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Background Delirium is a common complication of critical illness with a significant impact on patient morbidity and mortality. The Greater Manchester Critical Care Network established the Delirium Reduction Working Group in 2015. This article describes a region-wide delirium improvement project launched by that group. Methods Multiple Plan-Do-Study-Act cycles were undertaken. Cycle 1: April 2015 demonstrated only 48% of patients had a formal delirium screen. Following this a network-wide event took place and the Delirium Standards for the Greater Manchester Critical Care Network were produced. Cycle 2: May 2016 quarterly audits across the network monitored compliance against the agreed standards. Group events involved implementation of a delirium care bundle, sharing best practice, educating staff and providing guidance on the management of delirium. Cycle 3: November 2016 quarterly audit continued and a regional delirium study day was rolled out across the region. Results We have 14 different units across our network, all of which have participated in the audit. The first audit showed a delirium point prevalence of 28%, subsequent point prevalence audits demonstrated rates as low as 13%. There has also been an improvement in the use of delirium screening tools. In the first audit 37% of patients had two delirium screens in 24 h, this has increased to 60% in the latest audit. Improvements were also made in availability of sensory aids and pain assessments. Conclusion The project has demonstrated the feasibility of delivering a coordinated delirium improvement project across multiple critical care units.

Background Pelvic organ prolapse is estimated to affect 41–50% of women aged > 40 years. A multicentre randomised controlled trial of individualised pelvic floor muscle training found that pelvic floor muscle training was effective in reducing symptoms of prolapse, improved quality of life and showed clear potential to be cost-effective. Provision of pelvic floor muscle training for prolapse has continued to vary across the UK, with limited availability of specialist physiotherapists to deliver it. Objectives This project aimed to study the implementation and outcomes of different models of delivery to increase the service provision of pelvic floor muscle training, and to follow up treatment outcomes for the original trial participants. Design A realist evaluation of pelvic floor muscle training implementation conducted within three full case study sites and two partial case study sites; an observational prospective cohort study comparing patient-reported outcomes pre and post intervention in all five sites; and a long-term follow-up study linking previous trial participants to routine NHS hospital data. Setting The setting for the realist evaluation was pelvic floor muscle training service delivery models in three NHS sites. The setting for the patient-reported outcome measures study was pelvic floor muscle training services in five NHS sites. Methods Realist evaluation qualitative data were collected at four time points in three case study sites to understand the implementation models, uptake, adherence and impact. Interviews involved service managers/leads, consultants, staff delivering pelvic floor muscle training and women receiving pelvic floor muscle training. Main outcomes measures Patient-reported outcomes were collected at baseline and at 6 and 12 months across five sites, including the Pelvic Organ Prolapse Symptom Score, health-related quality of life (measured using the EuroQol-5 Dimensions, five-level version, questionnaire), prolapse severity (measured using the Pelvic Organ Prolapse Quantification System), urinary incontinence (measured using International Consultation on Incontinence Questionnaire – Urinary Incontinence Short Form) and need for further treatment. Results A total of 102 women were recruited to the patient-reported outcome measures cohort study (target, n = 120), and 65 women had matched baseline and 6-month Pelvic Organ Prolapse Symptom Scores. The mean Pelvic Organ Prolapse Symptom Score was 10.18 (standard deviation 5.63) at baseline and 6.98 (standard deviation 5.23) at 6 months, representing a statistically significant and clinically meaningful difference. There was no statistically significant difference between the outcomes obtained from delivery by specialist physiotherapists and the outcomes obtained from delivery by other health-care professionals (mean change in Pelvic Organ Prolapse Symptom Score: –3.95 vs. –2.81, respectively). Services delivered using higher-band physiotherapists only were more costly than services delivered using other staff mixes. The effect of the original pelvic floor muscle training intervention, over a post-intervention period of > 10 years, was a reduction in the odds of any treatment during follow-up (odds ratio 0.61, 95% confidence interval 0.37 to 0.99). The realist evaluation revealed stark differences in implementation. The site with a specialist physiotherapy service resisted change because of perceived threats to the specialist role and concerns about care quality. Pelvic floor muscle training delivery by other health-care staff was easier when there was a lack of any existing specialist service; staff had prior training and interest in pelvic health; staff had support, autonomy, time and resources to deliver pelvic floor muscle training as part of their core role; and surrounding services supported a flow of pelvic floor muscle training referrals. Limitations The number of available matched pre and post outcomes for women and the lack of Pelvic Organ Prolapse Quantification System examinations were limitations of this study. Conclusions It is possible to train different staff to effectively deliver pelvic floor muscle training to women. Women’s self-reported outcomes significantly improved across all service models. Training should be adequately tailored to differential skill mix needs. Future work Future work should include further implementation of pelvic floor muscle training and should include pre- and post-outcome data collection using the Pelvic Organ Prolapse Symptom Score. Study registration This study is registered as Research Registry 4919. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 47. See the NIHR Journals Library website for further project information.

Background Pelvic Floor Muscle Training (PFMT) has been shown to be effective for pelvic organ prolapse in women, but its implementation in routine practice is challenging due to lack of adequate specialist staff. It is important to know if PFMT can be delivered by different staff skill mixes, what barriers and facilitators operate in different contexts, what strategies enable successful implementation and what are the underlying mechanisms of their action. PROPEL intervention was designed to maximise the delivery of effective PFMT in the UK NHS using different staff skill mixes. We conducted a realist evaluation (RE) of this implementation to understand what works, for whom, in what circumstances and why. Methods Informed by the Realist and RE-AIM frameworks, the study used a longitudinal, qualitative, multiple case study design. The study took place in five, purposively selected, diverse NHS sites across the UK and proceeded in three phases to identify, test and refine a theory of change. Data collection took place at 4 time points over an 18 month implementation period using focus groups and semi-structured interviews with a range of stakeholders including service leads/managers, senior practitioners, newly trained staff and women receiving care in the new service models. Data were analysed using thematic framework approach adapted to identify Context, Mechanism and Outcome (CMO) configurations of the RE. Results A heightened awareness of the service need among staff and management was a mechanism for change, particularly in areas where there was a shortage of skilled staff. In contrast, the most established specialist physiotherapist-delivered PFMT service activated feelings of role protection and compromised quality, which restricted the reach of PFMT through alternative models. Staff with some level of prior knowledge in women’s health and adequate organisational support were more comfortable and confident in new role. Implementation was seamless when PFMT delivery was incorporated in newly trained staff’s role and core work. Conclusion Roll-out of PFMT delivery through different staff skill mixes is possible when it is undertaken by clinicians with an interest in women’s health, and carefully implemented ensuring adequate levels of training and ongoing support from specialists, multi-disciplinary teams and management.

This article reports findings from a process and impact study of a residential early parenting centre programme in Australia. The programme supports parents with young children under the age of three, referred from health and child protection services. Multiple sources of data were used from interviews, focus groups, direct observations, observer notes and a parenting sense of competence questionnaire. Qualitative data were analysed using thematic analyses, and paired t-tests were used to test data from the questionnaire. Three themes emerged from thematic analysis of the qualitative data: engaging families, building parenting capacity and transitioning back to the community. Parents’ perceptions of parent competence improved significantly between admission and discharge for participating families. Detailed accounts of the way in which nurses work to achieve positive outcomes in relation to parenting confidence and satisfaction in the short term have provided useful insights into often taken-for-granted support processes in working with referred parents. The complexity of the nurses’ role and implications for nursing practice in residential parenting centres are discussed. Future research is warranted to determine longer-term benefits of this programme being delivered in a residential early parenting centre.

The demonstration of monitored natural attenuation (MNA) of chlorinated hydrocarbons in groundwater is typically conducted through the evaluation of concentration trends and parent-daughter product relationships along prevailing groundwater flow paths. Unfortunately, at sites contaminated by mixtures of chlorinated ethenes, ethanes, and methanes, the evaluation of MNA by using solely concentration data and parent-daughter relationships can result in erroneous conclusions regarding the degradation mechanisms that are truly active at the site, since many of the daughter products can be derived from multiple parent compounds. Stable carbon isotope analysis was used, in conjunction with concentration data, to clarify and confirm the active degradation pathways at a former waste solvent disposal site where at least 14 different chlorinated hydrocarbons have been detected in the groundwater. The isotope data indicate that TCE, initially believed to be present as a disposed product and/or a PCE dechlorination intermediate, is attributable to dehydrochlorination of 1,1,2,2-PCA. The isotope data further support that vinyl chloride and ethene in the site groundwater result from dichloroelimination of 1,1,2-trichlorethane and 1,2-dichloroethane, respectively, rather than from reductive dechlorination of the chlorinated ethenes PCE, TCE, or 1,2-DCE. The isotope data confirm that the chlorinated ethanes and chlorinated methanes are undergoing significant intrinsic degradation, whereas degradation of the chlorinated ethenes may be limited. In addition to the classical trend of enriched isotope values of the parent compounds with increasing distance associated to biodegradation, shifts of isotope ratios of degradation byproduct in the opposite direction due to mixing of isotopically light byproducts of biodegradation with compounds from the source are shown to be of high diagnostic value. These data underline the value of stable isotope analysis in confirming transformation processes at sites with complex mixtures of chlorinated compounds.

To examine the attitudes to and knowledge and beliefs about homosexuality of nurses and allied professionals in two early parenting services in Australia.Early parenting services employ nurses and allied professionals. Access and inclusion policies are important in community health and early childhood service settings. However, little is known about the perceptions of professionals who work within early parenting services in relation to lesbian, gay, bisexual and transgender families.This is the final in a series of studies and was undertaken in two early parenting services in two states in Australia using a cross-sectional design with quantitative and qualitative approaches.Validated questionnaires were completed by 51 nurses and allied professionals and tested with chi-squared test of independence (or Fisher's exact test), Mann-Whitney U-test, Kruskal-Wallis one-way analysis of variance or Spearman's rank correlation. Thematic analysis examined qualitative data collected in a box for free comments.Of the constructs measured by the questionnaires, no significant relationships were found in knowledge, attitude and gay affirmative practice scores by sociodemographic variables or professional group. However, attitude scores towards lesbians and gay men were significantly negatively affected by conservative political affiliation (p = 0·038), held religious beliefs (p = 0·011) and frequency of praying (p = 0·018). Six overall themes were found as follows: respect, parenting role, implications for the child, management, disclosure, resources and training.The study provided an in-depth analysis of the attitudes, knowledge and beliefs of professionals in two early parenting services, showing that work is needed to promote acceptance of diversity and the inclusion of lesbian, gay, bisexual and transgender families in planning, developing, evaluating and accessing early parenting services.Access and inclusion plans for lesbian, gay, bisexual and transgender families are crucial in early parenting services in Australia and should be included in professional development programmes.

A naturally occurring retirement community (NORC) with supportive service programs holds great promise for providing cost-effective services to enable seniors to age in place. This article describes program activities, services, partnerships, and indicators for a successful 3-mile suburban neighborhood NORC. Program evaluation of participation and exit data are powerful indicators of success: St. Louis NORC's nursing home placement rate is 2% compared to the national average of 4.5%, and its state average of 4.8%. A case study demonstrates the importance of resident awareness of availability of NORC services and home modifications.

(R)-N-{1-[3-(4-Ethoxy-phenyl)-4-oxo-3,4-dihydro-pyrido[2,3-d]-pyrimidin-2-yl]-ethyl}-N-pyridin-3-yl-methyl-2-(4-trifluoromethoxyphenyl)-acetamide (AMG 487) is a potent and selective orally bioavailable chemokine (C-X-C motif) receptor 3 (CXCR3) antagonist that displays dose- and time-dependent pharmacokinetics in human subjects after multiple oral dosing. Although AMG 487 exhibited linear pharmacokinetics on both days 1 and 7 at the 25-mg dose, dose- and time-dependent kinetics were evident at the two higher doses. Nonlinear kinetics were more pronounced after multiple dosing. Area under the plasma concentration-time curve from 0 to 24 h [AUC(0–24 h)] increased 96-fold with a 10-fold increase in dose on day 7 compared with a 28-fold increase in AUC(0–24 h) on day 1. These changes were correlated with time- and dose-dependent decreases in the metabolite to parent plasma concentrations, suggesting that these changes result from a decrease in the oral clearance (CL) of AMG 487 (e.g., intestinal/hepatic first-pass metabolism and systemic CL). The biotransformation of AMG 487 is dependent on CYP3A and results in the formation of two primary metabolites, a pyridyl N-oxide AMG 487 (M1) and an O-deethylated AMG 487 (M2). One of these metabolites, M2, undergoes further metabolism by CYP3A. M2 has also been demonstrated to inhibit CYP3A in a competitive (Ki = 0.75 μM) manner as well as via mechanism-based inhibition (unbound KI = 1.4 μM, kinact = 0.041 min–1). Data from this study implicate M2-mediated CYP3A mechanism-based inhibition as the proximal cause for the time-dependent pharmacokinetics of AMG 487. However, the sequential metabolism of M2, nonlinear AMG 487 pharmacokinetics, and the inability to accurately determine the role of intestinal AMG 487 metabolism complicates the correlation between M2 plasma concentrations and the time-dependent AMG 487 pharmacokinetic changes.

The authors of this article noticed that the first-grade students in their urban elementary school were producing writing that was dry, dull, and filled with “listy” sentences with little detail or description. They decided to try adding free-verse poetry writing at the beginning of the school year and then including poetry all year long in the curriculum to improve the quality of student writing. The article outlines their journey as they incorporated poetry writing in their curriculum. The free-verse poetry used in the lessons doesn't require rhyming, thus freeing the young authors to focus on elements such as feelings, rich vocabulary, and literary devices. The authors outline their beginning lessons around a Halloween theme. They modeled writing for students and included the use of repetition in their poetry. Even the most reluctant writers began to write with exuberance and voice. Subsequent lessons included using poetry with nonfiction topics and with small guided-writing groups. The students ultimately wrote more confidently and enthusiastically, creating interesting pieces all year long.

Emotional labour is a state that exists when there is a discrepancy between the emotional demeanour that an individual displays and the genuinely felt emotions that would be inappropriate to display (Mann 1999b). The study examined levels of emotional labour in university lecturers and compared these data to other occupations. Employing a mixed methods design, a sample of 61 university lecturers participated in the study. Emotional labour was measured using Mann’s Emotional Requirements Inventory (MERI). Results showed that university lecturers reported significantly higher levels of emotional labour than other occupations including mental health nurses and a mix of frontline and back office employees. Age and length of service were found to be significant factors for emotional labour in university lecturers. Qualitative findings identified the main themes as increased workloads, eroding job autonomy, uncertainty about the future and job satisfaction. Based on findings from the study, a conceptual model of emotional labour in higher education was proposed, the Higher Education Emotional Labour Model (HEEL). Implications for university senior management in recognising the high levels of emotional labour levels were considered. Further suggested research directions considered include work to determine the frequency of emotional labour in university lecturers, testing the validity of the proposed Higher Education Emotional Labour Model and investigating the job role characteristics of a university lecturer.

Objective: The objective of this paper is to report on the development and implementation of a community-based perinatal and infant mental health day program for mothers with psychiatric illness. The program was initiated through interagency collaboration between adult mental health, infant mental health and community child health services in Queensland, Australia in response to calls for an integrated approach that could be delivered state-wide if successful. Preliminary results of the program’s evaluation are provided. Method: A pre-post survey design was used to assess the influence the program had on maternal mental and emotional well-being and the maternal-infant relationship. Twenty-one women receiving treatment for perinatal mental illness gave consent to attend the 6-week day program integrating three currently separate and discrete services: adult mental health, infant mental health and community child health. Results: Clinically and statistically significant improvements were observed for maternal mental health, and parent-infant relationships following the program. Conclusions: These findings support interagency collaboration between adult mental health, infant mental health and community child health services to deliver services to women with mental illness with newborns and their families. The utility of using a collaborative approach in a community setting endorses more comprehensive and longer-term evaluation of effectiveness and cost benefit.

A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.

A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.

(R)-N-{1-[3-(4-Ethoxy-phenyl)-4-oxo-3,4-dihydro-pyrido[2,3-d]-pyrimidin-2-yl]-ethyl}-N-pyridin-3-yl-methyl-2-(4-trifluoromethoxyphenyl)-acetamide (AMG 487) is a potent and selective orally bioavailable chemokine (C-X-C motif) receptor 3 (CXCR3) antagonist that displays dose- and time-dependent pharmacokinetics in human subjects after multiple oral dosing. Although AMG 487 exhibited linear pharmacokinetics on both days 1 and 7 at the 25-mg dose, dose- and time-dependent kinetics were evident at the two higher doses. Nonlinear kinetics were more pronounced after multiple dosing. Area under the plasma concentration-time curve from 0 to 24 h [AUC((0-24 h))] increased 96-fold with a 10-fold increase in dose on day 7 compared with a 28-fold increase in AUC((0-24 h)) on day 1. These changes were correlated with time- and dose-dependent decreases in the metabolite to parent plasma concentrations, suggesting that these changes result from a decrease in the oral clearance (CL) of AMG 487 (e.g., intestinal/hepatic first-pass metabolism and systemic CL). The biotransformation of AMG 487 is dependent on CYP3A and results in the formation of two primary metabolites, a pyridyl N-oxide AMG 487 (M1) and an O-deethylated AMG 487 (M2). One of these metabolites, M2, undergoes further metabolism by CYP3A. M2 has also been demonstrated to inhibit CYP3A in a competitive (K(i)=0.75 microM) manner as well as via mechanism-based inhibition (unbound K(I)=1.4 microM, k(inact)=0.041 min(-1)). Data from this study implicate M2-mediated CYP3A mechanism-based inhibition as the proximal cause for the time-dependent pharmacokinetics of AMG 487. However, the sequential metabolism of M2, nonlinear AMG 487 pharmacokinetics, and the inability to accurately determine the role of intestinal AMG 487 metabolism complicates the correlation between M2 plasma concentrations and the time-dependent AMG 487 pharmacokinetic changes.

The cellular changes that take place as the intestinal cell migrates from crypt to villus are morphologically and biochemically remarkable. It is fortunate that many of these phenomena can be delineated by following enzymic activities. Sucrase-isomaltase is a particularly fascinating enzyme complex because it is a marker of the differentiated cell. Sucrase is inducible with steroids and protected by the substrate sucrose. Purified enzyme can be used to stimulate production of specific antibodies in goats; these antibodies have been used as probes to locate enzymically active and inactive antigen in the cells of the crypt and villus respectively. Further examination of the enzyme has indicated a molecular weight of 200 000--350 000. These higher molecular weight components are located in the brush border of the enterocytes. Lower molecular weight subunits are antigenically active and are in the cytosol. It is assumed that these smaller components are enzymically inactive pre-combination subunits of the sucrase-isomaltase complex and that the sucrase-isomaltase of the brush border is an aggregate of these subunits. The California sea lion, which is deficient in intestinal sucrase activity, does have isomaltase activity. This finding supports the concept that there are different gene complexes for sucrase and for isomaltase.

3051 Antibody-based B-cell specific therapeutic approaches have revolutionized the treatment of non-Hodgkin's lymphomas (NHL) as well as other hematological malignancies. However, a large variability in clinical response has been observed, and the need to develop effective new treatments remains urgent. A promising approach is the use of antibody-drug conjugates (ADCs), cytotoxic drugs covalently linked to antibodies through specialized chemical linkers for the treatment of NHL. CMC-544, an antibody to a B-cell specific glycoprotein CD22 conjugated to the cytotoxin calicheamicin, has shown clinical activity in patients. In addition, antibodies directed to B-cell targets such as rituximab and epratuzumab are in clinical trials for the treatment of NHL and autoimmune disorders. We have generated10F4v3, an anti-CD22 antibody conjugated to the antimitotic agent maytansine (10F4v3-DM1). DM1 disrupts cellular mitosis through inhibition of tubulin polymerization when internalized into cells. The anti-CD22 DM1 conjugate was shown to have significant potency in preclinical efficacy models of NHL. In order to further characterize this antibody-drug conjugate in preclinical studies, we first evaluated the binding characteristics of the 10F4v3 to peripheral blood B-cells from various geographical sources of cynomolgus monkeys. 10F4v3 bound to peripheral blood B-cells from all cynomolgus monkeys of Indonesian and Mauritian origins, but displayed only limited binding to cynomolgus monkeys of Chinese and Cambodian origins. Therefore, further preclinical evaluation of 10F4v3-DM1 was conducted in Indonesian cynomolgus monkeys to examine the safety, pharmacokinetic, and pharmacodynamic effects in monkeys. B-cells and B-cell subsets were depleted in peripheral blood and lymphoid tissue (spleen, bone marrow) at all doses, with no apparent dose-dependent effects or substantial safety limitations. Based on the nonclinical data, 10F4v3-DM1 exhibits an encouraging pharmacodynamic profile for the potential treatment of non-Hodgkin's lymphoma. [Table: see text]

Antibody-based therapeutic approaches have revolutionized the treatment of non-Hodgkin's lymphomas (NHL) as well as other hematological malignancies. However, a large variability in clinical response has been observed and patients with refractory or relapsed lymphomas have limited therapeutic options. Antibody drug conjugates (ADC) may prove valuable in this respect. The B cell surface antigen, CD79b, is an attractive target for this approach as it is rapidly internalized upon antibody engagement and has an appropriate expression pattern, being expressed only on normal and malignant B-cells. Anti-CD79b-MCC-DM1 is an ADC consisting of a chimeric monoclonal anti-CD79b antibody, 10D10, conjugated via a thioether linker to a cytotoxic drug, DM1 (a potent tubulin polymerization inhibitor). To investigate the pharmacodynamics (PD), pharmacokinetics (PK), and tolerability of 10D10-MCC-DM1 in nonhuman primates, we administered 10D10-MCC-DM1 or unconjugated antibody 10D10 to cynomolgus monkeys. 10D10-MCC-DM1 and 10D10 resulted in sustained depletion of B-cells and B cell subsets in blood, with more substantial depletion in the group given 10D10-MCC-DM1. These findings correlated well with the depletion of B-cells observed in lymphoid tissues (bone marrow, lymph nodes, and spleen). Both 10D10-MCC-DM1 and 10D10 were well tolerated. Taken together, these preclinical data suggest that targeting CD79b with ADCs may provide a safe and effective therapy for B-cell malignancies in humans.

Chronic graft-versus-host disease (cGVHD) is the most common late complication after allogeneic hematopoietic cell transplantation (HCT). Its pathophysiology is poorly understood, a problem hampered by the scarcity of mouse models that accurately reproduce the human scenario. While acute (aGVHD) is characterized by donor T cell (doTC) infiltration damaging target tissues, cGVHD displays a wider range of alterations, often resulting in fibrosis with disrupted tissue architecture. Whether or not doTC drive this process versus (vs) other cell types has not yet been clarified. Indirect disruption of normal immunity caused by destruction of lymphoid tissues could contribute to the autoimmune-like syndrome. Here, we describe the progression of lymphocyte infiltrations of GVH targets post-HCT. Two MHC-matched, minor antigen-mismatched strain combinations were studied. Myeloablated BALB. B (H2b) and BALB/c (H2d) recipients were given FACS purified hematopoietic stem cells (HSC: c-Kit+Thy1.1loLin-Sca-1+) + 10^7 splenocytes (SP) from C57BL/6 (B6) (H2Db) or B10.D2 (H2d) donors, respectively. Mononuclear cells (MNC) from bone marrow (BM), spleen, lymph nodes (LN), thymus, peripheral blood, and liver were FACS analyzed for cell (sub-) type and chimerism 14, 28, 50 and 150 days (d) post-HCT. BALB.B recipients of B6 HSC + SP developed aGVHD with severe weight loss (>30%) and a mortality of 22%. Survivors never fully recovered baseline weight. Histologic changes shifted from defined infiltrates to disseminated disruptions of tissue structures. In contrast, BALB/c recipients showed sclerodermatous skin changes, but no mortality or other signs of systemic disease. In both strains the BM was markedly infiltrated with doTC during the acute phase: 14d post-HCT BALB.B BM consisted of ~50% mature doTC, and the majority (2/3) of these were CD8+ with an effector memory (EM) phenotype (CD8 TC, naïve TC phenotypes exceeding EM, and ~40% BC. In conclusion, doTC infiltration of host organs is not inevitably associated with impairment of organ function and clinical disease. Nonspecific invasion of doTC likely occurs throughout the organism post-allogeneic HCT, and specific stimuli, such as minor antigens or cytokines are required to activate and perpetuate pathology. These data further suggest that characterizing the composition in the infiltrate in the acute setting may permit prediction of whether or not the initial infiltrates will lead to the fibrotic and sclerotic changes, the hallmarks of cGVHD.

CD22 is a B cell-specific glycoprotein expressed on the cell surface of all mature B cells. A candidate therapeutic anti-CD22 antibody, 10F4v3, was conjugated to the anti-mitotic agent maytansine (10F4v3-DM1). DM1 disrupts cellular mitosis through inhibition of tubulin polymerization when internalized into cells. The anti-CD22 DM1 conjugate was shown to have significant potency in preclinical efficacy models of NHL. In order to further characterize this antibody-drug conjugate in preclinical studies, we first evaluated the binding characteristics of the 10F4v3 to peripheral blood B cells from various geographical sources of cynomolgus monkeys. 10F4v3 bound to peripheral blood B cells from all cynomolgus monkeys of Indonesian and Mauritian origins, but displayed only limited binding to cynomolgus monkeys of Chinese and Cambodian origins. Therefore, further pre-clinical evaluation of 10F4v3-DM1 was conducted in Indonesian cynomolgus monkeys to examine the safety, pharmacokinetic, and pharmacodynamic effects in monkeys dosed at 10, 20, and 30 mg/kg (2000, 4000, and 6000 mg/m2 DM1). Pharmacodynamic assessments of peripheral blood and lymphoid tissues included examination of B cells, B cell subsets, CD4+ T cells, CD8+ T cells, and CD3−CD20− (NK) cells. B cell subsets included CD20+, CD20+CD21+, CD20+CD21−, CD20+CD21+CD27+, CD20+CD21+CD27−, and CD20+CD21high lymphocytes which are phenotypically similar to human B cells, mature B cells, germinal center B cells, memory B cells, naïve B cells, and marginal zone B cells, respectively. B cells and B cell subsets were substantially depleted in peripheral blood at all doses, with no apparent dose-dependent effects. In lymphoid tissue, B cells were also depleted, with substantial depletion of CD20+CD21− and CD20+CD21high B cell subsets in spleen and bone marrow. Based on the nonclinical data, 10F4v3-DM1 exhibits an encouraging pharmacodynamic profile that supports clinical development for the potential treatment of non-Hodgkin’s lymphoma.

Heteroduplex DNA molecules, prepared by hybridizing DNA of adenovirus serotypes 1, 2 and 5 in all three combinations, have been shown by electron microscopy to contain two specifically located mismatched regions. Single-strand specific nucleases from Neurospora crassa cleaved the heteroduplexes into three fragments as demonstrated by sucrose gradient analysis, agarose gel electrophoresis and electron microscopy. These were produced in equimolar amounts, and were shown by alkaline sucrose gradient analysis to be free of internal single-strand interruptions. The size of each of the fragments was determined by sucrose gradient analysis and by electron microscopic measurements of the contour lengths. The three values obtained correspond to the lengths of the three double-stranded regions in the untreated heteroduplex molecules. The fragments, free of detectable single-stranded tails, have been isolated preparatively from neutral sucrose gradients. Renaturation kinetic analyses support the conclusion that each fragment represents a unique segment of the adenovirus genome.

Attribution of responsibility for sexual dysfunction among couples seeking sexual counseling was investigated in relation to sex of respondent and traditionalism of religious affiliation. Subjects were 190 married couples applying for treatment of sexual dysfunction. The results indicated a tendency for women to attribute responsibility to their spouses complemented by men's attribution of responsibility to themselves. However, when traditionalism of religious group affiliation was employed as a moderator, these sex differences in attribution were found to characterize only members of nontraditional religious groups. No sex differences were found for members of traditional religious groups, with average attribution scores falling around the midpoint of the spouse-self attribution dimension. Implications of the findings for further research and for practice are discussed.

The response of increasingly large numbers of American young men to compulsory military service is immigration to Canada. Viewing interaction between these men (and their wives) and their families, their society, and their new country of choice, provides insights into their commitments versus their alienation.

Serial passage of the non-defective form of a simian virus 40-like virus (DAR) isolated from human brain results in the appearance of three distinct classes of supercoiled DNAs: R I resistant, R I sensitive (one cleavage site) and R I “supersensitive” (three cleavage sites). The R I cleavage product of the “super sensitive” form is one-third the physical size of simian virus 40 DNA (10.4 S) and reassociates about three times more rapidly than “standard” viral DNA. To identify the portions of the DAR genome present in the 10.4 S segment, the plus strand of each of the 11 fragments of 32 P-labeled simian virus 40 DNA, produced by cleavage with the Hemophilus influenzae restriction endonuclease, was hybridized in solution with the sheared R I cleavage product of the “supersensitive” class of viral DNA. Reaction was observed with fragments located in two distinct regions of the simian virus 40 genome: (1) Hin -A and C; (2) Hin -G, J, F and K. Further studies indicated that simian virus 40 complementary RNA transcribed in vitro with Escherichia coli RNA polymerase from one strand of simian virus 40 DNA reacts with both strands of the denatured 10.4 S cleavage product when hybridization is monitored with hydroxyapatite. Treatment of the 10.4 S DNA-simian virus 40 cRNA hybrid with the single-strand spcific nuclease, S 1 , converted approximately 50% of the radioactive counts to an acid-soluble product. These results indicate that the 10.4 S product contains a transposition of sequences originally present on one of the DAR DNA strands to the other strand. Examination of heteroduplexes formed between the 10.4 S segment and unique linear forms of DAR DNA produced with the R · Eco RI restriction endonuclease have confirmed these observations. Thus it appears that a molecular rearrangement(s) has resulted in the recombination and inversion of viral DNA sequences from two separate loci on the parental DAR genome. This 1.1 × 10 6 dalton segment is reiterated three times in a supercoiled molecule equivalent in physical size to parental DAR DNA.