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Objective: The Exercise Program in Cancer and Cognition (EPICC) Study was a randomized controlled trial (RCT) designed to determine whether six months of moderate-intensity aerobic exercise improves neurocognitive function in women with breast cancer (BC) receiving endocrine therapy (ET)., Methods: Postmenopausal women with hormone receptor+, early-stage BC, within two years post-primary therapy were randomized to the exercise intervention (six months, ≥150 minutes of moderate-intensity aerobic exercise/week) or usual care control condition. Outcomes were assessed at pre-randomization and after intervention completion. Groups were compared using linear mixed-effects modeling., Results: Participants (N=153) were X ¯ = 62.09 ± 8.27 years old, with stage I BC (64.1%) and a median of 4.7 months post-diagnosis. We found a group-by-time interaction (p=0.041) and a trend for the main effect of time (p=0.11) for processing speed with improved performance in the exercise group and no change in the controls. Similar main effects of time were observed for learning and memory (p=0.024) and working memory (p=0.01). Better intervention adherence was associated with improved processing speed (p=0.017)., Conclusions: Six months of moderate-intensity aerobic exercise improves processing speed in postmenopausal women with BC receiving ET who initiate exercise within two years of completing primary therapy (surgery +/- chemotherapy). This is the first large-scale study to examine the effects of aerobic exercise on neurocognitive function in women with BC. Additional research is needed to address the long-term effects of aerobic exercise on cognitive function.

Reading musical notation while interpreting it on a musical instrument poses problems for musicians with a visual impairment (VI). This study sought to describe the visual aids, adaptations and compensatory strategies used by five amateur pianists with low vision when reading music, to identify the problems they face when using these aids, and to verify whether a head-mounted display (HMD) such as eSight Eyewear can be used to overcome some of them. In this exploratory study, the participants read and interpreted two excerpts of musical notation using eSight Eyewear. The data, collected through interviews, were coded using a qualitative method and a phenomenological approach. The results suggest that musicians with a VI use various visual aids, adaptations and compensatory strategies. However, these approaches are not without significant problems, particularly when they involve magnification. On the other hand, eSight Eyewear allows users to adjust magnification, have their hands free and use adapted musical notation. Many magnification-related problems are overcome with this HMD, which can be used to simultaneously read and interpret standard musical notation. However, reading sheet music with such a device remains a complex task, given the need to control head movements accordingly.

Zizania palustris L. (northern wild rice, NWR) is an aquatic grass native to North America that is notable for its nutritious grain. This is an important species with ecological, cultural and agricultural significance, specifically in the Great Lakes region of the USA. Using flow cytometry, we first estimated the NWR genome size to be 1.8 Gb. Using long- and short-range sequencing, Hi-C scaffolding and RNA-seq data from eight tissues, we generated an annotated whole-genome de novo assembly of NWR. The assembly was 1.29 Gb in length, highly repetitive (approx. 76.0%) and contained 46 421 putative protein-coding genes. The expansion of retrotransposons within the genome and a whole-genome duplication (WGD) after the Zizania-Oryza speciation event have both led to an increase in the genome size of NWR in comparison with Oryza sativa L. and Zizania latifolia. Both events depict a genome rapidly undergoing change over a short evolutionary time. Comparative analyses revealed the conservation of large syntenic blocks between NWR and O. sativa, which were used to identify putative seed-shattering genes. Estimates of divergence times revealed that the Zizania genus diverged from Oryza approximately 26-30 million years ago (26-30 MYA), whereas NWR and Z. latifolia diverged from one another approximately 6-8 MYA. Comparative genomics confirmed evidence of a WGD in the Zizania genus and provided support that the event occurred prior to the NWR-Z. latifolia speciation event. This genome assembly and annotation provides a valuable resource for comparative genomics in the Oryzeae tribe and provides an important resource for future conservation and breeding efforts of NWR., (© 2021 Society for Experimental Biology and John Wiley & Sons Ltd.)

Emerging foodborne pathogens present a threat to public health. It is now recognized that several foodborne pathogens originate from wildlife as demonstrated by recent global disease outbreaks. Zoonotic spillover events are closely related to the ubiquity of parasitic, bacterial, and viral pathogens present within human and animal populations and their surrounding environment. Foodborne diseases have economic and international trade impacts, incentivizing effective wildlife disease management. In North America, there are no food safety standards for handling and consumption of free-ranging game meat. Game meat consumption continues to rise in North America; however, this growing practice could place recreational hunters and game meat consumers at increased risk of foodborne diseases. Recreational hunters should follow effective game meat food hygiene practices from harvest to storage and consumption. Here, we provide a synthesis review that evaluates the ecological and epidemiological drivers of foodborne disease risk in North American hunter populations that are associated with the harvest and consumption of terrestrial mammal game meat. We anticipate this work could serve as a foundation of preventive measures that mitigate foodborne disease transmission between free-ranging mammalian and human populations.

Background: The Mesure de l'impact de la déficience visuelle dans les activités quotidiennes (MIDVAQ) is the Canadian-French adaptation of the Melbourne Low-Vision ADL Index. It measures performance, personal importance and handicap situation in 16 instrumental activities requiring near vision (standardized material, part A) and in 9 self-care and domestic activities (self-report questionnaire, part B). This study aimed at measuring the MIDVAQ reliability and its relationship with measures of visual functions and functional vision. Methods: The MIDVAQ was administered twice to 100 visually impaired participants, at home, with their personal visual and non-visual aid. A second rater was present at T1. Two different versions of part A were used alternately at T1 and T2. Results: The total Handicap scale demonstrates good internal reliability (Cronbach's alpha coefficient = 0.82) and very high inter-rater and test-retest reliability ( ICC s = 1.00 and 0.86). Part A alternative versions are highly comparable. Vision function measures are significantly correlated with total Handicap score, for which 48% of the variance is explained by functional vision estimates, age, and education. Conclusions: The MIDVAQ is highly valid and reliable. It can be useful to measure the functional impact of the visual impairment, its progression, and the outcomes of low vision rehabilitation services.Implications for rehabilitationEven if administered at home in an ecological way, this measure of the impact of the visual impairment in daily activities is very reliable.Given its good metric properties, this tool can be confidently used to assess the functional impact of visual impairment, outcomes of the low vision rehabilitation services, etc.This measurement tool provides complementary information to those obtained from clinical measures of visual functions, by reflecting the interaction between the functional abilities with the requirements of the environment.

Significance: Lighting assessments are an important component of low-vision rehabilitation but are rarely studied systematically. Our study indicates that preferred lighting levels support improvements in reading ease and enjoyment, independently of the evaluation technique. To determine preferred illumination level and color temperature, the LuxIQ is quicker to administer and covers broad options of settings., Purpose: The purpose of this study was to determine if preferred lighting, as assessed by the LuxIQ versus a standard lighting assessment, leads to better reading outcomes in individuals with low vision., Methods: Preferred lighting was assessed at home with visually impaired persons (mean age, 75.3 years), using the LuxIQ (n = 18) or a standard technique based on trying out light bulbs of various intensity and color temperature (n = 16). Maximum reading speed and reading acuity were measured before the lighting intervention and then under the preferred lighting conditions. A 1-month telephone follow-up evaluated the (1) compliance with the lighting recommendations and, for those who modified their lighting, (2) their level of satisfaction with the length of reading time and eye strain felt during reading., Results: Compared with usual lighting conditions, most participants preferred a cooler temperature at a higher illuminance level. Neither lighting assessment type appeared to lead to substantially improved objectively measurable reading outcomes. At the 1-month follow-up, 56% of the participants had modified their lighting, having a significant effect on satisfaction (P < .01), independent of assessment method. Of 18 respondents, 16 (87.5%) mentioned that reading was more enjoyable or easier with the lighting modifications., Conclusions: Both lighting assessment methods lead to comparable results, but the LuxIQ is easier and faster to use. More research is needed to determine whether the LuxIQ is suitable to be incorporated into clinical practice.

Background: Cardiac and major vascular surgeries are common surgical procedures associated with high rates of postsurgical complications and related hospital readmission. In-hospital remote automated monitoring (RAM) and virtual hospital-to-home patient care systems have major potential to improve patient outcomes following cardiac and major vascular surgery. However, the science of deploying and evaluating these systems is complex and subject to risk of implementation failure., Objective: As a precursor to a randomized controlled trial (RCT), this user testing study aimed to examine user performance and acceptance of a RAM and virtual hospital-to-home care intervention, using Philip's Guardian and Electronic Transition to Ambulatory Care (eTrAC) technologies, respectively., Methods: Nurses and patients participated in systems training and individual case-based user testing at two participating sites in Canada and the United Kingdom. Participants were video recorded and asked to think aloud while completing required user tasks and while being rated on user performance. Feedback was also solicited about the user experience, including user satisfaction and acceptance, through use of the Net Promoter Scale (NPS) survey and debrief interviews., Results: A total of 37 participants (26 nurses and 11 patients) completed user testing. The majority of nurse and patient participants were able to complete most required tasks independently, demonstrating comprehension and retention of required Guardian and eTrAC system workflows. Tasks which required additional prompting by the facilitator, for some, were related to the use of system features that enable continuous transmission of patient vital signs (eg, pairing wireless sensors to the patient) and assigning remote patient monitoring protocols. NPS scores by user group (nurses using Guardian: mean 8.8, SD 0.89; nurses using eTrAC: mean 7.7, SD 1.4; patients using eTrAC: mean 9.2, SD 0.75), overall NPS scores, and participant debrief interviews indicated nurse and patient satisfaction and acceptance of the Guardian and eTrAC systems. Both user groups stressed the need for additional opportunities to practice in order to become comfortable and proficient in the use of these systems., Conclusions: User testing indicated a high degree of user acceptance of Philips' Guardian and eTrAC systems among nurses and patients. Key insights were provided that informed refinement of clinical workflow training and systems implementation. These results were used to optimize workflows before the launch of an international RCT of in-hospital RAM and virtual hospital-to-home care for patients undergoing cardiac and major vascular surgery., (©Michael Hugh McGillion, Carley Ouellette, Amber Good, Marissa Bird, Shaunattonie Henry, Wendy Clyne, Andrew Turner, Paul Ritvo, Sarah Ritvo, Nazari Dvirnik, Andre Lamy, Richard Whitlock, Christopher Lawton, Jake Walsh, Ken Paterson, Janine Duquette, Karla Sanchez Medeiros, Fadi Elias, Ted Scott, Joseph Mills, Deborah Harrington, Mark Field, Prathiba Harsha, Stephen Yang, Elizabeth Peter, Sanjeev Bhavnani, PJ Devereaux. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 18.03.2020.)

Objective: The purpose of this study was to develop a French Canadian questionnaire for the detection of Charles Bonnet syndrome that allows for (i) valid screening and (ii) the examination of different dimensions of the client's visual hallucinations in order to better assess the resulting needs., Method: Questionnaire development was guided by interviews with visually impaired individuals experiencing visual hallucinations, as well as supported by scientific literature and expert experience. A clinical study involving 76 individuals with low vision was conducted to determine the sensitivity and specificity of the instrument according to criterion validation., Results: Of the 54 closed-ended questions, a subset of 11 revealed a sensitivity of 1.00 and a specificity of 0.77. Two additional questions showed high discriminating potential. Improvements to the wording and structure of some questions aiming at needs assessment were identified and applied. The improved version consists of 55 questions grouped in 8 dimensions: (1) Screening; (2) Characteristics of hallucinations; (3) Psychological impact; (4) Psychopathological origin; (5) Coping strategies; (6) Context of appearance of hallucinations; (7) Time-related matters; (8) Psychosocial support. The screening is operationalized through an algorithm applied to the set of 13 questions., Conclusion: The questionnaire will be a valuable aid in screening for Charles Bonnet syndrome among the low vision clientele. However, the screening will need to be supplemented by a focused low vision interdisciplinary assessment including a visual examination and a clinical interview with a psychologist., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Optimization of the potency and pharmacokinetic profile of 2,3,4-trisubstituted quinoline, 4, led to the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 6a (AM-0687) and 7 (AM-1430). On the basis of their improved profile, these analogs were selected for in vivo pharmacodynamic (PD) and efficacy experiments in animal models of inflammation. The in vivo PD studies, which were carried out in a mouse pAKT inhibition animal model, confirmed the observed potency of 6a and 7 in biochemical and cellular assays. Efficacy experiments in a keyhole limpet hemocyanin model in rats demonstrated that administration of either 6a or 7 resulted in a strong dose-dependent reduction of IgG and IgM specific antibodies. The excellent in vitro and in vivo profiles of these analogs make them suitable for further development.

Background: Tens of thousands of cardiac and vascular surgeries (CaVS) are performed on seniors in Canada and the United Kingdom each year to improve survival, relieve disease symptoms, and improve health-related quality of life (HRQL). However, chronic postsurgical pain (CPSP), undetected or delayed detection of hemodynamic compromise, complications, and related poor functional status are major problems for substantial numbers of patients during the recovery process. To tackle this problem, we aim to refine and test the effectiveness of an eHealth-enabled service delivery intervention, TecHnology-Enabled remote monitoring and Self-MAnagemenT-VIsion for patient EmpoWerment following Cardiac and VasculaR surgery (THE SMArTVIEW, CoVeRed), which combines remote monitoring, education, and self-management training to optimize recovery outcomes and experience of seniors undergoing CaVS in Canada and the United Kingdom., Objective: Our objectives are to (1) refine SMArTVIEW via high-fidelity user testing and (2) examine the effectiveness of SMArTVIEW via a randomized controlled trial (RCT)., Methods: CaVS patients and clinicians will engage in two cycles of focus groups and usability testing at each site; feedback will be elicited about expectations and experience of SMArTVIEW, in context. The data will be used to refine the SMArTVIEW eHealth delivery program. Upon transfer to the surgical ward (ie, post-intensive care unit [ICU]), 256 CaVS patients will be reassessed postoperatively and randomly allocated via an interactive Web randomization system to the intervention group or usual care. The SMArTVIEW intervention will run from surgical ward day 2 until 8 weeks following surgery. Outcome assessments will occur on postoperative day 30; at week 8; and at 3, 6, 9, and 12 months. The primary outcome is worst postop pain intensity upon movement in the previous 24 hours (Brief Pain Inventory-Short Form), averaged across the previous 14 days. Secondary outcomes include a composite of postoperative complications related to hemodynamic compromise-death, myocardial infarction, and nonfatal stroke- all-cause mortality and surgical site infections, functional status (Medical Outcomes Study Short Form-12), depressive symptoms (Geriatric Depression Scale), health service utilization-related costs (health service utilization data from the Institute for Clinical Evaluative Sciences data repository), and patient-level cost of recovery (Ambulatory Home Care Record). A linear mixed model will be used to assess the effects of the intervention on the primary outcome, with an a priori contrast of weekly average worst pain intensity upon movement to evaluate the primary endpoint of pain at 8 weeks postoperation. We will also examine the incremental cost of the intervention compared to usual care using a regression model to estimate the difference in expected health care costs between groups., Results: Study start-up is underway and usability testing is scheduled to begin in the fall of 2016., Conclusions: Given our experience, dedicated industry partners, and related RCT infrastructure, we are confident we can make a lasting contribution to improving the care of seniors who undergo CaVS., Competing Interests: In-kind industry support is provided by the following industry partners: Philips, QoC Health, XAHIVE, and mPath. The following authors are employed by Philips: Karsten Russell Wood, Michael Weber, Jolene McNeil, and Robyn Alpert. Sarah Sharpe is Co-Founder and shareholder, QoC Health; Sue Bhella is employed by QoC Health. David Mohajer is Co-Founder, Chief Executive Officer, and Vice President, XAHIVE; Sem Ponnambalem is Co-Founder, Chief Operating Officer, and President, XAHIVE. Naeem Lakhani and Rabia Khan are Co-Founders, mPath.

Lead optimization efforts resulted in the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 1 (AM-8508) and 2 (AM-9635), with good pharmacokinetic properties. The compounds inhibit B cell receptor (BCR)-mediated AKT phosphorylation (pAKT) in PI3Kδ-dependent in vitro cell based assays. These compounds which share a benzimidazole bicycle are effective when administered in vivo at unbound concentrations consistent with their in vitro cell potency as a consequence of improved unbound drug concentration with lower unbound clearance. Furthermore, the compounds demonstrated efficacy in a Keyhole Limpet Hemocyanin (KLH) study in rats, where the blockade of PI3Kδ activity by inhibitors 1 and 2 led to effective inhibition of antigen-specific IgG and IgM formation after immunization with KLH.

The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.

Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (KD from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.

We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb(+)) and U937 (FLT3(WT)) and induced cell death in MOLM13 (FLT3(ITD)) and even in MOLM13 (FLT3(ITD, D835Y)), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.

We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.

We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Our continued search for potent and diverse analogues led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 emerged as an inhibitor with remarkable biochemical potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 25 nM), as well as pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein.

We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Continued research investigation of the N-alkyl substituent of this series, focused in particular on a previously underutilized interaction in a shallow cleft on the MDM2 surface, led to the discovery of a one-carbon tethered sulfone which gave rise to substantial improvements in biochemical and cellular potency. Further investigation produced AMG 232 (2), which is currently being evaluated in human clinical trials for the treatment of cancer. Compound 2 is an extremely potent MDM2 inhibitor (SPR KD = 0.045 nM, SJSA-1 EdU IC50 = 9.1 nM), with remarkable pharmacokinetic properties and in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft model (ED50 = 9.1 mg/kg).

Purpose: Moderate deep inspiration breath-hold (mDIBH), using an Active Breathing Control device, has been used in our clinic since 2002 to reduce cardiac dose for patients receiving left-sided breast irradiation. We report our routine use of the mDIBH technique in clinically localized breast cancer, treated to the intact breast, reconstructed breast, or chest wall., Materials and Methods: Ninety-nine patients with left-sided breast cancer were evaluated for Active Breathing Control treatment, of which, 87 patients were treated with mDIBH. Plans for both the free-breathing (FB) and mDIBH computed tomography scans were evaluated. Dose-volume histograms (DVHs) were analyzed for the heart and ipsilateral lung, comparing results for mDIBH versus FB plans., Results: Eighty-seven patients were included for analysis. Of those, 66% received adjuvant chemotherapy with cardiotoxic agents. The mean dose for the whole breast was 47.6 Gy. There was a statistically significant decrease in all DVH parameters evaluated, favoring the delivery of mDIBH over FB plans. mDIBH plans significantly reduced cardiac mean dose (4.23 vs. 2.54 Gy; P<0.001), a relative reduction of 40%. In addition, there were significant reductions in all other heart parameters evaluated (ie, volume of heart treated, V30, V25, V20, V15, V10, and V5). mDIBH also significantly reduced lung dose, including a reduction of the left lung mean dose (9.08 vs. 7.86 Gy; P<0.001), a relative reduction of 13%, as well as significant reduction of all lung DVH parameters evaluated., Conclusions: To date, this series represents the largest experience utilizing mDIBH to reduce cardiac irradiation during left-sided breast cancer treatment. Statistically significant reductions in all heart and lung DVH parameters were achieved with mDIBH over FB plans. mDIBH, for the treatment of left-sided breast cancer, is a proven technique for reducing cardiac dose that may lead to reduced cardiotoxicity and can be routinely integrated into the clinic.

The discovery and initial optimization of a series of phenylalanine based agonists for GPR142 is described. The structure-activity-relationship around the major areas of the molecule was explored to give agonists 90 times more potent than the initial HTS hit in a human GPR142 inositol phosphate accumulation assay. Removal of CYP inhibition by exploration of the pyridine A-ring is also described., (Copyright © 2012. Published by Elsevier Ltd.)

The optimization of a series of 8-aza-quinazolinone analogs for antagonist activity against the CXCR3 receptor is reported. Compounds were optimized to avoid the formation of active metabolites and time-dependent-inhibitors of CYP3A4. In addition, antagonists showed potent against CXCR3 activity in whole blood and optimized to avoid activity in the chromosomal aberration assay. Compound 25 was identified as having the optimal balance of CXCR3 activity and pharmacokinetic properties across multiple pre-clinical species, which are reported herein., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objectives: We sought to determine whether the partial administration of the Cognitive Behavioral Driver's Inventory (CBDI) has a significant effect on its concurrent validity., Method: Data were extracted from charts of clients with cerebrovascular accident or traumatic brain injury from three centers. The CBDI was administered either completely or partially (right and left perimetry or Wechsler Adult Intelligence Scale-Revised (WAIS-R; Wechsler, 1982; Picture Completion and Digit Symbol tests were not completed). Concurrent validity indicators were calculated for the CBDI and three different scenarios of partial administration of the CBDI., Results: Only 52% of the road test failures were predicted correctly by the completely administered CBDI. Nonadministration of the WAIS-R rarely modified the CBDI results. Omission of perimetry scores tended to increase the sensitivity and decrease the specificity (not significantly)., Conclusion: The CBDI should be used as a complement, not a substitution, for a road test. Partially administrating the CBDI, specifically excluding perimetry measures, can affect its concurrent validity.

A general way of improving the potency of CXCR3 antagonists with fused hetero-bicyclic cores was identified. Optimization efforts led to the discovery of a series of imidazo-pyrazine derivatives with improved pharmacokinetic properties in addition to increased potency. The efficacy of the lead compound 21 is evaluated in a mouse lung inflammation model.

A series of six-six and six-five fused heterocyclic CXCR3 antagonists has been synthesized and their activities evaluated in an [(125)I]-IP-10 displacement assay and an ITAC mediated in vitro cell migration assay. The pharmacokinetic properties of several top compounds have also been studied. This effort led to the discovery of compounds with increased potency and improved pharmacokinetic properties that could serve as useful tools to study the role of the CXCR3 receptor in vivo.

A series of imidazole derivatives have been designed and optimized for CXCR3 antagonism, pharmacokinetic properties, and reduced formation of glutathione conjugates. Our efforts led to the discovery of potent CXCR3 antagonists with good pharmacokinetic properties. These compounds are useful tools for in vivo studies of CXCR3 function.

A 29-year-old male with AIDS was treated with bleomycin and vincristine for visceral Kaposi's sarcoma. Three days later, he developed two distinct eruptions simultaneously. One eruption was characterized by tender, erythematous, edematous plaques and nodules on the palmar and dorsal surfaces of the hands, forearms, and elbows. The other consisted of grouped, erythematous, hyperpigmented streaks on the trunk, buttocks, and extremities. The patient subsequently received a second treatment consisting of vincristine with adriamycin, without bleomycin, and no cutaneous effects were seen. Diagnoses of flagellate erythema and acral nodular eruption secondary to bleomycin were made and confirmed histopathologically. To our knowledge, this is the first report of two cutaneous side effects of bleomycin appearing simultaneously in a patient with AIDS.

We have developed a modification of the Miyaura arylboronate synthesis(1a) by substituting a ligandless palladium catalyst for PdCl(2)(dppf). Palladium acetate, free of ligand, was found highly effective for such coupling reactions. This modified procedure is advantageous over the original Miyaura synthesis in ease of workup, catalyst removal, and low catalyst cost. Furthermore, the boronates formed in this manner can be used directly for Suzuki coupling reactions in a one-pot fashion. The biaryl products have improved impurity profiles and reduced heavy metal contamination.

This report discusses the development of a coping skill training program for parents of substance-abusing adolescents and presents preliminary data on the effects of the program on parent functioning and adolescent substance use. The behavioral-analytic model of program development was used to sample representative problematic situations experienced by parents of substance-abusing adolescents, obtain an effectiveness-scaling of responses to these situations, and derive alternate forms of a situational role-play measure of parental coping. These situations and scoring guidelines were then used to create the skill training program. Parents of substance-abusing adolescents not in treatment subsequently were randomly assigned in a pilot investigation to either a skill training or delayed treatment condition. Skill training resulted in significant improvement in parental coping skills relative to delayed treatment. Moderate to large improvement in the parent's report of their own functioning, family communication, and the teen's marijuana use also favored the skill training group.

The study objective was to describe the perceptions of airplane assemblers on job demand for the back and how back pain modulated these perceptions. One hundred and seventy-six workers answered two questionnaires concerning back pain and the perception of work related difficulties (work activities, work contexts, tools, work positions, efforts). Results show that positions and work contexts are perceived as greater sources of difficulty than efforts or dynamic activities. The duration of a given position is more important than its frequency. Back pain has a significant but complex impact on the perception of difficulty. Assemblers appear to integrate several factors when evaluating their difficulties as opposed to individual aspects, as it is often measured in ergonomic studies. The results have important implications for the measurement of ergonomic factors in the genesis of back pain and illustrates the potential for misclassification and biases in current epidemiologic studies.

Urokinase-type plasminogen activator (uPA) is thought to be an important mediator in the proteolytic degradation of extracellular matrix components observed in a wide variety of normal physiological and pathological conditions. However, the phenotype of a recently developed strain of urokinase-deficient (uPA-/-) mice appears to be normal when maintained under ideal nonstressful conditions. We report an outbreak of botryomycosis, an unusual staphylococcal infection, in a colony of uPA-deficient mice. A detailed histological examination of these uPA-deficient animals also revealed a variety of previously unreported phenotypic abnormalities such as pleuritis and the effacement of lymphoid follicles in the regional lymph nodes and spleen. Additional phenotypic abnormalities such as dystrophic calcifications and rectal prolapse were also observed in the uPA-deficient population. These abnormalities were also noted in ostensibly healthy uPA-deficient animals. Botryomycosis did not affect a colony of wild-type (uPA+/+) animals maintained concurrently under identical conditions in the same room. The peculiar predisposition of the uPA-deficient animals to this rare bacterial infection and the development of phenotypic abnormalities associated with the targeted disruption the uPA gene suggests that uPA contributes significantly to the cutaneous microenvironment and is additional evidence of the extensive involvement of the plasminogen activators in mammalian physiology.

Evidence suggests that the plasminogen activators (PAs), in particular urokinase-type PA (uPA), play a pivotal role in tumor invasion and metastasis. We studied the contribution of the PAs to the malignant phenotype through the chemical induction of melanocytic neoplasms in uPA-deficient mice. Primary tumors were induced and promoted concurrently in 35 uPA-/- deficient and 35 uPA+/+ wild-type mice using a single application of 7,12-dimethylbenz(a)anthracene followed by repetitive applications of croton oil. Animals were sacrificed at 60-day intervals for 1 year. At necropsy, the four largest pigmented lesions in each animal were excised, characterized histologically, and evaluated microscopically for evidence of invasion. The regional lymph nodes, lungs, and solid abdominal visceral organs were sectioned and examined microscopically for evidence of metastatic disease. Cellular blue nevi were induced in 100% of uPA-/- and uPA+/+ promoted animals. Although a reduction in the radial and vertical progression of these lesions was noted in the uPA-deficient mice compared with the wild-type group, more than 95% of cellular blue nevi induced in both groups of animals invaded the underlying tissues. These lesions did not metastasize to the regional lymph nodes. Malignant melanoma arose in 5 of 35 (14.3%) of promoted wild-type mice. These tumors were locally aggressive, produced tissue-type PA, but were not metastatic to the regional nodes, lungs, or abdominal viscera. These results indicate that the invasive capability of melanocytic lesions may depend more on tissue-type PA than uPA activity. No melanomas were induced in the uPA-/- mice. The resistance of the uPA -/- strain to melanoma induction suggests that uPA contributes to malignant progression. We propose that the absence of uPA negatively affects tumorigenesis by decreasing the liberation and availability of growth factors such as basic fibroblast growth factor.

Total Quality Management (TQM) processes have been effectively implemented in manufacturing, revolutionizing the automotive, electronic, and semiconductor industries. The application of TQM processes in healthcare providers' patient financial services departments can help these departments to improve collections, decrease bad debt write-offs, achieve cost savings, and increase overall efficiency.