Intraflagellar transport speed is sensitive to genetic and mechanical perturbations to flagellar beating.

Two sets of motor proteins underpin motile cilia/flagella function. The axoneme-associated inner and outer dynein arms drive sliding of adjacent axoneme microtubule doublets to periodically bend the flagellum for beating, while intraflagellar transport (IFT) kinesins and dyneins carry IFT trains bidirectionally along the axoneme. Despite assembling motile cilia and flagella, IFT train speeds have only previously been quantified in immobilized flagella-mechanical immobilization or genetic paralysis. This has limited investigation of the interaction between IFT and flagellar beating. Here, in uniflagellate Leishmania parasites, we use high-frequency, dual-color fluorescence microscopy to visualize IFT train movement in beating flagella. We discovered that adhesion of flagella to a microscope slide is detrimental, reducing IFT train speed and increasing train stalling. In flagella free to move, IFT train speed is not strongly dependent on flagella beat type; however, permanent disruption of flagella beating by deletion of genes necessary for formation or regulation of beating showed an inverse correlation of beat frequency and IFT train speed.

Shifting equilibriums in Alzheimer's disease: the complex roles of microglia in neuroinflammation, neuronal survival and neurogenesis.

Alzheimer's disease is the leading cause of dementia. Its increased prevalence in developed countries, due to the sharp rise in ageing populations, presents one of the costliest challenges to modern medicine. In order to find disease-modifying therapies to confront this challenge, a more complete understanding of the pathogenesis of Alzheimer's disease is necessary. Recent studies have revealed increasing evidence for the roles played by microglia, the resident innate immune system cells of the brain. Reflecting the well-established roles of microglia in reacting to pathogens and inflammatory stimuli, there is now a growing literature describing both protective and detrimental effects for individual cytokines and chemokines produced by microglia in Alzheimer's disease. A smaller but increasing number of studies have also addressed the divergent roles played by microglial neurotrophic and neurogenic factors, and how their perturbation may play a key role in the pathogenesis of Alzheimer's disease. Here we review recent findings on the roles played by microglia in neuroinflammation, neuronal survival and neurogenesis in Alzheimer's disease. In each case, landmark studies have provided evidence for the divergent ways in which microglia can either promote neuronal function and survival, or perturb neuronal function, leading to cell death. In many cases, the secreted molecules of microglia can lead to divergent effects depending on the magnitude and context of microglial activation. This suggests that microglial functions must be maintained in a fine equilibrium, in order to support healthy neuronal function, and that the cellular microenvironment in the Alzheimer's disease brain disrupts this fine balance, leading to neurodegeneration. Thus, an understanding of microglial homeostasis, both in health and across the trajectory of the disease state, will improve our understanding of the pathogenic mechanisms underlying Alzheimer's disease, and will hopefully lead to the development of microglial-based therapeutic strategies to restore equilibrium in the Alzheimer's disease brain.

Morphometric growth changes of the nasopharyngeal space in subjects with different vertical craniofacial features.

INTRODUCTION: The purpose of this study was to morphometrically investigate the growth pattern of the adenoids in growing subjects with hyperdivergent and hypodivergent vertical craniofacial features. METHODS: In this retrospective study, we used a longitudinal sample of lateral cephalometric radiographs of 28 hyperdivergent and 30 hypodivergent subjects from 4 to 13 years of age. The radiographs were obtained from the American Association of Orthodontists Foundation Craniofacial Growth Legacy Collection. Measurements were made using digital tracings of the lateral cephalograms and point distribution models. Mixed-model analyses were used for statistical analysis. RESULTS: The mean distance between the sphenoid bone and the posterior nasal spine increased up to 5.3 mm over a 9-year span (95% CI, 4.1-6.5 mm; P <0.001). Furthermore, the mean distance between the sphenoid bone and the posterior nasal spine differed significantly (P = 0.029) between facial types; it was consistently greater (1.8 mm; 95% CI, 0.2-3.3 mm) in the hyperdivergent group. The nasopharyngeal airway area showed a trend to increase with age up to 12-fold (P <0.001). A significant interaction (P = 0.004) was found between age and facial type. Assessment of the adenoid shapes showed greater convexities in the hyperdivergent group, which were observable from an earlier age and for a longer duration. CONCLUSIONS: Clear differences in the morphometric growth pattern of the adenoids were found between facial types. Evaluation of adenoid shapes showed more prominent convexities that lasted longer in the long facial types than in the short facial types.

HOX transcription factors are potential targets and markers in malignant mesothelioma.

BACKGROUND: The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development and which are dys-regulated in some cancers. In this study we examined the expression and oncogenic function of HOX genes in mesothelioma, a cancer arising from the pleura or peritoneum which is associated with exposure to asbestos. METHODS: We tested the sensitivity of the mesothelioma-derived lines MSTO-211H, NCI-H28, NCI-H2052, and NCI-H226 to HXR9, a peptide antagonist of HOX protein binding to its PBX co-factor. Apoptosis was measured using a FACS-based assay with Annexin, and HOX gene expression profiles were established using RT-QPCR on RNA extracted from cell lines and primary mesotheliomas. The in vivo efficacy of HXR9 was tested in a mouse MSTO-211H flank tumor xenograft model. RESULTS: We show that HOX genes are significantly dysregulated in malignant mesothelioma. Targeting HOX genes with HXR9 caused apoptotic cell death in all of the mesothelioma-derived cell lines, and prevented the growth of mesothelioma tumors in a mouse xenograft model. Furthermore, the sensitivity of these lines to HXR9 correlated with the relative expression of HOX genes that have either an oncogenic or tumor suppressive function in cancer. The analysis of HOX expression in primary mesothelioma tumors indicated that these cells could also be sensitive to the disruption of HOX activity by HXR9, and that the expression of HOXB4 is strongly associated with overall survival. CONCLUSION: HOX genes are a potential therapeutic target in mesothelioma, and HOXB4 expression correlates with overall survival.

Morphometric analysis of cervical vertebrae in relation to mandibular growth.

INTRODUCTION: Cervical vertebral maturation (CVM) methods have been criticized because of their subjective nature. The aims of this study were (1) to analyze the morphometric changes in the outline of the second to fourth cervical vertebrae with growth and (2) to test the validity of the CVM method for determining the mandibular growth peak. METHODS: Lateral cephalograms of 25 participants from ages 10 to 16 years were acquired from the Burlington Growth Study, and the CVM stage was qualitatively determined. Mandibular and cervical vertebral semilandmarks were then digitized, and point distribution models were used to describe the morphometric templates of the vertebrae in relation to chronologic age and the timing of peak mandibular growth. Mixed model analysis was used to determine the relationship between mandibular length, sex, CVM stage, and chronologic age. RESULTS: Morphometric changes of the second to fourth cervical vertebrae during growth were consistent with the CVM descriptions. However, mandibular length changes were not significantly associated with CVM stages after adjusting for chronologic age. Morphometric templates of vertebral shapes before and during the mandibular growth peak were similar, with changes detectable only after the growth peak had passed. Morphometric vertebral shape changes varied between the sexes. CONCLUSIONS: Morphometric changes of the cervical vertebrae and the CVM method could not accurately identify the mandibular growth peak.

Colorectal Liver Metastasis, Primary Gallbladder Carcinoma and Myelofibrosis Present Simultaneously in a Liver Resection Specimen.

Myelofibrosis and gallbladder carcinoma are both very rare diseases. This case report describes a patient with a history of myelofibrosis and colorectal carcinoma who was diagnosed with colorectal liver metastases. Surgery was performed to remove the metastases, and on site, the gallbladder was removed because of involvement in one of the liver lesions. After pathological examination, a primary gallbladder carcinoma and myelofibrosis were found in addition to the liver metastases. The combination of diseases was not likely to be interconnected but rather an unlucky course of events for the patient.

[A woman with a symptomatic abdominal swelling]. / Een vrouw met een symptomatische zwelling in de buik.

A 51-year-old woman visited the surgery outpatient clinic with an abdominal swelling. The swelling had become larger over the past few years and caused mechanical complaints. With MRI a liver cyst measuring 14 x 11 cm was diagnosed. The patient underwent laparoscopic deroofing of the liver cyst.

Herbal medicines--a cautionary tale.

We report an extensive intra-operative bleed which may have occurred as a result of the patient taking a herbal medicine. The patient underwent orthognathic surgery as a part of his orthodontic treatment, and lost approximately 3.5 litres of blood during the procedure. Preoperative blood tests were normal; the patient took no prescription medications and an appendectomy had been performed without incident. To aid healing, however, the patient had taken arnica the day before his operation. A concise literature review is presented which outlines the causes of surgical bleeding and discusses some of the bleeding concerns that herbal medicine use may raise for clinicians. Herbal medicines may contribute to unexplained surgical bleeding in the absence of other causative factors; it would therefore be useful to include an enquiry about the taking of herbal remedies at the history-taking stage for dental and maxillofacial surgical procedures.

HOX genes in pancreatic development and cancer.

The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development and which are subsequently re-expressed in many types of cancer. Some recent studies have shown that HOX genes may have key roles both in pancreatic development and in adult diseases of the pancreas, including cancer. In this review we consider recent advances in elucidating the role of HOX genes in these processes, how they may connect early developmental events to subsequent adult disease, and their potential both as diagnostic markers and therapeutic targets.