Maldevelopment of the cranio-facial-respiratory complex: A Darwinian perspective.

AIM: The mammalian Cranio-Facial-Respiratory Complex (CFRC) comprises several different biological tissues that collectively function under coordination from the central nervous and cardiorespiratory systems, primarily to breathe, eat and drink as well as integrating the sensory and motor systems for speech, communication and protective mechanisms. Anthropologists have long recognised that lifelong exposure to modern feeding regimens of readily available and highly processed foods, changes in breastfeeding and weaning, can impact expression of various phenotypic traits affecting the CFRC quite differently than does lifelong exposure to more traditional ancestral feeding regimens, typical of hunter-gather/foraging in non-Western-exposed cultures. The aim of this study is to highlight the role of the paediatric dentist in a multidisciplinary approach in which professionals working in and around the CFRC can actively prevent tooth decay and skeletal-dental malocclusion in the light of evolutionary oral medicine. RESULTS: As a result of changes in the environment, in the food quality, in eating and feeding practices starting from day one, two oral diseases of civilisation, tooth decay and skeletal-dental malocclusion, have both relatively recently reached worldwide epidemic proportions and afflict people of all ages. CONCLUSION: A multidisciplinary approach in which professionals working in and around the CFRC can actively promote prevention or reversal of dento-skeletal and myofunctional disorders, diagnose them when present and coordinate the appropriate therapy and life long maintenance programme.

Defective replication stress response inhibits lymphomagenesis and impairs lymphocyte reconstitution.

DNA replication stress promotes genome instability in cancer. However, the contribution of the replication stress response to the development of malignancies remains unresolved. The DNA replication stress response protein SMARCAL1 stabilizes DNA replication forks and prevents replication fork collapse, a cause of DNA breaks and apoptosis. While the fork regression/remodeling functions of SMARCAL1 have been investigated, its in vivo functions in replication stress and cancer are unclear. Using a gamma radiation (IR)-induced replication stress T-cell lymphoma mouse model, we observed a significant inhibition of lymphomagenesis in mice lacking one or both alleles of Smarcal1. Notably, a quarter of the Smarcal1-deficient mice did not develop tumors. Moreover, hematopoietic stem/progenitor cells (HSPCs) and developing thymocytes in Smarcal1-deficient mice showed increased DNA damage and apoptosis during the proliferation burst following IR and an impaired ability to repopulate the thymus after IR. Additionally, mice lacking Smarcal1 showed significant HSPC defects when challenged to respond to other replication stress stimuli. Thus, our data reveal the critical function of the DNA replication stress response and, specifically, Smarcal1 in hematopoietic cell survival and tumor development. Our results also provide important insight into the immunodeficiency observed in individuals with mutations in SMARCAL1 by suggesting that it is an HSPC defect.

Diagnostic SOX10 gene signatures in salivary adenoid cystic and breast basal-like carcinomas.

BACKGROUND: Salivary adenoid cystic carcinoma (ACC) is an insidious slow-growing cancer with the propensity to recur and metastasise to distant sites. Basal-like breast carcinoma (BBC) is a molecular subtype that constitutes 15-20% of breast cancers, shares histological similarities and basal cell markers with ACC, lacks expression of ER (oestrogen receptor), PR (progesterone receptor), and HER2 (human epidermal growth factor receptor 2), and, similar to ACC, metastasises predominantly to the lung and brain. Both cancers lack targeted therapies owing to poor understanding of their molecular drivers. METHODS: Gene expression profiling, immunohistochemical staining, western blot, RT-PCR, and in silico analysis of massive cancer data sets were used to identify novel markers and potential therapeutic targets for ACC and BBC. For the detection and comparison of gene signatures, we performed co-expression analysis using a recently developed web-based multi-experiment matrix tool for visualisation and rank aggregation. RESULTS: In ACC and BBC we identified characteristic and overlapping SOX10 gene signatures that contained a large set of novel potential molecular markers. SOX10 was validated as a sensitive diagnostic marker for both cancers and its expression was linked to normal and malignant myoepithelial/basal cells. In ACC, BBC, and melanoma (MEL), SOX10 expression strongly co-segregated with the expression of ROPN1B, GPM6B, COL9A3, and MIA. In ACC and breast cancers, SOX10 expression negatively correlated with FOXA1, a cell identity marker and major regulator of the luminal breast subtype. Diagnostic significance of several conserved elements of the SOX10 signature (MIA, TRIM2, ROPN1, and ROPN1B) was validated on BBC cell lines. CONCLUSION: SOX10 expression in ACC and BBC appears to be a part of a highly coordinated transcriptional programme characteristic for cancers with basal/myoepithelial features. Comparison between ACC/BBC and other cancers, such as neuroblastomaand MEL, reveals potential molecular markers specific for these cancers that are likely linked to their cell identity. SOX10 as a novel diagnostic marker for ACC and BBC provides important molecular insight into their molecular aetiology and cell origin. Given that SOX10 was recently described as a principal driver of MEL, identification of conserved elements of the SOX10 signatures may help in better understanding of SOX10-related signalling and development of novel diagnostic and therapeutic tools.

The 2008 ACVP role delineation survey and initial data analysis: from the Role Delineation Task Force.

The American College of Veterinary Pathologists commissioned a role delineation survey to define the specialized tasks, knowledge, and tools that define the current practice of veterinary clinical pathology and veterinary anatomic pathology. The survey also identified when competence was acquired for each task (i.e., before certification or after certification). The response rate by diplomates was high, with approximately 50% of practicing pathologists within each specialty responding to each survey. Using the survey results, all tasks for each specialty were classified as either appropriate or unsuitable for testing in the certifying examinations. The role delineation survey data will facilitate the creation of test plans that objectively define the content in each certifying examination, the evaluation and enhancement of training curricula, and the optimization of continuing education opportunities for practicing veterinary pathologists.

Hepatic hyaline globules in an Eclectus parrot (Eclectus roratus).

Hepatic hyaline globules, similar to those reported in some human livers, were observed in liver tissue from an Eclectus parrot (Eclectus roratus). The cytoplasmic inclusions were periodic acid-Schiff positive and diastase resistant and failed to stain by acid-fast or Congo red techniques. Ultrastructurally, the hepatic globules were composed of granular amorphous material with small peripheral striations that extended into the cytoplasm.

Jelly beans as an alternative to a cola beverage containing fifty grams of glucose.

OBJECTIVE: Our purpose was to test the diagnostic value and patient tolerance of jelly beans as an alternative to a 50 gm glucose solution. STUDY DESIGN: Pregnant women between 26 to 30 weeks of gestation confirmed by early ultrasonography were recruited to participate in the study. Each participant was given a cola beverage containing 50 gm of glucose. The plasma glucose level was determined 1 hour later. Within 2 weeks of the 50 gm glucose test, each patient ate 18 jelly beans and had her plasma glucose levels tested after 1 hour. Finally, within 2 weeks of the jelly bean test a 100 gm, 3-hour glucose tolerance test was performed on each subject. The results of the 3-hour test were used to define the presence or absence of gestational diabetes and carbohydrate intolerance by the criteria of The American College of Obstetricians and Gynecologists. Patient tolerance was rated by responses to questions regarding side effects. RESULTS: One hundred fifty-seven women completed the study. The mean maternal age, gravidity, parity, and number of abortions were 26.06 years, 2.66, 0.96, and 0.69. By use of a 140 mg/dl threshold, the sensitivity, specificity, and positive predictive value of the cola beverage was 46%, 81%, and 18%. These values at a 120 mg/dl threshold for jelly beans were 54%, 81%, and 20%, respectively. The patient tolerance was greater for the jelly beans compared with the 50 gm cola beverage. CONCLUSION: Jelly beans may serve as an alternative to a cola beverage containing 50 gm of glucose.

Molecular dissection of functional domains of the E1E2-ATPase using sodium and calcium pump chimeric molecules.

Proposed models for the catalytic subunit of the E1E2-ATPases (ion pumps) predict that the first four transmembrane domains (M1 - M4) reside in the NH2 terminal one-third of the molecule, and the remainder (M5 - M10) in the COOH terminal one-third. The amino-acid sequences for the 5'-(p-fluorosulfonyl)-benzoyl-adenosine (FSBA) binding region residing just before M5 segment are very well conserved among distinct ion pumps. Taking advantage of these models, we have constructed a set of chicken chimeric ion pumps between the (Na++ K+)-ATPase alpha-subunit and the Ca(2+)-ATPase using the FSBA-binding site as an exchange junction, thereby preserving overall topological structure as E1E2 ATPases. From various functional assays on these chimeric ion pumps, including ouabain-inhibitable ATPase activity, Ca2+ binding, Ca2+ uptake, and subunit assembly based on immuno-coprecipitation, the following conclusions were obtained: (a) A (Na++ K+)-ATPase inhibitor, ouabain, binds to the regions before M4 in the alpha-subunit and exerts its inhibitory effect. (b) The regions after M5 of the (Na++ K+)-ATPase alpha-subunit bind the beta-subunit, even when these regions are incorporated into the corresponding domains in the Ca(2+)-ATPase. (c) The corresponding domains of the Ca(2+)-ATPase, the regions after M5, bind 45Ca even when it is incorporated into the corresponding position of the (Na++ K+)-ATPase alpha-subunit.

Ouabain- and Ca2(+)-sensitive ATPase activity of chimeric Na- and Ca-pump molecules.

Chimeric ion-pumps, consisting of the N-terminal 2/3 of the alpha 1-subunit of the ouabain-sensitive chicken Na+,K(+)-ATPase and the C-terminal 1/3 of the sarcoplasmic reticulum Ca2(+)-ATPase, were expressed in ouabain-insensitive mouse L cells. These chimeric molecules exhibited ouabain-sensitive ATPase activity very similar to that of the wild-type chicken Na+, K(+)-ATPase. This ATPase activity could be stimulated by adding Ca2+ to the assay system. These results suggest that the sites for ouabain-inhibition are restricted to the N-terminal 2/3 of the Na-pump, and the C-terminal 1/3 of the Ca-pump interacts with Ca2+.

The effects of pore size and endothelial cell seeding upon the performance of small-diameter e-PTFE vascular grafts under controlled flow conditions.

The purpose of this study was to determine the effects of endothelial cell seeding and graft internodal distance upon the performance of 4-mm-ID e-PTFE grafts during acute reduced blood flow conditions. PTFE grafts especially manufactured with three different mean internodal distances (28, 40, and 52 microns) were evaluated. Fifteen dogs (n = 5 for each design of PTFE graft) underwent bilateral carotid artery replacements with 6 cm lengths of 4-mm-ID PTFE grafts. In each dog one graft was seeded with enzymatically derived endothelial cells; the contralateral graft was nonseeded. All grafts were evaluated 5 weeks postoperatively. Dogs with bilaterally patent grafts were subsequently subjected to flow conditions through the graft that were maintained at 30% of the initial flow rates for 4 hr. Following controlled low flows the grafts were excised and assessed for patency, thrombus-free surface area, inner capsule thickness and prostacyclin production. Endothelial cell seeding of these small-diameter e-PTFE vascular grafts improved patency and thrombus-free surface areas in grafts of all pore sizes, with these parameters being greatest in the 40-microns grafts. Inner-capsule healing in these grafts was controlled and related to the pore size. PGI2 production was improved in endothelial cell seeded grafts of all pore sizes. However, neither endothelial cell seeding nor graft pore size affected the performance of these e-PTFE grafts under conditions of reduced blood flows.