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The purpose of this study was to evaluate a facilitated interactive role-playing activity on increasing human papillomavirus (HPV) vaccine recommendation skills for school nurses and school-based health center staff. A 1-day workshop was implemented for school-based clinicians focused on improving HPV vaccination rates in schools. The workshop included a facilitated interactive role-playing activity involving five scenarios related to recommending the HPV vaccine to parents. Participants completed a usability survey with open-ended questions assessing their experience. A general inductive approach was used to examine responses. Sixteen participants completed the usability survey. The major strength identified specific to the activity included opportunity to practice evidence-based recommendation skills (n = 10). Weaknesses of the activity identified included lack of diversity (n = 4) and complexity within the scenarios (n = 2). Results could shift current educational and clinical paradigms through the implementation of hands-on education strategies to effectively train school-based clinicians to strongly recommend the HPV vaccine., (© 2021. American Association for Cancer Education.)

Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19. Here, we developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of β-lactams to kill Mycobacterium tuberculosis (Mtb). In the TB Drug Accelerator (TBDA), a consortium organized by the Bill & Melinda Gates Foundation, individual pharmaceutical companies collaborate with academic screening laboratories. We developed a higher order consortium within the TBDA in which four pharmaceutical companies (GlaxoSmithKline, Sanofi, MSD, and Lilly) collectively collaborated with screeners at Weill Cornell Medicine, the Infectious Disease Research Institute (IDRI), and the National Institute of Allergy and Infectious Diseases (NIAID), pharmacologists at Rutgers University, and medicinal chemists at the University of North Carolina to screen ∼8900 β-lactams, predominantly cephalosporins, and characterize active compounds. In a striking contrast to historical expectation, 18% of β-lactams screened were active against Mtb, many without a β-lactamase inhibitor. One potent cephaloporin was active in Mtb-infected mice. The steps outlined here can serve as a blueprint for multiparty, intra- and intersector collaboration in the development of anti-infective agents.

Missed clinical opportunities and the lack of strong and consistent vaccine recommendations are key reasons for low HPV vaccination rates. The purpose of this study was to conduct a pilot evaluation of a web-based training's impact on knowledge, attitudes, and self-efficacy related to providing evidence-based HPV vaccine recommendations. Participants completed three online interactive learning modules and the HPV Vaccine: Same Way, Same Day ™ smartphone application (app). Participants completed a pre-training survey, immediate post-training survey, and two-month post-survey. Participants demonstrated a statistically significant increase in knowledge scores from T1 to T2 and T1 to T3. Mean attitudes for recommending HPV vaccination for female patients increased from T1 to T2 and T1 to T3. Mean attitudes for recommending HPV vaccination for male patients increased from T1 to T2 and T1 to T3. Mean self-efficacy scores increased from T1 to T2 and T1 to T3. The HPV Vaccine: Same Way, Same Day ™ app is a promising strategy for improving HPV vaccine recommendations among physicians. Future research should explore long-term effects and enroll attending and community physicians to examine its efficacy in other physician populations.

Ljungan virus (LV), a Parechovirus of the Picornavirus family, first isolated from a bank vole at the Ljungan river in Sweden, has been implicated in the risk for autoimmune type 1 diabetes. An assay for neutralizing Ljungan virus antibodies (NLVA) was developed using the original 87-012 LV isolate. The goal was to determine NLVA titres in incident 0-18 years old newly diagnosed type 1 diabetes patients ( n =67) and school children controls ( n =292) from Jämtland county in Sweden. NLVA were found in 41 of 67 (61 %) patients compared to 127 of 292 (44 %) controls ( P =0.009). In the type 1 diabetes patients, NLVA titres were associated with autoantibodies to glutamic acid decarboxylase (GADA) ( P =0.023), but not to autoantibodies against insulin (IAA) or islet antigen-2 (IA-2A). The NLVA assay should prove useful for further investigations to determine levels of LV antibodies in patients and future studies to determine a possible role of LV in autoimmune type 1 diabetes.

The use of the oral poliovirus vaccine (OPV) in developing countries has reduced the incidence of poliomyelitis by >99% since 1988 and is the primary tool for global polio eradication. Spontaneous reversions of the vaccine virus to a neurovirulent form can impede this effort. In persons with primary B-cell immunodeficiencies, exposure to OPV can result in chronic infection, mutation, and excretion of immunodeficiency-associated vaccine-derived polioviruses, (iVDPVs). These iVDPVs may have the potential for transmission in a susceptible population and cause paralysis. The extent to which sera from OPV recipients are able to neutralize iVDPVs with varying degrees of antigenic site substitutions is investigated here. We tested sera from a population immunized with a combination vaccine schedule (both OPV and inactivated polio vaccine) against a panel of iVDPVs and found that increases in amino acid substitution in the P1 capsid protein resulted in a decrease in the neutralizing capacity of the sera. This study underscores the importance of maintaining high vaccine coverage in areas of OPV use as well as active surveillance of those known to be immunocompromised., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

The historical view of β-lactams as ineffective antimycobacterials has given way to growing interest in the activity of this class against Mycobacterium tuberculosis ( Mtb ) in the presence of a β-lactamase inhibitor. However, most antimycobacterial β-lactams kill Mtb only or best when the bacilli are replicating. Here, a screen of 1904 β-lactams led to the identification of cephalosporins substituted with a pyrithione moiety at C3' that are active against Mtb under both replicating and nonreplicating conditions, neither activity requiring a β-lactamase inhibitor. Studies showed that activity against nonreplicating Mtb required the in situ release of the pyrithione, independent of the known class A β-lactamase, BlaC. In contrast, replicating Mtb could be killed both by released pyrithione and by the parent β-lactam. Thus, the antimycobacterial activity of pyrithione-containing cephalosporins arises from two mechanisms that kill mycobacteria in different metabolic states.

A systematic study of the stability of a set of cephalosporins in mouse plasma reveals that cephalosporins lacking an acidic moiety at C-2 may be vulnerable to β-lactam cleavage in mouse plasma.

The α-alkylation of ketones is a fundamental synthetic transformation. The development of asymmetric variants of this reaction is important given that numerous natural products, drugs, and related compounds exist as α-functionalized ketones or derivatives thereof. We previously reported our preliminary studies on the development of a new enantioselective ketone α-alkylation procedure using N-amino cyclic carbamate (ACC) auxiliaries. In comparison to other auxiliary-based methods, ACC alkylation offers a number of advantages and is both highly enantioselective and high yielding. Herein, we provide a full account of our studies on the enantioselective ACC ketone α-alkylation method.

Background: Human papillomavirus (HPV) vaccination rates fall far short of Healthy People 2020 objectives. A leading reason is that clinicians do not recommend the vaccine consistently and strongly to girls and boys in the age group recommended for vaccination. Although Web-based HPV vaccine educational interventions for clinicians have been created to promote vaccination recommendations, rigorous evaluations of these interventions have not been conducted. Such evaluations are important to maximize the efficacy of educational interventions in promoting clinician recommendations for HPV vaccination., Objective: The objectives of our study were (1) to expand previous research by systematically identifying HPV vaccine Web-based educational interventions developed for clinicians and (2) to evaluate the quality of these Web-based educational interventions as defined by access, content, design, user evaluation, interactivity, and use of theory or models to create the interventions., Methods: Current HPV vaccine Web-based educational interventions were identified from general search engines (ie, Google), continuing medical education search engines, health department websites, and professional organization websites. Web-based educational interventions were included if they were created for clinicians (defined as individuals qualified to deliver health care services, such as physicians, clinical nurses, and school nurses, to patients aged 9 to 26 years), delivered information about the HPV vaccine and how to increase vaccination rates, and provided continuing education credits. The interventions' content and usability were analyzed using 6 key indicators: access, content, design, evaluation, interactivity, and use of theory or models., Results: A total of 21 interventions were identified, out of which 7 (33%) were webinars, 7 (33%) were videos or lectures, and 7 (33%) were other (eg, text articles, website modules). Of the 21 interventions, 17 (81%) identified the purpose of the intervention, 12 (57%) provided the date that the information had been updated (7 of these were updated within the last 6 months), 14 (67%) provided the participants with the opportunity to provide feedback on the intervention, and 5 (24%) provided an interactive component. None of the educational interventions explicitly stated that a theory or model was used to develop the intervention., Conclusions: This analysis demonstrates that a substantial proportion of Web-based HPV vaccine educational interventions has not been developed using established health education and design principles. Interventions designed using these principles may increase strong and consistent HPV vaccination recommendations by clinicians., (©Brittany L Rosen, James M Bishop, Skye L McDonald, Jessica A Kahn, Gary L Kreps. Originally published in JMIR Cancer (http://cancer.jmir.org), 16.02.2018.)

Professionally facilitated multi-stakeholder meetings of marine mammal Take Reduction Teams, such as the Harbor Porpoise Take Reduction Team, are mandated by the U.S. Marine Mammal Protection Act of 1972. These meetings employ consensus-based decision-making to create policies to safeguard marine mammals. This opportunistic case study examines the history of the Harbor Porpoise Take Reduction Team multi-stakeholder group, and policy decisions the team made to address harmful interactions between harbor porpoises and the New England and mid-Atlantic groundfish fishery. For more than a decade, stakeholders regularly met to create regulations designed to mitigate the accidental entanglement of harbor porpoises in gillnets, called bycatch. A series of disruptions, including a new political appointee and the addition of new team members, altered how stakeholders interacted with one another and how regulations were implemented. These shocks to the formerly well-functioning team, placed the future of consensus-based policy creation at risk. Lessons from this case study can be applied to increase understanding of how multi-stakeholder methods, which are incorporated into many regulatory decision-making processes operate in practice and illustrate the fragile nature of long-standing consensus.

Direct amination of heteroarenes and arenes has been achieved in a one-pot CH zincation/copper-catalyzed electrophilic amination procedure. This amination method provides an efficient and rapid approach to access a diverse range of heteroaromatic and aromatic amines including those previously inaccessible using CH amination methods. The mild reaction conditions and good functional-group compatibility demonstrate its great potential for the synthesis of important and complex amines., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Vitamin A supplementation significantly reduces all-cause mortality when given between 6-59 months of age, but has a null or detrimental effect when given between 1-5 months. Studies of neonatal vitamin A supplementation conducted across Africa and South Asia have produced conflicting findings. These age-pattern variations might result from immunological interactions between vitamin A supplementation and vaccines. Knowledge on the potential immunological sequelae of human neonatal vitamin A supplementation is so scarce that the foremost aim of this study is to seek indicative data on aspects of immunity likely to be affected by neonatal vitamin A supplementation. The objective of this trial is to test whether human neonatal vitamin A supplementation modulates immune function including improved thymic maturation in infancy and improved systemic immune responses to routine immunization., Methods/design: In an area of moderate vitamin A deficiency in a peri-urban area of The Gambia, 200 mother-infant pairs were enrolled in a double-blind randomised controlled trial. Within 48 hours of birth, neonates were randomised with stratification by birth weight and sex to receive either an oral dose of 50,000 IU vitamin A or placebo. Expanded Programme of Immunisation birth vaccinations were administered after supplementation, with subsequent vaccinations administered at 8, 12 and 16 weeks of age. A range of immunological outcomes were examined up to 17 weeks of age, with additional morbidity and anthropometry follow-up carried out throughout the first year of life. The primary endpoint of this trial is the frequency of circulating T regulatory (Treg) cells expressing gut homing receptors in infants at 17 week post-supplementation, with secondary outcomes including thymus maturation and B cell immune responses., Discussion: Indicative immunological data from this trial (and its Bangladeshi counterpart), will complement the larger randomised controlled trials (conducted in India, Tanzania and Ghana), on the effectiveness and safety of neonatal vitamin A supplementation in improving infant survival. Combined these trials, in addition to the existing trials, will inform policy., Trial Registration: clinicaltrials.gov NCT01476358.

Reversible acetylation of α-tubulin is an evolutionarily conserved modification in microtubule networks. Despite its prevalence, the physiological function and regulation of microtubule acetylation remain poorly understood. Here we report that macrophages challenged by bacterial lipopolysaccharides (LPS) undergo extensive microtubule acetylation. Suppression of LPS-induced microtubule acetylation by inactivating the tubulin acetyltransferase, MEC17, profoundly inhibits the induction of anti-inflammatory interleukin-10 (IL-10), a phenotype effectively reversed by an acetylation-mimicking α-tubulin mutant. Conversely, elevating microtubule acetylation by inhibiting the tubulin deacetylase, HDAC6, or stabilizing microtubules via Taxol stimulates IL-10 hyper-induction. Supporting the anti-inflammatory function of microtubule acetylation, HDAC6 inhibition significantly protects mice from LPS toxicity. In HDAC6-deficient macrophages challenged by LPS, p38 kinase signalling becomes selectively amplified, leading to SP1-dependent IL-10 transcription. Remarkably, the augmented p38 signalling is suppressed by MEC17 inactivation. Our findings identify reversible microtubule acetylation as a kinase signalling modulator and a key component in the inflammatory response.

Selective α-amination and α-acylation of esters and amides have been developed, employing O-acylhydroxylamines as a dually reactive aminating and acylating reagent. Treatment of zinc enolates with O-acylhydroxylamines provides solely 1,3-dicarbonyl compounds under mild conditions. Introduction of a copper catalyst into the system shifts the reactivity entirely, yielding α-amination products exclusively.

A direct approach to important α-amino phosphonic acids and its derivatives has been developed by using copper-catalyzed electrophilic amination of α-phosphonate zincates with O-acyl hydroxylamines. This amination provides the first example of CN bond formation which directly introduces acyclic and cyclic amines to the α-position of phosphonates in one step. The reaction is readily promoted at room temperature with as little as 0.5 mol % of catalyst, and demonstrates high efficiency on a broad substrate scope., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A new approach to access o-haloaminoarenes has been achieved by insertion of arynes into a nitrogen-halide bond (N-X). This transition-metal-free transformation displays a broad substrate scope of arynes, good compatibility with functional groups, and high regioselectivity. Representative transformations of the o-haloaminoarenes are described to highlight their utility for rapid access to diversely functionalized aminoarene derivatives.

Chemotherapy is an integral part of treatment for colorectal cancer (CRC), especially in the context of metastatic cancer. Targeted therapies in the form of monoclonal antibodies directed against the endothelial growth factor receptor or the vascular endothelial growth factor have met with success, and have demonstrated the advantages of molecularly targeted therapy in colorectal cancer. Nevertheless, CRC remains a major cause of death, which demonstrates the urgent need for improved treatment strategies. The pathway activated by the Wingless-type mouse mammary tumour virus integration site (WNT) family members is constitutively active and promotes cancer growth in the majority of CRCs. As a result, there has been interest in developing therapeutics that circumvent it either by inhibiting WNT-mediated transcription or by inactivating the target genes. This review considers the current therapies approved for use in CRC and discusses the progress with therapies designed to target the WNT signalling pathway., (© 2011 The Authors. Colorectal Disease © 2011 The Association of Coloproctology of Great Britain and Ireland.)

Determination of varicella zoster virus (VZV) immunity in healthcare workers without a history of chickenpox is important for identifying those in need of vOka vaccination. Post immunisation, healthcare workers in the UK who work with high risk patients are tested for seroconversion. To assess the performance of the time-resolved fluorescence immunoassay (TRFIA) for the detection of antibody in vaccinated as well as unvaccinated individuals, a cut-off was first calculated. VZV-IgG specific avidity and titres six weeks after the first dose of vaccine were used to identify subjects with pre-existing immunity among a cohort of 110 healthcare workers. Those with high avidity (≥ 60%) were considered to have previous immunity to VZV and those with low or equivocal avidity (<60%) were considered naive. The former had antibody levels ≥ 400 mIU/mL and latter had levels < 400 mIU/mL. Comparison of the baseline values of the naive and immune groups allowed the estimation of a TRFIA cut-off value of > 130 mIU/mL which best discriminated between the two groups and this was confirmed by ROC analysis. Using this value, the sensitivity and specificity of TRFIA cut-off were 90% (95% CI 79-96), and 78% (95% CI 61-90) respectively in this population. A subset of samples tested by the gold standard Fluorescence Antibody to Membrane Antigen (FAMA) test showed 84% (54/64) agreement with TRFIA., (Copyright © 2010 Elsevier B.V. All rights reserved.)

The chimpanzee is the only animal model for investigating the pathogenesis of viral hepatitis types A through E in humans. Studies of the host response, including microarray analyses, have relied on the close relationship between these two primate species: chimpanzee samples are commonly tested with human-based reagents. In this study, the host responses to two dissimilar viruses, hepatitis E virus (HEV) and hepatitis C virus (HCV), were compared in multiple experimentally infected chimpanzees. Affymetrix U133+2.0 human microarray chips were used to assess the entire transcriptome in serial liver biopsies obtained over the course of the infections. Respecting the limitations of microarray probes designed for human target transcripts to effectively assay chimpanzee transcripts, we conducted probe-level analysis of the microarray data in conjunction with a custom mapping of the probe sequences to the most recent human and chimpanzee genome sequences. Time points for statistical comparison were chosen based on independently measured viremia levels. Regardless of the viral infection, the alignment of differentially expressed genes to the human genome sequence resulted in a larger number of genes being identified when compared with alignment to the chimpanzee genome sequence. This probably reflects the lesser refinement of gene annotation for chimpanzees. In general, the two viruses demonstrated very distinct temporal changes in host response genes, although both RNA viruses induced genes that were involved in many of the same biological systems, including interferon-induced genes. The host response to HCV infection was more robust in the magnitude and number of differentially expressed genes compared to HEV infection.

Wnt-5a is one of the most highly investigated non-canonical Wnts and has been implicated in almost all aspects of non-canonical Wnt signalling. In terms of cancer development, Wnt-5a has, until recently, lived in the shadow of its better-characterised relatives. This was largely because of its apparent inability to transform cells or signal through the canonical beta-catenin pathway that is so important in cancer, particularly colorectal cancer. Recent work in a wide range of human tumours has pointed to a critical role for Wnt-5a in malignant progression, but there is conflicting evidence whether Wnt-5a has a tumour-promoting or -suppressing role. Emerging evidence suggests that the functions of Wnt-5a can be drastically altered depending on the availability of key receptors. Hence, the presence or absence of these receptors may go some way to explain the conflicting role of Wnt-5a in different cancers. This review summarises our current understanding of Wnt-5a and cancer.

The isotype/subclass of immunoglobulin determines antibody function, but rather little is known about factors that direct class switching in vivo. To evaluate factors that might influence the maturation of the antibody response during infection, we conducted a seroepidemiological study of the immunoglobulin G (IgG) subclass response to four merozoite-associated antigens of Plasmodium falciparum in a mountainous region of northeastern Tanzania, where malaria endemicity declines with increasing altitudes. We found that IgG1/IgG3 class switching is independently affected by the nature of the antigen, cumulative exposure to the antigen, and the maturity of the immune system (i.e., the age of the individual). These observations provide insights into the effects of immune system maturity, the duration and intensity of antigen exposure, and inherent characteristics of individual antigens on the process of class switching in human B cells. Our data also throw light on the consequences of class switch decisions on the gradual acquisition of antimalarial immunity.

Docetaxel is one of the most effective chemotherapeutic agents in the treatment of breast cancer. Breast cancers can have an inherent or acquired resistance to docetaxel but the causes of this resistance remain unclear. In this study high-level, docetaxel-resistant human breast cancer cell lines (MCF-7 and MDA-MB-231) were created, and comparative genomic hybridisation was used to identify genomic regions associated with resistance to docetaxel. MCF-7 resistant cells showed an amplification of chromosomes 7q21.11-q22.1, 17q23-q24.3, 18, and deletion of chromosomes 6p, 10q11.2-qter and 12p. MDA-MB-231 resistant cells showed a gain of chromosomes 5p, 7q11.1-q35, 9, and loss of chromosomes 4, 8q24.1-qter, 10, 11q23.1-qter, 12q15-q24.31, 14q and 18. Whole chromosome paints confirmed these findings. Amplification of 7q21 and loss of 10q may represent a common mechanism of acquired docetaxel resistance in breast cancer cells. This study is the first description of a genomic approach specifically to identify genomic regions involved in resistance to docetaxel.

The implementation and evaluation of malaria control programs would be greatly facilitated by new tools for the rapid assessment of malaria transmission intensity. Because acquisition and maintenance of antimalarial antibodies depend on exposure to malaria infection, such antibodies might be used as proxy measures of transmission intensity. We have compared the prevalence of IgG antibodies with three Plasmodium falciparum asexual stage antigens in individuals of all ages living at varying altitudes encompassing a range of transmission intensities from hyper- to hypoendemic in northeastern Tanzania, with alternative measures of transmission intensity. The prevalence of antibodies to merozoite surface protein-1(19) was significantly more closely correlated with altitude than either point-prevalence malaria parasitemia or single measures of hemoglobin concentration. Analysis of age-specific seroprevalence rates enabled differentiation of recent (seasonal) changes in transmission intensity from longer-term transmission trends and, using a mathematical model of the annual rate of seroconversion, estimation of the longevity of the antibody response. Thus, serological tools allow us to detect variations in malaria transmission over time. Such tools will be invaluable for monitoring trends in malaria endemicity and the effectiveness of malaria control programs.

Microarray profiling is a powerful approach to establish gene expression patterns for different histopathological stages of a malignancy, and at the same time, to identify individual genes that may have important functions in the early and/or advanced stages of a neoplasm. To identify genes that hitherto have not been shown to be expressed or play a role in advanced-stage melanomas, we conducted microarray analyses with RNAs from primary melanoma and melanoma-positive lymph node specimens. Using RT-PCR, quantitative, real-time RT-PCR, and fluorochrome oligonucleotide-based optical imaging, we established the level and pattern of expression of five of the identified known genes [Suppression of Tumorigenicity 13 (ST13), Cystatin 8 (CST-8), Dyskeratosis Congentia 1 (DKC1), Neuroendocrine Secretory Protein 55 (NESP55), Niemann-Pick Disease, type C2 (NP-C2)], and a gene with unknown function (16.7 kD Hypothetical Protein) in benign and atypical nevocytic lesions, advanced-stage melanomas, and melanoma-positive lymph nodes.

Introduction: Docetaxel is one of the most effective chemotherapeutic agents in the treatment of breast cancer. Breast cancers can have an inherent or acquired resistance to docetaxel but the causes of this resistance remain unclear. However, apoptosis and cell cycle regulation are key mechanisms by which most chemotherapeutic agents exert their cytotoxic effects., Methods: We created two docetaxel-resistant human breast cancer cell lines (MCF-7 and MDA-MB-231) and performed cDNA microarray analysis to identify candidate genes associated with docetaxel resistance. Gene expression changes were validated at the RNA and protein levels by reverse transcription PCR and western analysis, respectively., Results: Gene expression cDNA microarray analysis demonstrated reduced p27 expression in docetaxel-resistant breast cancer cells. Although p27 mRNA expression was found to be reduced only in MCF-7 docetaxel-resistant sublines (2.47-fold), reduced expression of p27 protein was noted in both MCF-7 and MDA-MB-231 docetaxel-resistant breast cancer cells (2.83-fold and 3.80-fold, respectively)., Conclusions: This study demonstrates that reduced expression of p27 is associated with acquired resistance to docetaxel in breast cancer cells. An understanding of the genes that are involved in resistance to chemotherapy may allow further development in modulating drug resistance, and may permit selection of those patients who are most likely to benefit from such therapies.

When predicting future performance on tests over text material, do individuals estimate retention in addition to assessing comprehension? In Experiment 1, participants either rated their comprehension or predicted performance for each text, with lower ratings indicating lower confidence either in comprehension or in eventual performance. Judgement magnitude was significantly lower for performance predictions than for comprehension ratings, suggesting that predictions were based partly on retention estimates. In Experiment 2, predictions varied with anticipated test delay (15 min or 2 weeks) whereas comprehension ratings did not, providing further evidence that individuals estimate retention when predicting performance. Analyses of individual differences suggest that both good and poor performers incorporate retention estimates when predicting performance, but better performers do so in a more discriminative manner. Implications for theory of metacognitive judgements are discussed.

In our morphometric study of the effects of exercise on the heart, male Wistar-Kyoto rats at 5 weeks of age were subjected daily to a moderate treadmill running program that lasted for 7 weeks. The heart responded to physical conditioning by different magnitudes of tissue growth of the right (22%) and left (7%) ventricular myocardium, the latter change not statistically significant. The increase in right ventricular volume was associated with a 25% enlargement of ventricular area, a 26% average lengthening of the myocytes, and no change in sarcomere length and in ventricular midwall thickness. Exercise produced significant alterations in the quantitative parameters of the microvasculature of the right ventricle, but no appreciable changes in the left ventricle. Right ventricular hypertrophy was characterized by an absolute 44% growth of the endothelial luminal surface brought about through a 16% increase in capillary numerical density, and a 41% augmentation of the total length of the capillary network. Maximum diffusion distance from the capillary wall to the mitochondria of myocytes decreased 10% as a result of capillary proliferation and the lack of lateral expansion of myocyte cross-sectional area. Evaluation of the subcellular constituents of myocytes showed no change in the mitochondria:myofibrils volume ratio, indicating a growth of these components proportional to each other and to the growth of the myocyte population as a whole. It was concluded that, as a result of running exercise, right ventricular growth is analogous to eccentric hypertrophy in which the structural adaptations of the capillary bed can be expected to improve the diffusion and transport of oxygen within the tissue.

A reproducible, sensitive immunoassay for murine interleukin-3 (IL-3) has been developed using two preparations of polyclonal antipeptide antibodies. Rabbits were immunized with the N-terminal peptide 1-29 (IL-3) coupled to KLH and the antibodies were affinity purified on immobilized peptide 1-29 (IL-3). This antibody preparation showed good reactivity with native IL-3, and was used to coat polyvinyl microtiter trays. IL-3 captured by this first antibody was detected by the addition of anti-IL-3 serum (second antibody) raised in sheep against synthetic full length IL-3 (1-140). This test reliably detects IL-3 from every source tested (T cells, WEHI-3B cells, recombinant material from transfected COS 7 cells or murine myeloid FDC-P1 cells transfected with an IL-3 containing retrovirus) with a sensitivity to 2 to 4 U/ml of bioactive IL-3 or about 60 pg synthetic IL-3/ml. The test is performed within 5 to 6 h compared to 2 to 3 d of a standard bioassay.

Effects on the myocardium, particularly those structural properties of the capillary network relevant to tissue oxygenation, were studied morphometrically in rats subjected to a severe running program. Physical conditioning produced a 31% increase in right ventricular weight and only a 12% increase in the weight of the left ventricle. Quantitative analysis of right ventricular myocardium demonstrated relative decreases in capillary luminal volume density (-27%) and capillary luminal surface density (-20%) and an increase in the average maximum distance from the capillary wall to the mitochondria of myocytes (14%). In contrast, the contractile mass expanded in proportion to the growth of the ventricle through augmentation of the cross-sectional area (17%) and length (19%) of the average myocyte. Evaluation of the subcellular constituents of myocytes showed no change in the mitochondria-to-myofibril volume ratio. In conclusion, the capillary bed controlling oxygen availability, diffusion, and transport suggests that excessive physical activity may be detrimental to the myocardium.

The adaptation of the structural components in the myocardium of the left ventricle to strenuous exercise was studied morphometrically in rats following a treadmill running program. The response of the left ventricle was evaluated separately in the interventricular septum and in the left ventricular free wall. Exercise produced a 24% growth of the septum without altering free wall volume. The hypertrophic expansion of the septum was characterized by a decrease in the volume fraction of capillary lumen in the myocardium (-20%), a reduction in the capillary luminal surface per unit volume of myocytes (-17%) and by an increase in the maximum distance from the capillary wall to the mitochondria of myocytes (9%). Although none of these changes were demonstrable on a statistical basis in the left ventricular free wall, similar results were obtained in the whole left ventricle by combining the data from the septum and free wall. Since the septum constitutes a functional unit with the free wall, it was concluded that the effect of excessive physical activity on the capillary parameters responsible for oxygen availability and diffusion could lead to a local reduction in the oxygenation potential of ventricular myocardium.

The growth response of the right ventricle was studied in rats following ligation of the left coronary artery, which produced infarcts comprising approximately 40% of the left ventricle. A month after surgery the weight of the right ventricle was increased 30%, and this hypertrophic change was characterized by a 17% wall thickening, consistent with the 13% greater diameter of myocytes. Myocardial hypertrophy was accompanied by an inadequate growth of the microvasculature that supports tissue oxygenation. This was seen by relative decreases in capillary luminal volume density (-27%) and capillary luminal surface density (-21%) and by an increase in the average maximum distance from the capillary wall to the mitochondria of myocytes (19%). In contrast, measurements of the mean myocyte volume per nucleus showed a proportional enlargement of these cells (32%), from 16,300 cu mu in control animals to 21,500 cu mu in experimental rats. Quantitative analysis of the right coronary artery revealed a 33% increase in its luminal area, commensurate with the magnitude of ventricular hypertrophy.