Tubulin glycylases are required for primary cilia, control of cell proliferation and tumor development in colon.

TTLL3 and TTLL8 are tubulin glycine ligases catalyzing posttranslational glycylation of microtubules. We show here for the first time that these enzymes are required for robust formation of primary cilia. We further discover the existence of primary cilia in colon and demonstrate that TTLL3 is the only glycylase in this organ. As a consequence, colon epithelium shows a reduced number of primary cilia accompanied by an increased rate of cell division in TTLL3-knockout mice. Strikingly, higher proliferation is compensated by faster tissue turnover in normal colon. In a mouse model for tumorigenesis, lack of TTLL3 strongly promotes tumor development. We further demonstrate that decreased levels of TTLL3 expression are linked to the development of human colorectal carcinomas. Thus, we have uncovered a novel role for tubulin glycylation in primary cilia maintenance, which controls cell proliferation of colon epithelial cells and plays an essential role in colon cancer development.

Chronic lymphocytic leukemia disease progression is accelerated by APRIL-TACI interaction in the TCL1 transgenic mouse model.

Although in vitro studies pointed to the tumor necrosis factor family member APRIL (a proliferation-inducing ligand) in mediating survival of chronic lymphocytic leukemia (CLL) cells, clear evidence for a role in leukemogenesis and progression in CLL is lacking. APRIL significantly prolonged in vitro survival of CD5(+)B220(dull) leukemic cells derived from the murine Eµ-TCL1-Tg (TCL1-Tg [transgenic]) model for CLL. APRIL-TCL1 double-Tg mice showed a significantly earlier onset of leukemia and disruption of splenic architecture, and survival was significantly reduced. Interestingly, clonal evolution of CD5(+)B220(dull) cells (judged by BCR clonality) did not seem to be accelerated by APRIL; both mouse strains were oligoclonal at 4 months. Although APRIL binds different receptors, APRIL-mediated leukemic cell survival depended on tumor necrosis factor receptor superfamily member 13B (TACI) ligation. These findings indicate that APRIL has an important role in CLL and that the APRIL-TACI interaction might be a selective novel therapeutic target for human CLL.

Burden of dry eye disease in Germany: a retrospective observational study using German claims data.

PURPOSE: To evaluate the clinical and economic burden of dry eye disease (DED) among affected patients in Germany. METHODS: Adult patients (≥18 years) with ≥1 confirmed diagnosis of DED during the study period (2008-2015) were identified from the medical claims of ~3.6 million insured patients from Betriebskrankenkassen, a German statutory health insurance database. Prevalence (per 1000 patients) and incidence (per 1000 person-years at risk) were estimated, and demographic and clinical characteristics, treatment history (excluding over-the-counter tear supplements), healthcare resource use (HCRU) and costs were assessed. RESULTS: In this population, the prevalence of DED increased from 20.24 in 2008 to 23.13 per 1000 patients in 2014. Overall incidence was 6.24 per 1000 person-years at risk (2008-2015). Prevalence and incidence increased with age and were higher in women. Mean age at index was 63.4 years (incident cohort, n = 35 026). The most common ocular comorbidity was cataract (48.5%), and ~36% of patients were dispensed a reimbursed DED-specific medication during the postindex period - most commonly, corticosteroids alone (13.2%) or in combination with anti-infectives (21.8%). HCRU was high in patients with DED, mostly due to comorbidities. HCRU and associated costs were highest in patients ≥60 years. Total costs during the postindex period were higher in the DED cohort than among matched controls (€117 million versus €107 million; p < 0.001). CONCLUSION: This retrospective database analysis provides a better understanding of the epidemiology, clinical characteristics, real-world treatment patterns, HCRU and costs associated with DED in patients living in Germany.

Fusion of intestinal epithelial cells with bone marrow derived cells is dispensable for tissue homeostasis.

The epithelial lining of the intestine is characterized by an immense cellular turn-over ascertaining an extensive regenerative capacity. Multiple reports suggest that besides the local intestinal stem cell pool, circulating cells of bone marrow origin (BMDCs) contribute to this process by fusing with the epithelial lineage. However, the functional relevance of these observations is unknown. In the present study we employ a model system in which we cannot only detect cell fusion but also examine the functional importance of this process in vivo. Our results indicate that fusion between BMDCs and intestinal epithelial cells is an extremely rare event under physiological conditions. More importantly, by employing a system in which fusion-derived cells can be specifically deleted after extensive tissue damage, we present evidence that cell fusion is not relevant for tissue regeneration. Our data decisively demonstrates that intestinal epithelial homeostasis and regeneration is not dependent on cell fusion involving BMDCs.

Intoxicación por plomo y su tratamiento farmacológico / Lead poisoning and pharmacological treatment

La intoxicación por plomo es un problema de saludpública. La evidencia de poblaciones afectadas por nivelestóxicos de plomo en sangre, confirma que hay que seguirtrabajando desde una visión pluridisciplinar. Es necesariodefinir políticas para la prevención, detección, diagnosticoy tratamiento de los efectos nocivos del plomo sobre lasalud. Los niños constituyen el segmento de la poblaciónmás vulnerable, con consecuencias de alto impactosocial, como una disminución del coeficiente intelectual ydeficiente desarrollo neurológico. En la práctica clínica, haycuatro medicamentos que se usan para el tratamiento de laintoxicación crónica, son el edetato cálcico disódico IV e IM,el dimercaprol IM, la penicilamina VO y el succímero VO.Si se tiene en cuenta que sólo penicilamina está autorizadaen nuestro país, el problema se torna mayor. Esta breverevisión pretende brindar información sobre la intoxicaciónpor exposición al plomo, los tratamientos recomendados ylos disponibles en nuestro país.

Lead exposure and poisoning is a public health concern.Evidence of people with toxic level of lead in blood confirmsINTOXICACIÓN PORPLOMO Y SU TRATAMIENTOFARMACOLOGICORecibido: 25 de Setiembrede 2012. Aprobado: 4 denoviembre de 2012Lead poisoning and pharmacological treatmentFontana Daniela,Lascano Valeria María,Solá Nancy,Martinez Samanta,Virgolini Miriam,Mazzieri Maria Rosa.Departamento de Farmacia,Facultad de Ciencias Químicas,Universidad Nacional deCórdoba.Medina Allende y Haya de laTorre, Ciudad Universitaria,(5000) Córdoba, ArgentinaTEL/FAX +54 351 535 3850(int 53351). E-mail: mrmazzie@fcq.unc.edu.ar that it is necessary to keep on working from a multidisciplinary approach. There shouldbe a well-defined policy for the prevention, detection, diagnosis and treatment of theharmful effects of lead. Children are the population at major risk, with high social impactconsequences such as lower IQ and inadequate neurological development. There arefour drugs used to treat chronic toxicity: sodium calcium edetate IV and IM, succimer(oral), dimercaprol IM, and penicillamine (oral). If we consider that the last one is theonly authorized drug in our country, the problem grows bigger. This brief review offersinformation about lead exposure and poisoning, the recommended drug treatments andtheir market availability.