for quantitation of serum levels of the HEPTAZYME™ ribozyme in mouse, monkey, and human pharmacokinetic studies.

Background. In order to optimize glycaemic control, substantial numbers of people with type 2 diabetes may require transfer from oral medication to insulin therapy. Although insulin conversion is traditionally a specialist secondary care function, as nursing roles change and expand there is growing pressure for this to be performed within primary care. However, little is known about the potential barriers to such a change, particularly from the standpoint of the frontline staff involved. Aims. The study aimed to explore the views of practice nurses in the United Kingdom (UK) about converting diabetic patients from oral hyperglycaemic agents to injected insulin within primary care, and to investigate what structures and resources might be useful in supporting such a change. Methods. Semi-structured interviews were conducted with 25 practice nurses, and interpreted using content analysis to extract key conceptual themes from the transcribed interview texts. Findings. Most of the nurses felt that converting to insulin in primary care had considerable benefits for patients. However, issues of time, training, confidence about performing the change, and the adequacy of support systems, both for patient and nurse, emerged as the main perceived barriers to performing insulin conversions in primary care. Worries about legal and accountability issues surrounding the nurse prescribing elements were also raised. Conclusions. Where insulin conversion within primary care is being considered, it is suggested that specific training is provided for practice nurses and general practitioners, protected time is made available, and a team-working approach is fostered to prevent isolation and boost patient support. Formal mentoring or supervision support for practice nurses may also help them to adapt to this new approach. Limitations. These findings are based on the views of nurses from a single UK locality, and so widespread consultation is recommended before applying them in other settings.

Elaboration of the oxazolidinedione series led to replacement of the exocyclic amides with substituted benzimidazoles. The structure–activity relationship (SAR) exploration resulted in the discovery of potent and selective nonsteroidal mineralocorticoid receptor (MR) antagonists with significantly improved microsomal stability and pharmacokinetic (PK) profile relative to the HTS hit 1a. One compound 2p possessed comparable efficacy as spironolactone (SPL) at 100 mg/kg (p.o.) in the rat natriuresis model. As such, this series was validated as a lead series for further optimization.

Sleep-disordered breathing (obstructive and central sleep apnea) is common in persons who have had a cerebrovascular accident (CVA). This article describes both sleep-disordered breathing and CVAs and reviews the related risk factors that link them together. In addition, the article discusses sleep-disordered breathing after CVA. The article concludes by presenting the clinical implications of this topic for nurses.

Before a Children's Court decision is reached, a clinical assessment may be ordered by the court. This assessment often occurs when tension is high for the family and when well-established defenses may falter, and it can provide a prime, critical opportunity to facilitate positive change. Comprehensive psychological assessment at the Children's Court Clinic in Melbourne, Australia, indicates the intervention value of a serious attempt to understand the complexity of the psychological issues facing a child and family. With the aid of illustrative case studies, this article discusses the therapeutic aspects and implications of such assessment.

Neoplastic diseases account for approximately one-half of all patients receiving home enteral nutrition, most of them with dysphagia due to the underlying cancer or antineoplastic therapies (malignant dysphagia). A review of the records of all patients with malignant dysphagia receiving home enteral nutrition for greater than 1 year was undertaken. The following factors were identified: age, primary cancer, type of enteral access, calories received, duration of therapy, complications, and need for tube replacement. Eighty-two patients were studied. On average, patients received 1978 cal/day (range: 500 to 3000) and were maintained on home enteral nutrition for 976 days (range: 367 to 3026). Complications at the tube site were infection in 4 patients (4.8%) and significant leakage in 2 patients (2.4%). Average durability of the enteral access devices was percutaneous endoscopic gastrostomies (PEG) = 690 days, low profile gastrostomy = 1701 days, percutaneous endoscopic jejunostomies (PEJ) = 591 days, low-p...

One nursing organization that closely tracks the direction of healthcare and nursing practice is the National Council of State Boards of Nursing, Inc. As the developer of the National Council Licensure Examination for Registered Nurses (NCLEX-RN examination), maintaining currency of the examination is of primary importance to the National Council. The authors discuss recent trends in the NCLEX-RN Test Plan.

Insulin lispro is an insulin analog in which the primary sequence has been altered by the inversion of amino acids B28 and B29. To date, it has not been possible to specifically measure insulin lispro in the presence of endogenous insulin because of the high degree of homology between these peptides. However, the specific determination of insulin lispro offers advantages over quantifying total concentrations of immunoreactive insulin. We therefore immunized guinea pigs and screened for antibodies with increased affinity and selectivity for insulin lispro. We prepared a monospecific antiserum by a novel immunoadsorption strategy using despentapeptide insulin. The antiserum was used to develop a competitive RIA for insulin lispro. The RIA has a low limit of quantification (17.2 pmol/L); has no interference from insulin, proinsulin, or C-peptide; and has interassay CVs of 2.6–13.4%. The new RIA is useful for measuring serum concentrations of insulin lispro.

A folk opera, AVE, explored issues of child abuse, sexual assault and violence through the character of Mary Magdelene. Using indigenous religious folklore images, Magdelene is befriended by Jesus's mother and healed of her childhood wound through a religious conversion. Six hundred secondary students attended three daytime performances and 486 returned a Likert‐scaled questionnaire. Results indicated most students perceived abuse as a personally relevant, real social problem, with felt relevance increasing with age. Significant trends supported initial expectations with an increase in community and personal awareness of child abuse/sexual assault and an increase in personal and community interest in helping others. Community risk factors contributing to denial of abuse were explored. More Hispanics responded positively to the sense of benefit. Findings suggest that performing arts can help increase awareness of child abuse as well as help stimulate personal and community interest in helping. Thi...

This study sought to validate a new noninvasive method to measure cardiac output, in the clinical setting, using color Doppler flow integration. This method, the automatic cardiac output measurement (ACOM), using color Doppler was recently developed and validated in vitro. ACOM was performed at the aortic valve and in the left ventricular outflow tract in 106 subjects (60 men, mean age 52 ± 18) and compared with the echocardiographic pulsed-wave Doppler and a 2-D volume method. In 14 patients the noninvasive methods were correlated with the thermodilution technique. ACOM was feasible in 101 subjects (95%). The correlation factor between the values obtained with ACOM in the apical 5-chamber view and apical long-axis view was 0.75 at the aortic valve and 0.74 in the left ventricular outflow tract. Interoperator variability for ACOM in the apical 5-chamber and apical long-axis views were 0.93 and 0.75, respectively. The best comparison of ACOM with the pulsed-wave echo-Doppler technique occurred in the apical long-axis view (n = 79, r = 0.62), whereas the correlation with the 2-D volume method was poor. The most favorable comparison of ACOM with the thermodilution technique (n = 14) was also obtained in the apical long-axis view (5.408 ± 1.72 vs. 3.356 ± l.281/min. [mean ± SD], r = 0.71). Assuming the thermodilution technique as ‘gold standard’, the pulsed-wave echo-Doppler technique showed a better correlation (5.408 ± 1.72 vs. 4.664 ± l.281/min., r = 0.84). ACOM is a useful, reproducible, noninvasive tool for rapid automated measurements of cardiac output. There is, however, an underestimation when compared with the pulsed-wave Doppler echocardiography and the thermodilution techniques. Good 2-D echocardiographic images, adequate color filling of the outflow tract and high frame rates are prerequisites for accurate values. Further refinements of this new technique are needed to enhance its clinical value in the future.

A series of conformationally restricted acetanilides were synthesized and evaluated as β3-adrenergic receptor agonists (β3-AR) for the treatment of overactive bladder (OAB). Optimization studies identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine β3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent β3-AR mediated responses in a rat bladder hyperactivity model.

Novel potent and selective mineralocorticoid receptor antagonists were identified, utilizing heterocyclic amide replacements in the oxazolidinedione series. Structure–activity relationship (SAR) efforts focused on improving lipophilic ligand efficiency (LLE) while maintaining nuclear hormone receptor selectivity and reasonable pharmacokinetic profiles.

Allison A Vanderbilt,1 Kim T Isringhausen,2 Patricia Brown Bonwell2,3 1Center on Health Disparities and School of Medicine, 2Department of Oral Health Promotion and Community Outreach, School of Dentistry, 3Dental Hygiene Program, School of Dentistry, Virginia Commonwealth University, Richmond, VA, USA Abstract: There is a lack of access to oral health care in the United States for rural, underserved, uninsured, and low-income populations. There are widely recognized problems with the US health care system, including rapidly increasing costs and access to oral health. During the last decade, there has been a huge influx and push toward interprofessional education programs; however, these programs conveniently leave out dental hygiene. Interprofessional education can bring forth the collaboration, communication, and teamwork necessary to provide a comprehensive health care plan to treat oral health care needs in patients. As the advanced practice for dental hygiene emerges, it is imperative that the educational qualifications of dental hygienists are sufficient to enable them to safely provide the scope of services and care encompassed in these new expanded roles and to effectively participate as an interprofessional team member. Keywords: interprofessional education, dental hygiene programs, dental hygiene education, oral health education

Objective: To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 ( C9ORF72 ), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases. Methods: A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72 . For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology. Results: We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin ( GRN : p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau ( MAPT : p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations. Conclusions: Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.

Human genetics studies in African Americans have shown a strong correlation between polymorphisms in the ApoL1 gene and chronic kidney disease (CKD). To gain further insight into the etiology of ApoL1-associated kidney diseases, the determination of circulating levels of both wild type as well as ApoL1 variants could be of significant use. To date, antibodies that discriminate between all three ApoL1 variant forms (wild type, G1 and G2) are not available. We aimed to develop a rapid method for detecting and quantifying ApoL1 variants and total levels in plasma.Ultra-performance liquid chromatography (UPLC) and tandem mass spectrometry (MS/MS) in multiple-reaction monitoring acquisition mode was used to quantify ApoL1.We demonstrated that it is feasible to detect and quantify ApoL1 variants (wild type, G1 and G2), and total ApoL1 concentrations in plasma. ApoL1 genotypes determined by LC/MS agreed perfectly with the traditional method DNA sequencing for 74 human subjects. The method exhibited at least three orders of linearity with a lower limit of quantification of 10 nM. Moreover, the method can readily be multiplexed for the quantification of a panel of protein markers in a single sample.The method reported herein obviates the need to perform DNA genotyping of ApoL1 variants, which is of significant value in cases where stored samples are unsuitable for DNA analysis. More importantly, the method could potentially be of use in the early identification of individuals at risk of developing CKD, and for the stratification of patients for treatment with future ApoL1-modifying therapies.

Studies in vitro suggest that the C-terminus of tropoelastin mediates elastin polymerization through an interaction with microfibril-associated proteins. In this study we have used cultured auricular chondrocytes as a model system to examine whether this interaction is critical for elastic fibre formation in vivo. Auricular chondrocytes, which deposit an abundant elastic fibre matrix, were cultured in the presence of Fab fragments of antibodies directed against the C-terminus (CTe) or an N-terminal domain (ATe) of tropoelastin. Immunofluorescent staining of the extracellular matrix deposited by the cells showed that the CTe antibody inhibited the deposition of elastin without affecting microfibril structure. Cells grown under identical conditions in the presence of ATe, however, formed fibres that stained normally for both elastin and microfibril proteins. Chondrocytes cultured in the presence of microfibril-associated glycoprotein (MAGP):21–35, an antibody directed against a domain near the N-terminus of MAGP, did not organize tropoelastin into fibres. However, immunostaining for MAGP and fibrillin revealed normal microfibrils. In agreement with the immunofluorescence staining patterns, fewer elastin-specific cross-links, indicative of insoluble elastin, were detected in the extracellular matrix of cells cultured in the presence of CTe. The medium from these cultures, however, contained more soluble elastin, consistent with an antibody-induced alteration of elastin assembly but not its synthesis. Northern analysis of antibody-treated and control cultures substantiated equivalent levels of tropoelastin mRNA. These results confirm that the C-terminus of tropoelastin interacts with microfibrils during the assembly of elastic fibres. Further, the results suggest that the interaction between tropoelastin and microfibrils might be mediated by a domain involving the N-terminal half of MAGP.

Surfactant protein D (SP-D) is preferentially secreted as dodecamers consisting of four collagenous trimers cross-linked by disulfide bonds. In these studies, we examined the biosynthesis of wild-type rat SP-D (RrSP-D) and selected mutants by stably transfected CHO-K1 cells to determine the roles of a conserved N-linked oligosaccharide, the collagen helix, and interchain disulfide bonds in SP-D assembly and secretion. The major intracellular form of RrSP-D accumulated in the RER as complexes containing up to four trimeric subunits. Disulfide cross-link formation and RrSP-D secretion were selectively inhibited by 2,2'-dipyridyl, an inhibitor of prolyl and lysyl hydroxylase, and by 2 mM dithiothreitol, but unaffected by tunicamycin or elimination of the consensus sequence for glycosylation at Asn70. Although mutants with serine substituted for Cys15 and Cys20 (RrSP-Dser15/20) are secreted as trimeric subunits, proteins with single cysteine substitutions were retained in the cell. Surprisingly, the secretion of RrSP-Dser15/20 was unaffected by 2,2'-dipyridyl. These studies strongly suggest that the most important and rate-limiting step for the secretion of SP-D involves the association of cross-linked trimeric subunits to form dodecamers stabilized by specific inter-subunit disulfide cross-links. Interference with collagen helix formation prevents secretion by interfering with efficient disulfide cross-linking of the NH2-terminal domain.

1. Some clients suffering from post-traumatic stress disorder (PTSD) are sensitive to having their personal space invaded by health care providers. 2. PTSD patients may react violently to personal space intrusions, such as when a health care provider wakes them suddenly, grabs them without permission, or when they are cornered and staff moves toward them without warning. 3. Through careful assessment and identification of violence as a nursing diagnosis, the nurse not only has information necessary to provide therapeutic intervention, but also has the capability to prevent physical harm to patients and staff.

Surfactant protein D (SP-D) molecules are preferentially assembled as dodecamers consisting of trimeric subunits associated at their amino termini. The NH2-terminal sequence of each monomer contains two conserved cysteine residues, which participate in interchain disulfide bonds. In order to study the roles of these residues in SP-D assembly and function, we employed site-directed mutagenesis to substitute serine for cysteine 15 and 20 in recombinant rat SP-D (RrSP-D), and have expressed the mutant (RrSP-Dser15/20) in Chinese hamster ovary (CHO-K1) cells. The mutant, which was efficiently secreted, bound to maltosyl-agarose, but unlike RrSP-D, was assembled exclusively as trimers. The constituent monomers showed a decreased mobility on SDS-polyacrylamide gel electrophoresis resulting from an increase in the size and sialylation of the N-linked oligosaccharide at Asn-70. Although RrSP-Dser15/20 contained a pepsin-resistant triple helical domain, it showed a decreased Tm, and acquired susceptibility to proteolytic degradation. Like RrSP-D, RrSP-Dser15/20 bound to the hemagglutinin of influenza A. However, it showed no viral aggregation and did not enhance the binding of influenza A to neutrophils (PMN), augment PMN respiratory burst, or protect PMNs from deactivation. These studies indicate that amino-terminal disulfides are required to stabilize dodecamers, and support our hypothesis that the oligomerization of trimeric subunits contributes to the anti-microbial properties of SP-D.

The alignment of elastin molecules in the mature elastic fiber was investigated by purifying and sequencing cross-link-containing peptides generated by proteolytic digestion of incompletely cross-linked insoluble elastin. Peptides of interest were purified by reverse phase and size exclusion high performance liquid chromatography and characterized by amino acid analysis and protein sequencing. One peptide, consisting of the cross-linking domain encoded by exon 10, contained a modified lysine residue that had not condensed to form a polyfunctional cross-link. Although this domain contains the characteristic paired lysine residues found in other cross-linking domains of elastin, protein sequence analysis indicated that the first but not the second lysine had been oxidized by lysyl oxidase. This finding suggests that lysine residues in an individual cross-linking domain may not have equal susceptibility to oxidation by lysyl oxidase. In a second peptide, we found that a major cross-linking site in elastin is formed through the association of sequences encoded by exons 10, 19, and 25 and that the three chains are joined together by one desmosine and two lysinonorleucine cross-links. Past structural studies and computer modeling predict that domains 19 and 25 are linked by a desmosine cross-link, while domain 10 bridges domains 19 and 25 through lysinonorleucine cross-links. These findings, together with the high degree of sequence conservation for these three domains, suggest an important function for these regions of the molecule, possibly nucleating the aggregation and polymerization of tropoelastin monomers in the developing elastic fiber.

This study of the differences between 23 men and 18 women who were convicted of partner homicide in Missouri found that the women were more likely to be injured and to seek medical attention as a result of the battering they received than were the men and had a higher level of fear of the batterers before they killed them. Furthermore, the modal sentence for these women was more severe than the modal sentence for the men.

Objectives To compare the prevalence of cognitive, neurologic, and behavioral outcomes at 10 years of age in 428 girls and 446 boys who were born extremely preterm. Study design A total of 889 of 966 eligible children previously enrolled in the multicenter Extremely Low Gestational Age Newborns Study from 2002-2004 were evaluated at 10 years of age. Children underwent a neuropsychological battery and testing for autism spectrum disorder (ASD), and parents reported on their child's behavior, development, and seizures. Results Of the children, 28% of boys and 21% of girls exhibited moderate to severe impairment on summary measures of cognitive abilities. Boys had a higher prevalence of impairment than girls in nearly all measures of cognition, were more than twice as likely to have microcephaly (15% in boys, 8% in girls), and require more often assistive devices to ambulate (6% in boys, 4% in girls). In contrast, boys and girls had comparable risk for a history of seizure (identified in 10% of the cohort) or epilepsy (identified in 7% of the cohort). The boy-to-girl ratio of ASD (9% in boys, 5% in girls) was lower than expected compared with the overall US autism population. Conclusions In this contemporary cohort of children born extremely premature and evaluated at school age, boys had higher prevalence of cognitive, neurologic, and behavioral deficits than girls. The ratio of boys to girls among those with ASD deserves further study as does the perinatal environmental-genetic interactions that might contribute to male preponderance of deficits in this high-risk sample.

Microfibril-associated glycoprotein (MAGP) is an integral component of microfibrillar structures that play a critical role in the organization of elastic fibers in the extracellular matrix. To study possible molecular interactions between MAGP and other elastic fiber components, we have generated native MAGP using a baculovirus expression system and tested its ability to associate with tropoelastin and fibrillin. MAGP produced by SF9 cells underwent processing similar to the mammalian protein, including correct cleavage of the signal peptide and sulfation of tyrosine residues. When tested in solid-phase binding assays, native MAGP specifically bound to tropoelastin but not fibrillin-1. Binding to tropoelastin was divalent cation-independent and was completely blocked by reduction and alkylation of either protein. Antibody inhibition studies indicated that the carboxyl terminus of tropoelastin mediated its interaction with MAGP. In addition to binding to elastin, MAGP was also a substrate for transglutaminase, which might explain its propensity to form high molecular weight aggregates that cannot be dissociated with reduction or denaturation. Together, the results of this study provide new insights into the functional relationship between microfibrillar proteins and have important implications for understanding elastic fiber assembly.