Social Network Characteristics Associated with More Frequent HIV and STI Prevention Conversations: The N2 Cohort Study in Chicago.

Black cisgender sexually minoritized men (SMM) and transgender women (TW) are subgroups at highest risk of HIV and sexually transmitted infections (STIs) in the US. We sought to identify factors facilitating continued conversations - social reinforcement - surrounding HIV/STI prevention among this subgroup. Participants were recruited in Chicago from 2018 to 2019 from community health spaces. Participants provided information about themselves (level 2) and ⩽5 confidants (level 1). We used multinomial multilevel modeling to identify associations with HIV/STI prevention conversation frequency. A total of 370 participants provided information on 987 confidants (mean = 2.6). We found significantly positive associations between having biweekly or more often HIV/STI prevention conversations and a confidant being a kin family member, older by 15 years or more, racially homophilous, and emotionally close. Future interventions should harness social networks by including components that consider racial homophily, respect for elders, and strong ties, in addition to applying kin family systems interventions approaches and decreasing stigma surrounding HIV/STIs.

Provision of trauma care in asymmetric warfare: a conceptual framework to support the decision to implement frontline care services.

INTRODUCTION: The emerging trends of asymmetric and urban warfare call for a revision of the needs and the way in which frontline trauma care is provided to affected population. However, there is no consensus on the process to decide when and how to provide such lifesaving interventions in form of Trauma Stabilization Point (TSP). METHODS: A three-step Delphi method was used to establish consensus. A focus group discussion was convened to propose a framework and develop the list of twenty-one (21) statements for validation of a group of experts. RESULTS: A panel of twenty-eight (28) experts reviewed the statements and participated to both first and second rounds. Comments and recommendations provided by the FGD and during round 1 were used to analyze the findings of the study. The proposed framework includes five main categories identified as interconnected components that facilitate the decision to implement or not the TSP. A total of sixteen (16) elements distributed across the five categories have been considered as being able to guide the decision to utilize such capability in high-risk security and resource constrained settings. CONCLUSION: The TSP has the potential to prevent death and disability. The proposed framework and categories add a structure to the decision-making process and represents an important step to support emergency and trauma care planning and implementation efforts.

Lyme disease and post-treatment Lyme disease syndrome: the neglected disease in our own backyard.

OBJECTIVES: A survey was developed to assess experience and opinions about Lyme disease and post-treatment Lyme disease syndrome (PTLDS) among faculties in public health. No previous surveys of public health faculties have been found in the literature. STUDY DESIGN: This is a cross sectional study of public health school faculty members designed to measure knowledge and experience with Lyme disease and PTLDS using an internet survey instrument. METHODS: Participants were recruited using all the publicly available e-mail addresses of faculty members in all the 50 accredited Schools of Public Health in the United States. RESULTS: A 15% response rate was seen for the survey. 50% of respondents were from Lyme endemic states. Less than 5% of faculty members consider themselves expert in Lyme or PTLDS. Many faculty members had known someone with Lyme disease or PTLDS, but few had been diagnosed themselves. Most believe that PTLDS can be severe and chronic, is not easy to treat, and does not resolve on its own, but were uncertain about its aetiology. Most respondents also felt that the incidence of Lyme disease will increase and that more education is needed. CONCLUSIONS: The need for further understanding and communication presents an opportunity for public health research and education in Lyme disease and the sequelae of PTLDS.

Novel adjunctive therapies for the treatment of tuberculosis.

Despite significant efforts to control tuberculosis (TB), the disease remains a major global threat, with an estimated 8.6 million new cases and 1.3 million deaths in 2012 alone. Significant treatment challenges include HIV co-infection, the dramatic rise of multidrug-resistant TB and the vast reservoir of latently infected individuals, who will develop active disease years after the initial infection. The long duration of chemotherapy also remains a major barrier to effective large scale treatment of TB. Significant advances are being made in the development of shorter and effective TB drug regimens and there is growing evidence that host-directed and "non-antimicrobial" pathogen-directed therapies, could serve as novel approaches to enhance TB treatments. This review highlights the rationale for using these therapies and summarizes some of the progress in this field.

Noninvasive determination of 2-[18F]-fluoroisonicotinic acid hydrazide pharmacokinetics by positron emission tomography in Mycobacterium tuberculosis-infected mice.

Tuberculosis (TB) is a global pandemic requiring sustained therapy to facilitate curing and to prevent the emergence of drug resistance. There are few adequate tools to evaluate drug dynamics within infected tissues in vivo. In this report, we evaluated a fluorinated analog of isoniazid (INH), 2-[(18)F]fluoroisonicotinic acid hydrazide (2-[(18)F]-INH), as a probe for imaging Mycobacterium tuberculosis-infected mice by dynamic positron emission tomography (PET). We developed a tail vein catheter system to safely deliver drugs to M. tuberculosis aerosol-infected mice inside sealed biocontainment devices. Imaging was rapid and noninvasive, and it could simultaneously visualize multiple tissues. Dynamic PET imaging demonstrated that 2-[(18)F]-INH was extensively distributed and rapidly accumulated at the sites of infection, including necrotic pulmonary TB lesions. Compared to uninfected animals, M. tuberculosis-infected mice had a significantly higher PET signal within the lungs (P < 0.05) despite similar PET activity in the liver (P > 0.85), suggesting that 2-[(18)F]-INH accumulated at the site of the pulmonary infection. Furthermore, our data indicated that similar to INH, 2-[(18)F]-INH required specific activation and accumulated within the bacterium. Pathogen-specific metabolism makes positron-emitting INH analogs attractive candidates for development into imaging probes with the potential to both detect bacteria and yield pharmacokinetic data in situ. Since PET imaging is currently used clinically, this approach could be translated from preclinical studies to use in humans.

On the emerging role of rabbit as human disease model and the instrumental role of novel transgenic tools.

The laboratory rabbit (Oryctolagus cuniculus) is widely used as a model for human diseases, because of its size, which permits non-lethal monitoring of physiological changes and similar disease characteristics. Novel transgenic tools such as, the zinc finger nuclease method and the sleeping beauty transposon mediated or BAC transgenesis were recently adapted to the laboratory rabbit and opened new opportunities in precise tissue and developmental stage specific gene expression/silencing, coupled with increased transgenic efficiencies. Many facets of human development and diseases cannot be investigated in rodents. This is especially true for early prenatal development, its long-lasting effects on health and complex disorders, and some economically important diseases such as atherosclerosis or cardiovascular diseases. The first transgenic rabbits models of arrhythmogenesis mimic human cardiac diseases much better than transgenic mice and hereby underline the importance of non-mouse models. Another emerging field is epigenetic reprogramming and pathogenic mechanisms in diabetic pregnancy, where rabbit models are indispensable. Beyond that rabbit is used for decades as major source of polyclonal antibodies and recently in monoclonal antibody production. Alteration of its genome to increase the efficiency and value of the antibodies by humanization of the immunoglobulin genes, or by increasing the expression of a special receptor (Fc receptor) that augments humoral immune response is a current demand.

Religion, spirituality and the well-being of informal caregivers: a review, critique, and research prospectus.

The purpose of this article is to review and critique the published literature examining the relationships between religion/spirituality and caregiver well-being and to provide directions for future research. A systematic search was conducted using bibliographic databases, reference sections of articles, and by contacting experts in the field. Articles were reviewed for measurement, theoretical, and design limitations. Eighty-three studies were retrieved. Research on religion/spirituality and caregiver well-being is a burgeoning area of investigation; 37% of the articles were published in the last five years. Evidence for the effects of religion/spirituality were unclear; the preponderance (n = 71, 86%) of studies found no or a mixed association (i.e., a combination of positive, negative, or non-significant results) between religion/spirituality and well-being. These ambiguous results are a reflection of the multidimensionality of religion/spirituality and the diversity of well-being outcomes examined. They also partially reflect the frequent use of unrefined measures of religion/spirituality and of atheoretical approaches to studying this topic. Investigators have a fairly large number of studies on religion/spirituality and caregiver well-being on which to build. Future studies should be theory driven and utilize psychometrically sound measures of religion/spirituality. Suggestions are provided to help guide future work.

Pseudomonas aeruginosa: the potential to immunise against infection.

Pseudomonas aeruginosa remains a serious pathogen for specific cohorts of patients where chronic infection is a poor prognostic indicator, such as those with cystic fibrosis, burn wounds or those who are immunocompromised. Significant disease burden is associated with a diverse spectrum of both nosocomial and community-acquired infections. To date, vaccines against P. aeruginosa have shown limited and often conflicting efficacy data, especially against heterologous strains, which are increasingly identified as co-colonisers of biofilms. While few studies have gone beyond Phase II clinical trials, a particular concern is the ability of P. aeruginosa to evade the immune system while provoking an immune response that contributes to the destructive nature of infection. Therefore, vaccine development needs to focus on preventing attachment and colonisation, as well as preventing conversion to a mucoid phenotype that is characteristic of the chronic condition that promotes pathology.

Characterization of the cydAB-encoded cytochrome bd oxidase from Mycobacterium smegmatis.

The cydAB genes from Mycobacterium smegmatis have been cloned and characterized. The cydA and cydB genes encode the two subunits of a cytochrome bd oxidase belonging to the widely distributed family of quinol oxidases found in prokaryotes. The cydD and cydC genes located immediately downstream of cydB encode a putative ATP-binding cassette-type transporter. At room temperature, reduced minus oxidized difference spectra of membranes purified from wild-type M. smegmatis displayed spectral features that are characteristic of the gamma-proteobacterial type cytochrome bd oxidase. Inactivation of cydA or cydB by insertion of a kanamycin resistance marker resulted in loss of d-heme absorbance at 631 nm. The d-heme could be restored by transformation of the M. smegmatis cyd mutants with a replicating plasmid carrying the highly homologous cydABDC gene cluster from Mycobacterium tuberculosis. Inactivation of cydA had no effect on the ability of M. smegmatis to exit from stationary phase at 37 or 42 degrees C. The growth rate of the cydA mutant was tested under oxystatic conditions. Although no discernible growth defect was observed under moderately aerobic conditions (9.2 to 37.5 x 10(2) Pa of pO(2) or 5 to 21% air saturation), the mutant displayed a significant growth disadvantage when cocultured with the wild type under extreme microaerophilia (0.8 to 1.7 x 10(2) Pa of pO(2) or 0.5 to 1% air saturation). These observations were in accordance with the two- to threefold increase in cydAB gene expression observed upon reduction of the pO(2) of the growth medium from 21 to 0.5% air saturation and with the concomitant increase in d-heme absorbance in spectra of membranes isolated from wild-type M. smegmatis cultured at 1% air saturation. Finally, the cydA mutant displayed a competitive growth disadvantage in the presence of the terminal oxidase inhibitor, cyanide, when cocultured with wild type at 21% air saturation in an oxystat. In conjunction with these findings, our results suggest that cytochrome bd is an important terminal oxidase in M. smegmatis.

An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans.

Two small temporal RNAs (stRNAs), lin-4 and let-7, control developmental timing in Caenorhabditis elegans. We find that these two regulatory RNAs are members of a large class of 21- to 24-nucleotide noncoding RNAs, called microRNAs (miRNAs). We report on 55 previously unknown miRNAs in C. elegans. The miRNAs have diverse expression patterns during development: a let-7 paralog is temporally coexpressed with let-7; miRNAs encoded in a single genomic cluster are coexpressed during embryogenesis; and still other miRNAs are expressed constitutively throughout development. Potential orthologs of several of these miRNA genes were identified in Drosophila and human genomes. The abundance of these tiny RNAs, their expression patterns, and their evolutionary conservation imply that, as a class, miRNAs have broad regulatory functions in animals.

The extracellular region of heregulin is sufficient to promote mammary gland proliferation and tumorigenesis but not apoptosis.

Heregulin (HRG) is a member of the neuregulin family of ligands that have been shown to interact with and activate erbB receptors. A transgenic mouse model in which full-length HRG is overexpressed has proven that this protein can induce carcinomas in the murine mammary gland. These tumors display a high level of apoptosis, which appears to be mediated by the cytoplasmic domain of HRG. Because both proliferation and apoptosis play a role in tumor formation, we wished to separately view those perturbations by removing the suspected apoptosis-inducing cytoplasmic domain of HRG. We thereby sought to determine whether overexpression of the extracellular region of HRG would be sufficient to induce mammary gland carcinomas. A HRG construct lacking the cytoplasmic domain was targeted to the mammary gland using the murine mammary tumor virus promoter. Multiple lines of transgenic mice carrying the transgene developed mammary gland tumors at approximately 15 months of age. These tumors did not display high levels of apoptosis as compared with tumors from murine mammary tumor virus/full-length HRG transgenic animals. In addition, virgin transgenic mice show a persistence of terminal end bud structures, which normally disappear at the onset of puberty in wild-type mice. To examine the signal transduction pathway activated by extracellular HRG in tumors, we investigated the phosphorylation status of the epidermal growth factor receptor family members. Western blot analysis showed activation of ErbB2 and ErbB3, suggesting a possible mode of action of extracellular HRG in mammary gland carcinomas. We conclude that the extracellular and transmembrane domains of HRG are sufficient for the induction of tumorigenesis but that induction of apoptosis requires the cytoplasmic tail.

A mouse model for breast cancer induced by amplification and overexpression of the neu promoter and transgene.

BACKGROUND: ErbB-2 is a critical oncogenic marker in human breast cancer. Its appearance correlates with poor prognosis and it is, therefore, an important target for physiologic investigation and therapeutic intervention. With this in mind, we have created and characterized two mouse breast cancer models that express rat wild type neu, the homologue of ErbB-2, and rat mutant neu under the control of the normal mouse neu promoter. These models in which the copy number of the neu gene is moderately amplified should more closely parallel the expression pattern of ErbB-2 seen in some cases of human breast cancer. MATERIALS AND METHODS: Transgenic mouse models were constructed by injecting one of the two pronuclei of a fertilized FVB/n egg and implanting it into a pseudopregnant Swiss /Webster mouse. Tissue expression was analyzed through the use of reverse transcription polymerase chain reaction and mammary histopathology examined by fixing, staining and mounting of the entire gland. RESULTS: In the former wild type model, we show that low level, long term expression of neu leads to abnormal lobuloalveolar development in virginal glands and incomplete regression in multiparous glands. Malignant foci form following multiple rounds of pregnancy and regression. In the latter model, a similarly directed transgene carrying the constitutively activated, mutant form of the rat neu gene, a stronger but similar phenotype is displayed. CONCLUSION: Evidently minor perturbations in amplified neu expression are sufficient to alter mammary development and induce malignant transformation.

Prothrombinase acceleration by oxidatively damaged phospholipids.

The optimally efficient production of thrombin by the prothrombinase complex relies on suitable positioning of its component factors and substrate on phosphatidylserine-containing lipid membranes. The presence of oxidatively damaged phospholipids in a membrane disrupts the normal architecture of a lipid bilayer and might therefore be expected to interfere with prothrombinase activity. To investigate this possibility, we prepared phosphatidylserine-containing lipid vesicles containing oxidized arachidonoyl lipids, and we examined their ability to accelerate thrombin production by prothrombinase. Oxidized arachidonoyl chains caused dose-dependent increases in prothrombinase activity up to 6-fold greater than control values. These increases were completely attenuated by the presence of alpha-tocopherol, gamma-tocopherol, or ascorbate. Over the course of a 300-min oxidation, the ability of arachidonoyl lipids to accelerate prothrombinase peaked at 60 min and then declined to base-line levels. These results suggest that instead of being impeded by oxidative membrane damage, prothrombinase activity is enhanced by one or more products of nonenzymatic lipid oxidation.

Isolation and identification of 1alpha-hydroxy-24-oxovitamin D3 and 1alpha,23-dihydroxy-24-oxovitamin D3: metabolites of 1alpha,24(R)-dihydroxyvitamin D3 produced in rat kidney.

1alpha,24(R)-Dihydroxyvitamin D3 [1alpha,24(R)(OH)2D3], a synthetic vitamin D3 analog, has been developed as a drug for topical use in the treatment of psoriasis. At present, the target tissue metabolism of 1alpha,24(R)(OH)2D3 is not understood completely. In our present study, we investigated the metabolism of 1alpha,24(R)(OH)2D3 in the isolated perfused rat kidney. The results indicated that 1alpha,24(R)(OH)2D3 is metabolized in rat kidney into several metabolites, of which 1alpha,24(R),25-trihydroxyvitamin D3, 1alpha,25-dihydroxy-24-oxovitamin D3, 1alpha,23(S),25-trihydroxy-24-oxovitamin D3, and 1alpha,23-dihydroxy-24,25,26,27-tetranorvitamin D3 are similar to the previously known metabolites of 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3]. In addition to these aforementioned metabolites, we also identified two new metabolites, namely 1alpha-hydroxy-24-oxovitamin D3 and 1alpha,23-dihydroxy-24-oxovitamin D3. The two new metabolites do not possess the C-25 hydroxyl group. Thus, the metabolism of 1alpha,24(R)(OH)2D3 into both 25-hydroxylated and non-25-hydroxylated metabolites suggests that 1alpha,24(R)(OH)2D3 is metabolized in the rat kidney through two pathways. The first pathway is initiated by C-25 hydroxylation and proceeds further via the C-24 oxidation pathway. The second pathway directly proceeds via the C-24 oxidation pathway without prior hydroxylation at the C-25 position. Furthermore, we demonstrated that rat kidney did not convert 1alpha-hydroxyvitamin D3 [1alpha(OH)D3] into 1alpha,25(OH)2D3. This finding indicates that the rat kidney does not possess the classical vitamin D3-25-hydroxylase (CYP27) activity. However, from our present study it is apparent that prior hydroxylation of 1alpha(OH)D3 at the C-24 position in the 'R' orientation allows 25-hydroxylation to occur. At present, the enzyme responsible for the C-25 hydroxylation of 1alpha,24(R)(OH)2D3 is unknown. Our observation that the side chain of 1alpha,24(R)(OH)2D3 underwent 24-ketonization and 23-hydroxylation even in the absence of the C-25 hydroxyl group suggests that 1alpha,25(OH)2D3-24-hydroxylase (CYP24) can perform some steps of the C-24 oxidation pathway without prior C-25 hydroxylation. Thus, we speculate that CYP24 may be playing a dual role in the metabolism of 1alpha,24(R)(OH)2D3.

The "stable" ruptured abdominal aortic aneurysm gives a false sense of security.

BACKGROUND: Operative mortality for ruptured abdominal aortic aneurysms (rAAA) has not changed over the past 4 decades. Previous studies have attempted to identify preoperative risk factors that impact upon survival. METHOD: A retrospective review of 25 patients with rAAA treated during a 2-year period was performed. Patients were divided into groups based upon the presence (GpI), absence (GpIIa), or subsequent development of preoperative hypotension (GpIIb). Time intervals from initial presentation to arrival in the operating room (IP-OR), to cross clamp application (IP-XC), and from observed hypotension to cross clamp (HYPO-XC) were recorded. RESULTS: Average time intervals for IP-OR and IP-XC were significantly shorter for GpI compared with GpIIa and GpIIb. No difference in HYPO-XC was noted between GpI and GpIIb. Mortality was 33% for GpI, 25% for GpIIa, and 87.5% for GpIIb. CONCLUSIONS: Normal admission blood pressure led to a decreased sense of urgency, creating avoidable delays and missed opportunities for salvage.

The oncogene heregulin induces apoptosis in breast epithelial cells and tumors.

The products of a growing number of genes have been shown to display seemingly contradictory functions; namely, the induction of tumorigenesis and the induction of apoptosis. Heregulin's involvement in oncogenesis occurs through its interactions with members of the EGF receptor tyrosine kinase family. Recently one isoform of heregulin, beta2b, was isolated in an in vitro screen for dominant, apoptosis-inducing genes in kidney epithelial cells. Here we show that heregulin is also capable of mediating apoptosis in human and murine mammary tumor cell lines and murine tumors. Furthermore, through transfection of the human breast cancer cell line MCF-7 with the truncated transmembrane/cytoplasmic segment of the heregulin gene, we show that the intracellular region of the heregulin precursor is sufficient for induction of apoptosis. Through the use of DNA fragmentation assays we also show that apoptosis occurs in cell lines established from heregulin-induced mammary gland tumors. TdT addition of digoxigenin labeled nucleotides to 3' OH ends of DNA breaks recapitulated these results in the actual tumors. Finally, over-expression of heregulin is shown to lead to the down-regulation of Bcl-2, an inhibitor of apoptosis. Conversely, the transfection of Bcl-2 into MCF-7 cells inhibits heregulin-mediated programmed cell death.

Neu differentiation factor (NDF), a dominant oncogene, causes apoptosis in vitro and in vivo.

Neu differentiation factor (NDF, also called neuregulin) is a potent inducer of epithelial cell proliferation and has been shown to induce mammary carcinomas in transgenic mice. Notwithstanding this proliferative effect, we have shown that a novel isoform of NDF can induce apoptosis when overexpressed. Here we report that this property also extends to other NDF isoforms and that the cytoplasmic portion of NDF is largely responsible for the apoptotic effect, whereas the proliferative activity is likely to depend upon the secreted version of NDF. In accordance with these contradictory properties, we find that tumors induced by NDF display extensive apoptosis in vivo. NDF is therefore an oncogene whose deregulation can induce transformation as well as apoptosis.

Elements of the art of practice in mental health.

OBJECTIVE: This qualitative study explored elements of artful practice of therapists practicing in mental health treatment settings. METHOD: In-depth interviews were conducted with three occupational therapists practicing in mental health who were considered exemplars of artful practice. Themes pertaining to their perspectives and approaches to practice were synthesized from interview data. RESULTS: The prevailing themes--therapeutic work as a vehicle for healing, collaborative guidance, and the Zen of therapy--are seen as elements forged by the therapist's compassion and unique personal style into a dynamic therapist-client interplay that creates a space for growth and healing to occur. Results affirmed the view of the art of practice in mental health as an intricate interplay of personal traits, interpersonal skills, and skilled use of meaningful activities within the context of a client's environment. CONCLUSION: The art of practice is a fluid, experiential process that takes place on a developmental continuum. The therapist's inner awareness of the subtlety of a multilayered healing process is an important basis of artful practice. One's practice art can be informed by knowledge of specific elements that contribute to artful practice and can be developed through education, self-reflection, personal growth, and the maturation process.