Discovery of a cholecystokinin-gastrin-like signaling system in nematodes

Members of the cholecystokinin (CCK)/gastrin family of peptides, including the arthropod sulfakinins, and their cognate receptors, play an important role in the regulation of feeding behavior and energy homeostasis. Despite many efforts after the discovery of CCK/gastrin immunoreactivity in nematodes 23 yr ago, the identity of these nematode CCK/gastrin-related peptides has remained a mystery ever since. The Caenorhabditis elegans genome contains two genes with high identity to the mammalian CCK receptors and their invertebrate counterparts, the sulfakinin receptors. By using the potential C. elegans CCK receptors as a fishing hook, we have isolated and identified two CCK-like neuropeptides encoded by neuropeptide-like protein-12 (nlp-12) as the endogenous ligands of these receptors. The neuropeptide-like protein-12 peptides have a very limited neuronal expression pattern, seem to occur in vivo in the unsulfated form, and react specifically with a human CCK-8 antibody. Both receptors and ligands share a high degree of structural similarity with their vertebrate and arthropod counterparts, and also display similar biological activities with respect to digestive enzyme secretion and fat storage. Our data indicate that the gastrin-CCK signaling system was already well established before the divergence of protostomes and deuterostomes.     

Protease inhibitors and cardiovascular outcomes in patients with HIV-1

Protease inhibitors for treatment of HIV-1 have been linked with increased risk of hyperlipidaemia and hyperglycaemia. In a cohort of 5672 outpatients with HIV-1 seen at nine US HIV clinics between January, 1993, and January, 2002, the frequency of myocardial infarctions increased after the introduction of protease inhibitors in 1996 (test for trend, p=0.0125). We noted that 19 of 3247 patients taking, but only two of 2425 who did not take, protease inhibitors had a myocardial infarction (odds ratio 7.1, 95% CI 1.6-44.3; Cox proportional hazards model-adjusted for smoking, sex, age, diabetes, hyperlipidaemia, and hypertension-hazard ratio 6.5, 0.9-47.8). Our findings suggest that, although infrequent, use of protease inhibitors is associated with increased risk of myocardial infarction in patients with HIV-1.     

Severe Bordetella holmesii infection in a previously healthy adolescent confirmed by gene sequence analysis.

We describe an immunocompetent adolescent who presented with exceptionally severe Bordetella holmesii infection, including previously undescribed manifestations. Sequelae included a severe restrictive lung defect due to pulmonary fibrosis.     

Cardiac hypertrophy is enhanced in PPAR alpha-/- mice in response to chronic pressure overload

AIMS: Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a nuclear receptor regulating cardiac metabolism that also has anti-inflammatory properties. Since the activation of inflammatory signalling pathways is considered to be important in cardiac hypertrophy and fibrosis, it is anticipated that PPARalpha modulates cardiac remodelling. Accordingly, in this study the hypothesis was tested that the absence of PPARalpha aggravates the cardiac hypertrophic response to pressure overload. METHODS AND RESULTS: Male PPARalpha-/- and wild-type mice were subjected to transverse aortic constriction (TAC) for 28 days. TAC resulted in a more pronounced increase in ventricular weight and left ventricular (LV) wall thickness in PPARalpha-/- than in wild-type mice. Compared with sham-operated mice, TAC did not affect cardiac function in wild-type mice, but significantly depressed LV ejection fraction and LV contractility in PPARalpha-/- mice. Moreover, after TAC mRNA levels of hypertrophic (atrial natriuretic factor, alpha-skeletal actin), fibrotic (collagen 1, matrix metalloproteinase-2), and inflammatory (interleukin-6, tumour necrosis factor-alpha, cyclo-oxygenase-2) marker genes were higher in PPARalpha-/- than in wild-type mice. The mRNA levels of genes involved in fatty acid metabolism (long-chain acyl-CoA synthetase, hydroxyacyl-CoA dehydrogenase) were decreased in PPARalpha-/- mice, but were not further compromised by TAC. CONCLUSION: The present findings show that the absence of PPARalpha results in a more pronounced hypertrophic growth response and cardiac dysfunction that are associated with an enhanced expression of markers of inflammation and extracellular matrix remodelling. These findings indicate that PPARalpha exerts salutary effects during cardiac hypertrophy.     

The effect of myosin light chain 2 dephosphorylation on Ca2+ -sensitivity of force is enhanced in failing human hearts

OBJECTIVE: Phosphorylation of the myosin light chain 2 (MLC-2) isoform expressed as a percentage of total MLC-2 was decreased in failing (21.1+/-2.0%) compared to donor (31.9+/-4.8%) hearts. To assess the functional implications of this change, we compared the effects of MLC-2 dephosphorylation on force development in failing and non-failing (donor) human hearts. METHODS: Cooperative effects in isometric force and rate of force redevelopment (K(tr)) were studied in single Triton-skinned human cardiomyocytes at various [Ca(2+)] before and after protein phosphatase-1 (PP-1) incubation. RESULTS: Maximum force and K(tr) values did not differ between failing and donor hearts, but Ca(2+)-sensitivity of force (pCa(50)) was significantly higher in failing myocardium (Deltap Ca(50)=0.17). K(tr) decreased with decreasing [Ca(2+)], although this decrease was less in failing than in donor hearts. Incubation of the myocytes with PP-1 (0.5 U/ml; 60 min) decreased pCa(50) to a larger extent in failing (0.20 pCa units) than in donor cardiomyocytes (0.10 pCa units). A decrease in absolute K(tr) values was found after PP-1 in failing and donor myocytes, while the shape of the K(tr)-Ca(2+) relationships remained unaltered. CONCLUSIONS: Surprisingly, the contractile response to MLC-2 dephosphorylation is enhanced in failing hearts, despite the reduced level of basal MLC-2 phosphorylation. The enhanced response to MLC-2 dephosphorylation in failing myocytes might result from differences in basal phosphorylation of other thin and thick filament proteins between donor and failing hearts. Regulation of Ca(2+)-sensitivity via MLC-2 phosphorylation may be a potential compensatory mechanism to reverse the detrimental effects of increased Ca(2+)-sensitivity and impaired Ca(2+)-handling on diastolic function in human heart failure.     

The Clara cell10 adenine38guanine polymorphism and sarcoidosis susceptibility in Dutch and Japanese subjects

CC10 (CC16, uteroglobin) is a pulmonary protein postulated to play a counter regulatory role in sarcoidosis pathogenesis. The adenine38guanine (A38G) polymorphism of the encoding CC10 gene (SCGB1A1) is functional. Recently, an association between the low CC10 producing 38A allele and sarcoidosis susceptibility has been reported in Japanese patients from Hokkaido. The aim of the present study was to confirm this association in a clinically well characterized population of Dutch white and Kyoto Japanese patients with sarcoidosis and control subjects. No difference in genotype or allele frequency was found between patients with sarcoidosis and control subjects in either ethnic population. Remarkably, however, a significant difference was found between the control subjects from Kyoto and Hokkaido, but not between the Japanese groups of patients with sarcoidosis. Furthermore, review of previously published A38G genotyping results showed a consistent difference in CC10 A38G allele frequencies between whites and Japanese subjects. We conclude that the CC10 A38G polymorphism does not influence sarcoidosis susceptibility in Dutch whites or in Japanese subjects from Kyoto. This stresses the importance of studying the influence of polymorphisms on disease susceptibility in multiple ethnically and geographically distinct disease and control populations before reaching conclusions.     

AIDS-related B-cell lymphoma (ARL): correlation of prognosis with differentiation profiles assessed by immunophenotyping

This study was undertaken to analyze the differentiation profiles assessed by immunophenotyping in AIDS-related B-cell lymphoma (ARL) and their relation to the clinical course. Paraffin-embedded sections of 89 ARL cases during 1989 to 2004 were stained immunohistochemically with antibodies to CD3, CD10, CD20, CD38, CD138/Syndecan-1 (Syn-1), multiple myeloma-1/interferon regulatory factor-4 (MUM1/IRF4), B-cell lymphoma protein-2 (BCL-2), BCL-6, latent membrane protein-1 (LMP-1), and Ki-67. Expression of CD10 and CD20 were associated with better overall survival (OS; P = .009 and P = .04, respectively). Expression of CD20 was associated with longer disease-free survival (DFS; P = .03), whereas expression of CD138/Syn-1 was associated with shorter DFS (P = .03). OS and DFS were worse in patients with immunophenotypic profiles related to post-germinal center (GC) differentiation (BCL-6 and CD10 negative, MUM1/IRF4 and/or CD138/Syn-1 positive) when compared with GC differentiation (P = .01). When controlled for age-adjusted International Prognostic Index (IPI), prior AIDS-defining illness (ADI), and year of ARL diagnosis, a post-GC differentiation remained significantly associated with poor OS and DFS. Expression of CD10 was associated with a preserved immunocompetence, whereas CD20 was less frequent in patients developing ARL while on highly active antiretroviral therapy (P = .04). In summary, lack of CD20 or CD10 expression and a post-germinal center signature are associated with a worse prognosis in ARL.     

Screening for Chemical Contributions to Breast Cancer Risk: A Case Study for Chemical Safety Evaluation

Background

Current approaches to chemical screening, prioritization, and assessment are being reenvisioned, driven by innovations in chemical safety testing, new chemical regulations, and demand for information on human and environmental impacts of chemicals. To conceptualize these changes through the lens of a prevalent disease, the Breast Cancer and Chemicals Policy project convened an interdisciplinary expert panel to investigate methods for identifying chemicals that may increase breast cancer risk.

Methods

Based on a review of current evidence, the panel identified key biological processes whose perturbation may alter breast cancer risk. We identified corresponding assays to develop the Hazard Identification Approach for Breast Carcinogens (HIA-BC), a method for detecting chemicals that may raise breast cancer risk. Finally, we conducted a literature-based pilot test of the HIA-BC.

Results

The HIA-BC identifies assays capable of detecting alterations to biological processes relevant to breast cancer, including cellular and molecular events, tissue changes, and factors that alter susceptibility. In the pilot test of the HIA-BC, chemicals associated with breast cancer all demonstrated genotoxic or endocrine activity, but not necessarily both. Significant data gaps persist.

Conclusions

This approach could inform the development of toxicity testing that targets mechanisms relevant to breast cancer, providing a basis for identifying safer chemicals. The study identified important end points not currently evaluated by federal testing programs, including altered mammary gland development, Her2 activation, progesterone receptor activity, prolactin effects, and aspects of estrogen receptor β activity. This approach could be extended to identify the biological processes and screening methods relevant for other common diseases.

Citation

Schwarzman MR, Ackerman JM, Dairkee SH, Fenton SE, Johnson D, Navarro KM, Osborne G, Rudel RA, Solomon GM, Zeise L, Janssen S. 2015. Screening for chemical contributions to breast cancer risk: a case study for chemical safety evaluation. Environ Health Perspect 123:1255–1264; http://dx.doi.org/10.1289/ehp.1408337     

Use of thoracic ultrasound by physiotherapists: a scoping review of the literature

Background

Use of diagnostic thoracic ultrasound (TUS) in medical professions to examine the pleura, lung parenchyma and diaphragm is gaining in popularity, however the ways in which physiotherapists are using TUS is unclear.

Involving people with dementia in developing an interactive web tool for shared decision-making: experiences with a participatory design approach

Purpose: The aim of this study was at gaining insight into the participatory design approach of involving people with dementia in the development of the DecideGuide, an interactive web tool facilitating shared decision-making in their care networks.

Method: An explanatory case study design was used when developing the DecideGuide. A secondary analysis focused on the data gathered from the participating people with dementia during the development stages: semi-structured interviews (n?=?23), four focus group interviews (n?=?18), usability tests (n?=?3), and a field study (n?=?4). Content analysis was applied to the data.

Results: Four themes showed to be important regarding the participation experiences of involving people with dementia in research: valuable feedback on content and design of the DecideGuide, motivation to participate, perspectives of people with dementia and others about distress related to involvement, and time investment.

Conclusions: People with dementia can give essential feedback and, therefore, their contribution is useful and valuable. Meaningful participation of people with dementia takes time that should be taken into account. It is important for people with dementia to be able to reciprocate the efforts others make and to feel of significance to others.

• Implications for Rehabilitation

• People with dementia can contribute meaningfully to the content and design and their perspective is essential for developing useful and user-friendly tools.

• Participating in research activities may contribute to social inclusion, empowerment, and quality of life of people with dementia.