Role of skeletal muscle in ear development.

The current paper is a continuation of our work described in Rot and Kablar, 2010. Here, we show lists of 10 up- and 87 down-regulated genes obtained by a cDNA microarray analysis that compared developing Myf5-/-:Myod-/- (and Mrf4-/-) petrous part of the temporal bone, containing middle and inner ear, to the control, at embryonic day 18.5. Myf5-/-:Myod-/- fetuses entirely lack skeletal myoblasts and muscles. They are unable to move their head, which interferes with the perception of angular acceleration. Previously, we showed that the inner ear areas most affected in Myf5-/-:Myod-/- fetuses were the vestibular cristae ampullaris, sensitive to angular acceleration. Our finding that the type I hair cells were absent in the mutants' cristae was further used here to identify a profile of genes specific to the lacking cell type. Microarrays followed by a detailed consultation of web-accessible mouse databases allowed us to identify 6 candidate genes with a possible role in the development of the inner ear sensory organs: Actc1, Pgam2, Ldb3, Eno3, Hspb7 and Smpx. Additionally, we searched for human homologues of the candidate genes since a number of syndromes in humans have associated inner ear abnormalities. Mutations in one of our candidate genes, Smpx, have been reported as the cause of X-linked deafness in humans. Our current study suggests an epigenetic role that mechanical, and potentially other, stimuli originating from muscle, play in organogenesis, and offers an approach to finding novel genes responsible for altered inner ear phenotypes.

What do urologists think patients need to know when starting on androgen deprivation therapy? The perspective from Canada versus countries with lower gross domestic product.

BACKGROUND: Androgen deprivation therapy (ADT) side effects are numerous and negatively impact prostate cancer patients' quality of life. There is considerable discrepancy though among Canadian urologists regarding what ADT side effects and side effect management strategies. Little is known about global differences in ADT patient education. METHODS: International respondents were recruited via online posting and at an international urology conference. Hypotheses suggest that economic and cultural differences influence patient education practices; therefore, international respondents were divided into 3 categories (high, medium, and low gross domestic product). RESULTS: No differences were found between responses from Canadian urologists and high GDP countries. Compared to responses from low GDP countries, Canadian urologists are more likely to endorse informing patients about: osteoporosis, loss of muscle mass, weight gain, fatigue/sleep disturbance, relationship changes, cognitive changes, and loss of body hair. Infertility was the only side effect more often disclosed by urologists in low GDP counties. Recommended management strategies for hot flashes are more likely to be pharmaceutical in Canada, and behavioral in low GDP countries. Management strategies for gynecomastia are emphasized more in low GDP countries. Physical exercise is endorsed consistently more often by Canadian urologists. CONCLUSIONS: ADT educational practices vary greatly between Canada and lower GDP countries. Factors that could contribute to differences include economics (e.g., ADT drug costs), differences in side effect presentation due to different ADT drugs used, racial differences in perceived side effect burden, disease status at ADT commencement, and cultural differences in patient-physician shared-decision making.

The Role of Skeletal Muscle in External Ear Development: A Mouse Model Histomorphometric Study.

BACKGROUND: Mechanical stimuli imparted by skeletal muscles play an important role during embryonic development in vertebrates. Little is known whether skeletal muscles are required for normal external ear development. METHODS: We used Myf5-/-:MyoD-/- (double-mutant) mouse embryos that completely lack skeletal musculature and analyzed the development of the external ear. We concentrated on the external ear because several studies have suggested a muscular cause to various congenital auricular deformities, and middle and inner ear development was previously reported using the same mouse model. Wild-type mouse embryos were used as controls to compare the histomorphometric outcomes. RESULTS: Our findings demonstrated an absence of the external auditory meatus, along with an abnormal auricular appearance, in the double-mutant mouse embryos. Specifically, the auricle did not protrude laterally as noted in the wild-type mouse ears. However, histomorphometric measurements were not significantly different between the wild-type and double-mutant mouse ears. CONCLUSION: Overall, our study showed that the development of the mouse external ear is dependent on the presence of skeletal muscles.

Role of skeletal muscle in mandible development.

As a continuation of the previous study on palate development (Rot and Kablar, 2013), here we explore the relationship between the secondary cartilage mandibular condyles (parts of the temporomandibular joint) and the contributions (mechanical and secretory) from the adjacent skeletal musculature. Previous analysis of Myf5-/-:MyoD-/- mouse fetuses lacking skeletal muscle demonstrated the importance of muscle contraction and static loading in mouse skeletogenesis. Among abnormal skeletal features, micrognathia (mandibular hypoplasia) was detected: small, bent and posteriorly displaced mandible. As an example of Waddingtonian epigenetics, we suggest that muscle, in addition to acting via mechanochemical signal transduction pathways, networks and promoters, also exerts secretory stimuli on skeleton. Our goal is to identify candidate molecules at that muscle-mandible interface. By employing Systematic Subtractive Microarray Analysis approach, we compared gene expression between mandibles of amyogenic and wild type mouse fetuses and we identified up- and down-regulated genes. This step was followed by a bioinformatics approach and consultation of web-accessible mouse databases. We searched for individual tissue-specific gene expression and distribution, and for the functional effects of mutations in a particular gene. The database search tools allowed us to generate a set of candidate genes with involvement in mandibular development: Cacna1s, Ckm, Des, Mir300, Myog and Tnnc1. We also performed mouse-to-human translational experiments and found analogies. In the light of our findings we discuss various players in mandibular morphogenesis and make an argument for the need to consider mandibular development as a consequence of reciprocal epigenetic interactions of both skeletal and non-skeletal compartments.

Knowledge of reproductive system cancers, their treatments and side effects.

We explored, via an online questionnaire, knowledge of breast and reproductive system cancers in patients and non-patients who access the internet for information on these diseases. We compared that knowledge to the attention the diseases have received in medical research and on the Internet. Data were collected from 690 respondents (37 % male, 63 % female) about their knowledge of prevalence, lethality, treatments and side effects of testicular, prostate, breast, uterine, cervical and ovarian cancers. Most males, but only half of the female participants, were patients themselves. Although participants showed better knowledge of cancers specific to their own sex, both sexes felt familiar with breast cancer and less aware of other cancers. Women were as aware as men of side effects of treatments for male reproductive cancers. Sex differences in awareness appear to reflect different attitudes towards illness, bias toward females as caregivers, and the disproportionate media attention given to breast cancer.

The influence of acoustic and static stimuli on development of inner ear sensory epithelia.

Mechanical stimuli affect differentiation of specific cell types in several organs of mouse fetuses that develop without any skeletal musculature. To that end, we employed Myf5(-/-):MyoD(-/-) mouse embryos that completely lack skeletal musculature, and analyzed the development of sensory fields in the inner ear. Amyogenic fetuses lack skeletal muscles that move the chain of three middle ear ossicles which normally transfers sound vibrations. They also cannot tilt their head, which prevents the perception of angular acceleration. While our findings in the spiral organ of Corti are surprisingly normal, our results show that the development of cristae ampullaris, vestibular sensory fields sensitive to the angular acceleration, was the most affected. In cristae, hair cells and supporting cells were significantly smaller in the mutant embryos, but hair cells completely lacked tenascin, while supporting cells were more numerous. In maculae, supporting cells were significantly smaller but more numerous in the mutants. Here, we propose that our finding of a specific type I hair cell absence in the mutant's crista may now be employed in the identification of a profile of genes specific for the lacking cell type.