Human and mouse enamel phenotypes resulting from mutation or altered expression of AMEL, ENAM, MMP20 and KLK4

Amelogenesis imperfecta (AI) is caused by AMEL, ENAM, MMP20 and KLK4 gene mutations. Mice lacking expression of the AmelX, Enam and Mmp20 genes have been generated. These mouse models provide tools for understanding enamel formation and AI pathogenesis. This study describes the AI phenotypes and relates them to their mouse model counterparts. Human AI phenotypes were determined in a clinical population of AI families and published cases. Human and murine teeth were evaluated using light and electron microscopy. A total of 463 individuals from 54 families were evaluated and mutations in the AMEL, ENAM and KLK4 genes were identified. The majority of human mutations for genes coding enamel nonproteinase proteins (AMEL and ENAM) resulted in variable hypoplasia ranging from local pitting to a marked, generalized enamel thinning. Specific AMEL mutations were associated with abnormal mineralization and maturation defects. Amel and Enam null murine models displayed marked enamel hypoplasia and a complete loss of prism structure. Human mutations in genes coding for the enamel proteinases (MMP20 and KLK4) cause variable degrees of hypomineralization. The murine Mmp20 null mouse exhibits both hypoplastic and hypomineralized defects. The currently available Amel and Enam mouse models for AI exhibit enamel phenotypes (hypoplastic) that are generally similar to those seen in humans. Mmp20 null mice have a greater degree of hypoplasia than humans with MMP20 mutations. Mice lacking expression of the currently known genes associated with the human AI conditions provide useful models for understanding the pathogenesis of these conditions.     

Exercise to reduce vasomotor and other menopausal symptoms: A review

Many women are reluctant to consider HRT as a therapeutic option for menopausal symptoms and are keen to use non-pharmacological treatments. Evidence from randomised controlled trials (RCTs) concerning the effects of aerobic exercise on vasomotor and other menopausal symptoms is limited but what evidence we do have suggests that aerobic exercise can improve psychological health and quality of life in vasomotor symptomatic women. In addition, several RCTs of middle-aged/menopausal-aged women have found that aerobic exercise can invoke significant improvements in several common menopause-related symptoms (e.g. mood, health-related QoL and insomnia), relative to non-exercise comparison groups. There is some evidence that alternative forms of low intensity exercise such as yoga are beneficial in reducing vasomotor symptoms and improving psychological well-being in menopausal women. Collectively, these RCTs highlight the broader potential that exercise could have for women during the menopause transition. Whilst both the Royal College of Obstetricians and Gynaecologists in the UK and the North American Menopause Society have recommended that women be advised to consider aerobic exercise as a treatment for vasomotor menopausal symptoms, to make any evidence-based conclusions regarding the effectiveness of exercise in managing these symptoms, more high quality research is needed.     

Disruption of Interleukin-1 Signaling Improves the Quality of Wound Healing

In this study, we investigated the role of interleukin (IL)-1 signaling in wound healing. IL-1 receptor type I (IL-1R) knockout (KO) mice showed reduced fibrosis in both cutaneous and deep tissue wounds, which was accompanied by a reduction in inflammatory cellular infiltration in cutaneous but not in deep tissue wounds. There were no differences in either total collagenolytic activity or in the expression of selected matrix metalloproteinases or tissue inhibitors of metalloproteinases between the wound fluids from wild-type or IL-1R KO mice. However, wound fluids from IL-1R KO mice contained lower levels of IL-6 compared with wild-type controls. In addition, the infusion of IL-6 into wounds in IL-1R KO mice did not increase fibrosis. Skin wounds in IL-1R KO animals had lower levels of collagen and improved restoration of normal skin architecture compared with skin wounds in wild-type mice. However, neither the tensile strength of incisional skin wounds nor the rate of closure of excisional wounds differed between IL-1R KO and wild-type animals. The reduced fibrotic response in wounds from IL-1R KO mice could be reproduced by the administration of an IL-1R antagonist. These findings suggest that pharmacological interference with IL-1 signaling could have therapeutic value in the prevention of hypertrophic scarring and in the treatment of fibrotic diseases.Progress in the therapeutic management of abnormal wound healing has fallen short of expectations. The promise of molecular medicine to normalize impaired healing, as seen in diabetes, vascular insufficiency, or other chronic diseases, through the use of exogenous cytokines or growth factors has not been realized. At the other end of the abnormal wound healing spectrum, no reliable prophylactic or therapeutic measures exist to address the pathologies of excessive repair, exemplified by hypertrophic burn scars, keloids, and stenosing gastrointestinal or vascular anastomoses. The availability of effective therapies that allow for the modulation of the wound healing response would be of substantial clinical relevance. Recent reports demonstrate a markedly reduced cellular inflammatory response in models of sterile inflammation^1,2,3,4 and decreased scarring after experimental myocardial infarction in mice deficient in the interleukin (IL)-1 receptor type I (IL-1R).⁴The present studies tested the hypothesis that genetic or pharmacological interference with IL-1 signaling would modulate the inflammatory response in skin and deep tissue wounds and reduce scar formation. Results using IL-1R knockout (KO) mice demonstrated that signaling through the IL-1R is required for the constitution of a normal cellular inflammatory response in cutaneous but not in deep tissue wounds. Most importantly, the quality of wound healing was different in IL-1R KOs, with cutaneous wounds in these animals attaining better restoration of normal skin architecture and a marked reduction in fibrosis without compromise in tensile strength. Additionally, deep tissue wounds in IL-1R KO mice showed a substantial reduction in collagen content, an observation that was reproduced by the administration of a human recombinant IL-1 R antagonist.Findings demonstrate a role for the IL-1/IL-1R axis in the regulation of wound healing. They suggest that interference with IL-1 signaling through the use of an IL-1R antagonist may find a clinical application in the prevention of excessive or hypertrophic scar formation.     

Evaluation of a standard provision versus an autonomy promotive exercise referral programme: rationale and study design

Background  

The National Institute of Clinical Excellence in the UK has recommended that the effectiveness of ongoing exercise referral schemes to promote physical activity should be examined in research trials. Recent empirical evidence in health care and physical activity promotion contexts provides a foundation for testing the utility of a Self Determination Theory (SDT)-based exercise referral consultation.     

Cdx4 is dispensable for murine adult hematopoietic stem cells but promotes MLL-AF9-mediated leukemogenesis

Background

Cdx4 is a homeobox gene essential for normal blood formation during embryonic development in the zebrafish, through activation of posterior Hox genes. However, its role in adult mammalian hematopoiesis has not been extensively studied and its requirement in leukemia associated with Hox gene expression alteration is unclear.

Design and Methods

We inactivated Cdx4 in mice through either a germline or conditional knockout approach and analyzed requirement for Cdx4 in both normal adult hematopoiesis and leukemogenesis initiated by the MLL-AF9 fusion oncogene.

Results

Here, we report that loss of Cdx4 had a minimal effect on adult hematopoiesis. Indeed, although an increase in white blood cell counts was observed, no significant differences in the distribution of mature blood cells, progenitors or stem cells were observed in Cdx4-deficient animals. In addition, long-term repopulating activity in competitive transplantation assays was not significantly altered. In vitro, B-cell progenitor clonogenic potential was reduced in Cdx4-deficient animals but no significant alteration of mature B cells was detected in vivo. Finally, induction of acute myeloid leukemia in mice by MLL-AF9 was significantly delayed in the absence of Cdx4 in a retroviral transduction/bone marrow transplant model.

Conclusions

These observations indicate that Cdx4 is dispensable for the establishment and maintenance of normal hematopoiesis in adult mammals. These results, therefore, outline substantial differences in the Cdx-Hox axis between mammals and zebrafish and support the hypothesis that Cdx factors are functionally redundant during mammalian hematopoietic development under homeostatic conditions. In addition, our results suggest that Cdx4 participates in MLL-AF9-mediated leukemogenesis supporting a role for Cdx factors in the pathogenesis of myeloid leukemia.     

"Once Bitten, Twice Shy": participant perspectives in the aftermath of an early HIV vaccine trial termination

The Step Study phase IIb HIV-1 vaccine trial was terminated early due to futility; subsequent analyses revealed increased susceptibility to HIV infection among a subset of test vaccine recipients. We conducted a mixed methods investigation, including a brief, self-administered baseline questionnaire and in-depth, semi-structured, 1-h interviews after unblinding, to explore experiences and perspectives among trial participants and key informants. Interviews were digitally recorded, transcribed, and analyzed using NVivo and thematic techniques. Forty-eight trial participants (46 gay/bisexual men) completed baseline surveys; 15 (14 gay/bisexual men) engaged in post-trial interviews. Participants indicated surprise and disappointment about the early trial termination and unexpected risks. Some articulated understanding the uncertainties of clinical trials, steadfast support and willingness to participate in the future; others reported greater risks than they deemed acceptable and unlikelihood of volunteering again. A few indicated mistrust of trial sponsors and ethics. Participants’ most profound criticism was not about unexpected results, but perceived delays in unblinding and gaps in post-trial dissemination of information. Future HIV vaccine trials may benefit from increased emphasis on: (1) communication mechanisms among participants, investigators and trial sponsors, and (2) post-trial dissemination of information and psychosocial support.