Educating Health Professionals about Disability: A Review of Interventions

Health professionals need to understand the human rights and health needs of disabled people. This review of evidence on interventions demonstrates that a range of often innovative approaches have been trialled. Lectures by faculty are less effective in changing attitudes than contact with disabled people themselves. Existing examples of good practice need to be scaled up, and better and more long-term evaluations of impact are required

26 Efekty uboczne kompleksowej raodioterapii u chorych na nowotwory narządów płciowych

Radioterapia jest jedną z podstawowych metod leczenia onkologicznego w raku szyjki i błony śluzowej macicy. Ze względu na różną radiowrażliwość narządów miednicy mniejszej autorzy pracy zwrócili szczególną uwagę na ewentualną obecność objawów uszkodzenia przewodu pokarmowego, układu moczowego i szpiku kostnego.W okresie 1998–2000 w Klinice Ginekologii Operacyjnej poddano obserwacji 40 chorych poddanych kompleksowej radioterapii. Wszystkie pacjentki w trakcie teleterapii otrzymały całkowitą dawkę 28 Gy na guz w okresie 4 tygodni oraz poddane zostały brachyterapii. W zależności od stopnia zaawansowania klinicznego nowotworu zastosowano:-u 25 chorych ze stopniem klinicznym nowotworu I i II – brachyterapię dopochwową w dawce 24 Gy (w 3 cotygodniowych frakcjach);-u 15 chorych ze stopniem zaawansowania II, III i IV – brachyterapię domaciczną w dawce 40 Gy (w 5 cotygodniowych frakcjach).Brachyterapię stosowano za pomocą microSelectronu HDR firmy Nucletron z użyciem żródła irydowego Ir192 z nominalną aktywnością 10 Ci (370GBq).Zaobserwowano:[[tgroup cols="3"]][[colspec colname="col1"/]][[colspec colname="col2"/]][[colspec colname="col3"/]][[tbody]][[row]][[entry align="left"]]1. Objawy uszkodzenia przewodu pokarmowego:[[/entry]][[entry align="left"]]nudności i wymioty[[/entry]][[entry align="left"]]− 4(10%)[[/entry]][[/row]][[row]][[entry/]][[entry align="left"]]biegunka[[/entry]][[entry align="left"]]− 6(15%)[[/entry]][[/row]][[row]][[entry align="left"]]2. Objawy podrażnienia układu moczowego (objawy dyzuryczne + zmiany w badaniu ogó1nym moczu):[[/entry]][[entry/]][[entry align="left"]]− 22 (55%)[[/entry]][[/row]][[row]][[entry align="left"]]3. Objawy uszkodzenia szpiku kostnego:[[/entry]][[entry align="left"]]niedokrwistość :[[/entry]][[entry align="left"]]− 3 (7,5%)[[/entry]][[/row]][[row]][[entry/]][[entry align="left"]]leukopenia:[[/entry]][[entry align="left"]]− 9 (22,5%)[[/entry]][[/row]][[/tbody]][[/tgroup]]Uzyskane wyniki potwierdzają względnie niski odsetek notowanych powikłań. Jest to dowodem na to, że tylko właściwa ocena kliniczna i prawidłowo prowadzona dozymetria przy kompleksowej radioterapii umożliwiają minimalizację objawów ubocznych

Deficiency in origin licensing proteins impairs cilia formation: implications for the aetiology of meier-gorlin syndrome

Mutations in ORC1, ORC4, ORC6, CDT1, and CDC6, which encode proteins required for DNA replication origin licensing, cause Meier-Gorlin syndrome (MGS), a disorder conferring microcephaly, primordial dwarfism, underdeveloped ears, and skeletal abnormalities. Mutations in ATR, which also functions during replication, can cause Seckel syndrome, a clinically related disorder. These findings suggest that impaired DNA replication could underlie the developmental defects characteristic of these disorders. Here, we show that although origin licensing capacity is impaired in all patient cells with mutations in origin licensing component proteins, this does not correlate with the rate of progression through S phase. Thus, the replicative capacity in MGS patient cells does not correlate with clinical manifestation. However, ORC1-deficient cells from MGS patients and siRNA-mediated depletion of origin licensing proteins also have impaired centrosome and centriole copy number. As a novel and unexpected finding, we show that they also display a striking defect in the rate of formation of primary cilia. We demonstrate that this impacts sonic hedgehog signalling in ORC1-deficient primary fibroblasts. Additionally, reduced growth factor-dependent signaling via primary cilia affects the kinetics of cell cycle progression following cell cycle exit and re-entry, highlighting an unexpected mechanism whereby origin licensing components can influence cell cycle progression. Finally, using a cell-based model, we show that defects in cilia function impair chondroinduction. Our findings raise the possibility that a reduced efficiency in forming cilia could contribute to the clinical features of MGS, particularly the bone development abnormalities, and could provide a new dimension for considering developmental impacts of licensing deficiency

A Novel Role for the Centrosomal Protein, Pericentrin, in Regulation of Insulin Secretory Vesicle Docking in Mouse Pancreatic β-cells

The centrosome is important for microtubule organization and cell cycle progression in animal cells. Recently, mutations in the centrosomal protein, pericentrin, have been linked to human microcephalic osteodysplastic primordial dwarfism (MOPD II), a rare genetic disease characterized by severe growth retardation and early onset of type 2 diabetes among other clinical manifestations. While the link between centrosomal and cell cycle defects may account for growth deficiencies, the mechanism linking pericentrin mutations with dysregulated glucose homeostasis and pre-pubertal onset of diabetes is unknown. In this report we observed abundant expression of pericentrin in quiescent pancreatic β-cells of normal animals which led us to hypothesize that pericentrin may have a critical function in β-cells distinct from its known role in regulating cell cycle progression. In addition to the typical centrosome localization, pericentrin was also enriched with secretory vesicles in the cytoplasm. Pericentrin overexpression in β-cells resulted in aggregation of insulin-containing secretory vesicles with cytoplasmic, but not centrosomal, pericentriolar material and an increase in total levels of intracellular insulin. RNAi- mediated silencing of pericentrin in secretory β-cells caused dysregulated secretory vesicle hypersecretion of insulin into the media. Together, these data suggest that pericentrin may regulate the intracellular distribution and secretion of insulin. Mice transplanted with pericentrin-depleted islets exhibited abnormal fasting hypoglycemia and inability to regulate blood glucose normally during a glucose challenge, which is consistent with our in vitro data. This previously unrecognized function for a centrosomal protein to mediate vesicle docking in secretory endocrine cells emphasizes the adaptability of these scaffolding proteins to regulate diverse cellular processes and identifies a novel target for modulating regulated protein secretion in disorders such as diabetes

Primary ciliogenesis defects are associated with human astrocytoma/glioblastoma cells

<p>Abstract</p> <p>Background</p> <p>Primary cilia are non-motile sensory cytoplasmic organelles that have been implicated in signal transduction, cell to cell communication, left and right pattern embryonic development, sensation of fluid flow, regulation of calcium levels, mechanosensation, growth factor signaling and cell cycle progression. Defects in the formation and/or function of these structures underlie a variety of human diseases such as Alström, Bardet-Biedl, Joubert, Meckel-Gruber and oral-facial-digital type 1 syndromes. The expression and function of primary cilia in cancer cells has now become a focus of attention but has not been studied in astrocytomas/glioblastomas. To begin to address this issue, we compared the structure and expression of primary cilia in a normal human astrocyte cell line with five human astrocytoma/glioblastoma cell lines.</p> <p>Methods</p> <p>Cultured normal human astrocytes and five human astrocytoma/glioblastoma cell lines were examined for primary cilia expression and structure using indirect immunofluorescence and electron microscopy. Monospecific antibodies were used to detect primary cilia and map the relationship between the primary cilia region and sites of endocytosis.</p> <p>Results</p> <p>We show that expression of primary cilia in normal astrocytes is cell cycle related and the primary cilium extends through the cell within a unique structure which we show to be a site of endocytosis. Importantly, we document that in each of the five astrocytoma/glioblastoma cell lines fully formed primary cilia are either expressed at a very low level, are completely absent or have aberrant forms, due to incomplete ciliogenesis.</p> <p>Conclusions</p> <p>The recent discovery of the importance of primary cilia in a variety of cell functions raises the possibility that this structure may have a role in a variety of cancers. Our finding that the formation of the primary cilium is disrupted in cells derived from astrocytoma/glioblastoma tumors provides the first evidence that altered primary cilium expression and function may be part of some malignant phenotypes. Further, we provide the first evidence that ciliogenesis is not an all or none process; rather defects can arrest this process at various points, particularly at the stage subsequent to basal body association with the plasma membrane.</p

CHOP Mediates Endoplasmic Reticulum Stress-Induced Apoptosis in Gimap5-Deficient T Cells

Gimap5 (GTPase of the immunity-associated protein 5) has been linked to the regulation of T cell survival, and polymorphisms in the human GIMAP5 gene associate with autoimmune disorders. The BioBreeding diabetes-prone (BBDP) rat has a mutation in the Gimap5 gene that leads to spontaneous apoptosis of peripheral T cells by an unknown mechanism. Because Gimap5 localizes to the endoplasmic reticulum (ER), we hypothesized that absence of functional Gimap5 protein initiates T cell death through disruptions in ER homeostasis. We observed increases in ER stress-associated chaperones in T cells but not thymocytes or B cells from Gimap5−/− BBDP rats. We then discovered that ER stress-induced apoptotic signaling through C/EBP-homologous protein (CHOP) occurs in Gimap5−/− T cells. Knockdown of CHOP by siRNA protected Gimap5−/− T cells from ER stress-induced apoptosis, thereby identifying a role for this cellular pathway in the T cell lymphopenia of the BBDP rat. These findings indicate a direct relationship between Gimap5 and the maintenance of ER homeostasis in the survival of T cells

The serologically defined colon cancer antigen-3 (SDCCAG3) is involved in the regulation of ciliogenesis

A primary cilium is present on most eukaryotic cells and represents a specialized organelle dedicated to signal transduction and mechanosensing. Defects in cilia function are the cause for several human diseases called ciliopathies. The serologically defined colon cancer antigen-3 (SDCCAG3) is a recently described novel endosomal protein mainly localized at early and recycling endosomes and interacting with several components of membrane trafficking pathways. Here we describe localization of SDCCAG3 to the basal body of primary cilia. Furthermore, we demonstrate that decreased expression levels of SDCCAG3 correlate with decreased ciliary length and a reduced percentage of ciliated cells. We show that SDCCAG3 interacts with the intraflagellar transport protein 88 (IFT88), a crucial component of ciliogenesis and intraciliary transport. Mapping experiments revealed that the N-terminus of SDCCAG3 mediates this interaction by binding to a region within IFT88 comprising several tetratricopeptide (TRP) repeats. Finally, we demonstrate that SDCCAG3 is important for ciliary localization of the membrane protein Polycystin-2, a protein playing an important role in the formation of polycystic kidney disease, but not for Rab8 another ciliary protein. Together these data suggest a novel role for SDCCAG3 in ciliogenesis and in localization of cargo to primary cilia