Heterogeneity in Lowe Syndrome: Mutations Affecting the Phosphatase Domain of OCRL1 Differ in Impact on Enzymatic Activity and Severity of Cellular Phenotypes.

Lowe Syndrome (LS) is a condition due to mutations in the OCRL1 gene, characterized by congenital cataracts, intellectual disability, and kidney malfunction. Unfortunately, patients succumb to renal failure after adolescence. This study is centered in investigating the biochemical and phenotypic impact of patient's OCRL1 variants (OCRL1VAR). Specifically, we tested the hypothesis that some OCRL1VAR are stabilized in a non-functional conformation by focusing on missense mutations affecting the phosphatase domain, but not changing residues involved in binding/catalysis. The pathogenic and conformational characteristics of the selected variants were evaluated in silico and our results revealed some OCRL1VAR to be benign, while others are pathogenic. Then we proceeded to monitor the enzymatic activity and function in kidney cells of the different OCRL1VAR. Based on their enzymatic activity and presence/absence of phenotypes, the variants segregated into two categories that also correlated with the severity of the condition they induce. Overall, these two groups mapped to opposite sides of the phosphatase domain. In summary, our findings highlight that not every mutation affecting the catalytic domain impairs OCRL1's enzymatic activity. Importantly, data support the inactive-conformation hypothesis. Finally, our results contribute to establishing the molecular and structural basis for the observed heterogeneity in severity/symptomatology displayed by patients.

Worldwide Assessment of the Mandibular First Molar Second Distal Root and Root Canal: A Cross-sectional Study with Meta-analysis.

INTRODUCTION: This study assessed the prevalence of radix entomolaris and 2 canals at the distal aspect of mandibular first molars among different geographic regions by means of cone-beam computed tomographic imaging. METHODS: Precalibrated observers from 23 worldwide geographic locations followed a standardized screening protocol to assess 5750 cone-beam computed tomographic images of mandibular first molars (250 per region), gathering demographic data and recording the presence of radix entomolaris and a second canal at the distal aspect of teeth. Intra- and interrater reliability tests were conducted and comparisons among groups were performed using proportions and odds ratio forest plots. The significance level was set at 5%. RESULTS: The results of intra- and interrater tests were above 0.79. The prevalence of radix entomolaris varied from 0.9% in Venezuela (95% confidence interval [CI], 0%-1.9%) to 22.4% in China (95% CI, 17.2%-27.6%). Regarding the proportion of a second distal canal, it ranged from 16.4% in Venezuela (95% CI, 11.8%-21.0%) to 60.0% in Egypt (95% CI, 53.9%-66.1%). The East Asia subgroup was associated with a significantly higher prevalence of an extra distolingual root, whereas the American subgroup, the American native ethnic group, and elderly patients were linked to significantly lower percentages of a second canal at the distal aspect of teeth. No significant differences were noted between male or female patients. CONCLUSIONS: The overall worldwide prevalence rates of radix entomolaris and a second canal at the distal aspect of the mandibular first molar were 5.6% and 36.9%, respectively. The East Asia geographic region and Asian ethnic group had a higher prevalence of a second distal root.

Worldwide Prevalence of a Lingual Canal in Mandibular Premolars: A Multicenter Cross-sectional Study with Meta-analysis.

INTRODUCTION: The presence of multiple root canals is an important morphologic aspect of mandibular premolars. This study aimed to perform a worldwide analysis on the prevalence of a lingual canal in mandibular premolars and to evaluate its influence on patients' demographics in 23 countries using cone-beam computed tomographic images. METHODS: Observers from 23 countries were instructed to evaluate cone-beam computed tomographic images of 300 first and 300 second premolars (13,800 teeth) regarding the presence of a lingual canal, canal configuration, and data related to patients' ethnicity, age, and sex following a standardized screening methodology. Intra- and interrater evaluations were performed using the Cohen kappa test and intraclass correlation coefficient. Proportion and odds ratio forest plots were calculated in order to compare groups. Statistical significance was set at 5%. RESULTS: Both kappa and intraclass correlation coefficient values were above 0.60, and the percentage of agreement was 94.9% (first premolar) and 97.8% (second premolar). A significant statistical difference was observed between the worldwide proportion of a lingual canal in mandibular first (23.8%; range, 12.0%-32.7%) and second (5.3%; range, 1.0%-15.3%) premolars (P < .05). Asians and patients over 60 years old were associated with the lowest proportions of a lingual canal (P < .05), whereas Africans and younger groups were associated with the highest proportions (P < .05). The prevalence of a lingual canal in males (27.9%) was higher than females (20.0%) for the first premolar only (P < .05). Males were associated with 1.533 and 1.597 higher odds of presenting a lingual root canal in the first and second premolars, respectively. CONCLUSIONS: The worldwide proportion of a lingual root canal was 23.6% and 5.3% for the first and second premolars, respectively. Ethnicity, geographic region, age, and sex had an influence on the outcomes.

A novel, safe, fast and efficient treatment for Her2-positive and negative bladder cancer utilizing an EGF-anthrax toxin chimera.

Bladder cancer is the sixth most common cancer in the United States, and it exhibits an alarming 70% recurrence rate. Thus, the development of more efficient antibladder cancer approaches is a high priority. Accordingly, this work provides the basis for a transformative anticancer strategy that takes advantage of the unique characteristics of the bladder. Unlike mucin-shielded normal bladder cells, cancer cells are exposed to the bladder lumen and overexpress EGFR. Therefore, we used an EGF-conjugated anthrax toxin that after targeting EGFR was internalized and triggered apoptosis in exposed bladder cancer cells. This unique agent presented advantages over other EGF-based technologies and other toxin-derivatives. In contrast to known agents, this EGF-toxin conjugate promoted its own uptake via receptor microclustering even in the presence of Her2 and induced cell death with a LC50 < 1 nM. Furthermore, our data showed that exposures as short as ≈3 min were enough to commit human (T24), mouse (MB49) and canine (primary) bladder cancer cells to apoptosis. Exposure of tumor-free mice and dogs with the agent resulted in no toxicity. In addition, the EGF-toxin was able to eliminate cells from human patient tumor samples. Importantly, the administration of EGF-toxin to dogs with spontaneous bladder cancer, who had failed or were not eligible for other therapies, resulted in ~30% average tumor reduction after one treatment cycle. Because of its in vitro and in vivo high efficiency, fast action (reducing treatment time from hours to minutes) and safety, we propose that this EGF-anthrax toxin conjugate provides the basis for new, transformative approaches against bladder cancer.

Worldwide Analyses of Maxillary First Molar Second Mesiobuccal Prevalence: A Multicenter Cone-beam Computed Tomographic Study.

INTRODUCTION: Maxillary first molar second mesiobuccal (MB2) root canal prevalence may change among different populations. The aim of this study was to analyze the worldwide prevalence of the MB2 root canal and understand its possible relation with sex, age, side, and root configuration using in vivo cone-beam computed tomographic (CBCT) assessment. METHODS: Observers from 21 regions were calibrated to achieve a similar CBCT assessment methodology and instructed to collect data from 250 maxillary first molars in previously existing examinations. Intra- and interrater reliability tests were performed. The sample size included 5250 molars and was defined by way of a preliminary trial. Data collected included MB2 presence, sex, age, side, number of roots per tooth, and mesiobuccal root configuration. The z test for proportions in independent groups was used to analyze the differences among subgroups. P < .05 was considered significant. RESULTS: The worldwide CBCT-assessed MB2 prevalence was 73.8%, ranging from 48.0% in Venezuela to 97.6% in Belgium. The prevalence in males and females was 76.3% and 71.8%, respectively (P < .05). Significantly higher MB2 proportions were found in younger patients and 3-rooted molar configurations. The group intraclass correlation coefficient and the percentage of agreement for the MB2 presence were 0.95 and 0.91, respectively. The intrarater Cohen kappa value was above 0.61 for all observers. CONCLUSIONS: MB2 prevalence in the analyzed regions varied widely. The differences may be associated with specificities within each region but also patient demographics. Males, younger patients, and 3-rooted configurations were associated with higher MB2 proportions.

Disaggregation of gold nanoparticles by Daphnia magna.

The use of manufactured nanomaterials is rapidly increasing, while our understanding of the consequences of releasing these materials into the environment is still limited and many questions remain, for example, how do nanoparticles affect living organisms in the wild? How do organisms adapt and protect themselves from exposure to foreign materials? How does the environment affect the performance of nanoparticles, including their surface properties? In an effort to address these crucial questions, our main aim has been to probe the effects of aquatic organisms on nanoparticle aggregation. We have, therefore, carried out a systematic study with the purpose to disentangle the effects of the freshwater zooplankter, Daphnia magna, on the surface properties, stability, and aggregation properties of gold (Au) nanoparticles under different aqueous conditions as well as identified the proteins bound to the nanoparticle surface. We show that Au nanoparticles aggregate in pure tap water, but to a lesser extent in water that either contains Daphnia or has been pre-conditioned with Daphnia. Moreover, we show that proteins generated by Daphnia bind to the Au nanoparticles and create a modified surface that renders them less prone to aggregation. We conclude that the surrounding milieu, as well as the surface properties of the original Au particles, are important factors in determining how the nanoparticles are affected by biological metabolism. In a broader context, our results show how nanoparticles released into a natural ecosystem become chemically and physically altered through the dynamic interactions between particles and organisms, either through biological metabolism or through the interactions with biomolecules excreted by organisms into the environment.

Kidney-differentiated cells derived from Lowe Syndrome patient's iPSCs show ciliogenesis defects and Six2 retention at the Golgi complex.

Lowe syndrome is an X-linked condition characterized by congenital cataracts, neurological abnormalities and kidney malfunction. This lethal disease is caused by mutations in the OCRL1 gene, which encodes for the phosphatidylinositol 5-phosphatase Ocrl1. While in the past decade we witnessed substantial progress in the identification and characterization of LS patient cellular phenotypes, many of these studies have been performed in knocked-down cell lines or patient's cells from accessible cell types such as skin fibroblasts, and not from the organs affected. This is partially due to the limited accessibility of patient cells from eyes, brain and kidneys. Here we report the preparation of induced pluripotent stem cells (iPSCs) from patient skin fibroblasts and their reprogramming into kidney cells. These reprogrammed kidney cells displayed primary cilia assembly defects similar to those described previously in cell lines. Additionally, the transcription factor and cap mesenchyme marker Six2 was substantially retained in the Golgi complex and the functional nuclear-localized fraction was reduced. These results were confirmed using different batches of differentiated cells from different iPSC colonies and by the use of the human proximal tubule kidney cell line HK2. Indeed, OCRL1 KO led to both ciliogenesis defects and Six2 retention in the Golgi complex. In agreement with Six2's role in the suppression of ductal kidney lineages, cells from this pedigree were over-represented among patient kidney-reprogrammed cells. We speculate that this diminished efficacy to produce cap mesenchyme cells would cause LS patients to have difficulties in replenishing senescent or damaged cells derived from this lineage, particularly proximal tubule cells, leading to pathological scenarios such as tubular atrophy.

Desviación de conducto radicular localizada con CBCT: reporte de un caso / Localized root canal deviation with CBCT: report of a case

En endodoncia la tomografía cone-beam (CBCT) permite el diagnóstico y planifi cación de tratamientos. Se presenta un caso en que se detectó una desviación del conducto radicular y perforación al instalar un poste, las cuales no fueron identifi cadas en la radiografía convencional. La tomografía cone-beam facilitó el diagnóstico y la defi nición del plan de tratamiento, el cual se realizó bajo microscopio y con ultrasonido para remover los materiales de obturación previos (gutapercha y poste). Las perforaciones iatrogénicas son causa de mal pronóstico en los tratamientos endodóncicos. El cone-beam es una herramienta que permite observar tridimensionalmente los conductos radiculares, lo que facilita el diagnóstico y tratamiento a seguir (AU)

Cone-beam (CBCT) tomography is more often used in endodontics, to improve diagnosis and treatment planifi cation. In the present study we were able to detect a deviation of the root canal and perforation during the colocation of a poste, which wasn't possible with conventional radiograph. The endodontic treatment was guided with cone-beam and was executed under microscope; help out with ultrasonic tips to remove the previous obturation materials (gutta-percha and post) to also detect the original tract and to clean and desinfect the original root canal. Iatrogenic perforations cause poor prognosis of the endodontic treatments. CBCT is a tool that allows observing three-dimensional the root canals; which facilitates the diagnosis and treatment planning (AU)

Intracanal Cryotherapy Reduces Postoperative Pain in Teeth with Symptomatic Apical Periodontitis: A Randomized Multicenter Clinical Trial.

INTRODUCTION: A prospective, multicentered, randomized clinical trial was designed to assess if controlled irrigation with cold saline could result in less incidence and intensity of postoperative pain in patients presenting with pulp necrosis and symptomatic apical periodontitis. METHODS: A total of 210 patients (presenting with necrotic uniradicular teeth with a diagnosis of symptomatic apical periodontitis and a preoperative visual analog scale (VAS) score higher than 7) were randomly allocated in the control or experimental group after the completion of shaping and cleaning procedures. The experimental group received a final irrigation with 20 mL sterile cold (2.5°C) saline solution delivered to the working length with a sterile, cold (2.5°C) Endovac microcannula (Kerr Endo, Orange Country, CA) for 5 minutes. The same protocol was used in the control group with room temperature saline solution. Patients were instructed to record the presence, duration and level of postoperative pain, and analgesic medication intake. A logistic regression was used to compare the incidence of postoperative pain and the need for painkillers between groups. Differences in general pain intensity between groups were analyzed using the ordinal (linear) chi-square test. Postoperative pain after 6, 24, and 72 hours (recorded in a VAS scale) and the need for analgesic medication intake between the 2 groups were assessed using the Mann-Whitney U test. RESULTS: Patients in the control group presented a significantly higher incidence of postoperative pain, intensity, and need for medication intake (P < .05). CONCLUSIONS: Cryotherapy reduced the incidence of postoperative pain and the need for medication intake in patients presenting with a diagnosis of necrotic pulp and symptomatic apical periodontitis.

Worldwide Prevalence of Mandibular Second Molar C-Shaped Morphologies Evaluated by Cone-Beam Computed Tomography.

INTRODUCTION: The aim of this study was to evaluate and compare the C-shaped mandibular second molar prevalence in different regions around the world with the aid of cone-beam computed tomography technology. METHODS: Nine field observers from 9 different geographic regions were calibrated. A total of 400 samples were collected in each region. The prevalence of C-shaped anatomy was calculated. The number of roots and the configuration of the C-shaped canals at 3 different axial levels were also evaluated. The z-test was used to analyze the difference between the means of each independent group. Intrarater reliability was also tested. RESULTS: A total of 3600 teeth from 2735 patients were included in this research; 499 teeth presented C-shaped root canal configuration, representing a global prevalence of 13.9%. China had a prevalence of 44.0%, which was significantly higher than any other region. The C-shape prevalence in women was 16.5%, which was significantly higher than the 10.4% prevalence found in men. No difference between sides (37 or 47) was evident in the global sample. CONCLUSIONS: Cone-beam computed tomography is a valuable tool to evaluate the C-shaped root canal configuration in vivo. In the present study, China presented the highest prevalence of C-shaped mandibular second molars when compared with other regions. Women exhibited a higher prevalence than men.

Malnutrition is an independent risk factor for mortality in Mexican patients with systemic sclerosis: a cohort study.

Factors for mortality in systemic sclerosis (SSc) vary in different cohorts around the world. Case-control study nested in a cohort. We included patients ≥16 years of age with SSc (ACR/EULAR 2013), from 2005 to 2015. Demographic and clinical variables and causes of mortality were recorded. We calculated Crude Mortality Rate (CMR), Standardized Mortality Ratio (SMR), and Kaplan-Meier survival analysis was performed. A Cox proportional hazard (HR) regression analysis of the potential risk factors associated with mortality was also performed. A total of 220 patients with SSc were included. During follow-up, 28 deaths occurred. The sum of total time contributed by all subjects was 1074 years-person, the CMR was 12.72%, the overall SMR was 4.5, in women 3.7, and in men 4.7. The survival rate at 5 and 10 years was 83 and 70%, respectively. The causes of death were definitively attributed to SSc in 21.4% of the cases, probably in 28.7%, unrelated in 35.6%, and unknown in 14.3%. The direct cause of death of the patients was infection in 25% of cases, cardiovascular disease in 14%, lung involvement in 14%, pulmonary embolism in 11%, and neoplasia in 11%. The Cox regression analysis showed that the factors associated with mortality were: male gender (HR 5.84, CI 95% 1.31-26, p = 0.013), severe Medsger's score for general symptoms (HR 5.12, CI 95% 1.74-14.97, p = 0.021) and severe malnutrition (HR 3.77, CI 95% 1.23-11.06, p = 0.008). Infections, cardiovascular disease, and lung involvement were the leading cause of death. Male gender and severe general affection and malnutrition were associated with a poorer prognosis of SSc.

Granulocyte colony-stimulating factor (G-CSF) upregulates ß1 integrin and increases migration of human trophoblast Swan 71 cells via PI3K and MAPK activation.

Multiple cytokines and growth factors expressed at the fetal-maternal interface are involved in the regulation of trophoblast functions and placental growth, but the role of G-CSF has not been completely established. Based on our previous study showing that G-CSF increases the activity of matrix metalloproteinase-2 and the release of vascular endothelial growth factor in Swan 71 human trophoblast cells, in this work we explore the possible contribution of G-CSF to cell migration and the G-CSF-triggered signaling pathway. We found that G-CSF induced morphological changes on actin cytoskeleton consistent with a migratory cell phenotype. G-CSF also up-regulated the expression levels of ß1 integrin and promoted Swan 71 cell migration. By using selective pharmacological inhibitors and dominant negative mutants we showed that PI3K, Erk 1/2 and p38 pathways are required for promoting Swan 71 cell motility. It was also demonstrated that PI3K behaved as an upstream regulator of Erk 1/2 and p38 MAPK. In addition, the increase of ß1 integrin expression was dependent on PI3K activation. In conclusion, our results indicate that G-CSF stimulates ß1 integrin expression and Swan 71 cell migration by activating PI3K and MAPK signaling pathways, suggesting that G-CSF should be considered as an additional regulatory factor that contributes to a successful embryo implantation and to the placenta development.

Ciliopathies: the trafficking connection.

The primary cilium (PC) is a very dynamic hair-like membrane structure that assembles/disassembles in a cell-cycle-dependent manner and is present in almost every cell type. Despite being continuous with the plasma membrane, a diffusion barrier located at the ciliary base confers the PC properties of a separate organelle with very specific characteristics and membrane composition. Therefore, vesicle trafficking is the major process by which components are acquired for cilium formation and maintenance. In fact, a system of specific sorting signals controls the right of cargo admission into the cilia. Disruption to the ciliary structure or its function leads to multiorgan diseases known as ciliopathies. These illnesses arise from a spectrum of mutations in any of the more than 50 loci linked to these conditions. Therefore, it is not surprising that symptom variability (specific manifestations and severity) among and within ciliopathies appears to be an emerging characteristic. Nevertheless, one can speculate that mutations occurring in genes whose products contribute to the overall vesicle trafficking to the PC (i.e. affecting cilia assembly) will lead to more severe symptoms, whereas those involved in the transport of specific cargoes will result in milder phenotypes. In this review, we summarize the trafficking mechanisms to the cilia and also provide a description of the trafficking defects observed in some ciliopathies which can be correlated to the severity of the pathology.

The 46359CT polymorphism of DNMT3B is associated with the risk of cervical cancer.

Abnormal methylation is related to cancer development. Since DNMT3B is an enzyme that modulates genomic methylation, we hypothesized that genetic variants of the promoter DNMT3B may be associated with an increased risk of developing cervical cancer. Our aim was to investigate the association between -579GT and 46359CT polymorphisms of DNMT3B and cervical cancer, high-grade squamous intraepithelial lesions (HSIL), and low-grade squamous intraepithelial lesions (LSIL). Samples from 200 healthy women and 130 women with squamous intraepithelial lesions (70 with cervical cancer, 30 with HSIL, and 30 with LSIL) were analyzed. Polymorphism genotyping was performed using PCR and restriction fragment length polymorphism. The -579GT polymorphism was not associated with cervical cancer, HSIL, or LSIL. The CT genotype of 46359CT polymorphism was significantly associated with cervical cancer risk (OR 8.75, CI 1.27-374.1), whereas the TT genotype was associated with a significantly decreased risk of HSIL (OR 0.66, CI 0.01-0.32) and LSIL (OR 0.11, CI 0.026-0.45). Our results suggest that genotyping the 46359CT polymorphism in DNMT3B may help identify women who are genetically susceptible to cervical cancer development. Additional studies with larger sample sizes are necessary to confirm our findings.

Rationale for gastrectomy with D2 lymphadenectomy in the treatment of gastric cancer.

BACKGROUND: In the surgical management of gastric cancer, D2 lymphadenectomy aims to reduce the incidence of locoregional relapse, and to increase patient survival. METHODS: A prospective study was made of 126 consecutive patients operated upon for gastric cancer, with gastrectomy and D2 lymphadenectomy. Hospital morbidity and mortality, relapses, and patient survival after 5 years were studied. RESULTS: The overall hospital mortality rate was 1.6%, with a mortality of 2.1% in the patients submitted to total gastrectomy. The overall morbidity rate was 29.4%. Dehiscence of the esophagojejunal anastomosis was recorded in 1.6%. The median follow-up was 73.6 months. Relapses were observed in 37% of the patients (76% in the first 2 years). Overall actuarial survival after 5 years was 52.3%, and 5-year survival in the patients with R0 resection with positive N2 lymph nodes according to the Japanese classification was 26.5%. CONCLUSION: Our results show that D2 lymphadenectomy can be performed with low morbidity-mortality, and a 5-year survival of more than 50%. The procedure offers benefit in terms of survival for a certain percentage of patients with positive level N2 lymph nodes.

Surgical treatment of recurrent gastric cancer.

BACKGROUND: The value of programs to detect recurrence of a previously operated gastric cancer is a controversial subject. D2 lymphadenectomy achieves better local control and a lower local recurrence rate than D1 lymphadenectomy. METHODS: The results achieved with surgical treatment of recurrent gastric cancer in a series of 126 consecutive patients who had been treated with gastrectomy with D2 lymphadenectomy are reported. In-hospital mortality was 1.6%. RESULTS: Follow-up of the remaining 124 patients for a median period of 73.6 months detected recurrence in 46 patients (37%). There were 14 local, 12 peritoneal, and 15 distant recurrences. Recurrent gastric cancer was detected within 2 years in 76% of the patients. Of the 46 patients with recurrence, 5 patients (11%) were selected for surgery (4 local and 1 peritoneal recurrence). The median disease-free time after surgery for recurrence was 26 months (range, 14-58 months). There was no in-hospital mortality. The median survival time after surgery for recurrence was 26 months (range, 9-87 months). One patient died during follow-up, while none of the other patients have any evidence of new recurrence. CONCLUSION: Surgery for recurrent gastric cancer is a valid alternative in selected patients, provided it is performed by specialized work teams.

[Morbidity and mortality in gastrectomy with D2 lymphadenectomy in a specialised unit]. / Morbilidad y mortalidad de la gastrectomía con linfadenectomía D2 en una unidad especializada.

INTRODUCTION: The combination of gastrectomy and D2 lymphadenectomy is still not a widely accepted therapeutic option by Western surgeons, due to its high post-operative morbidity and mortality. OBJECTIVE: To evaluate the morbidity and mortality in a series of patients with gastric cancer treated by gastrectomy and D2 lymphadenectomy, and compare these results with those published by centres with notable experience. PATIENTS AND METHOD: A descriptive and prospective study on a series of 126 consecutive patients with gastric cancer treated by gastrectomy and D2 lymphadenectomy. All complications were recorded, grouped into abdominal and non-abdominal, as well as surgical re-interventions. RESULTS: Total gastrectomy was performed on 95 (75.4%) of the 126 patients. It was combined with splenectomy in 22 cases (17.5%) and left pancreatectomy in 9 (7.1%). The stages, according to the AJCC, were: stage 0: 4.8%, IA: 17.5%, IB: 22.2%, II: 10.3%, IIIA: 16.7%, IIIB: 9.5%, and stage IV: 19%. Of these patients 52.4% were overweight and more than 60% had an ASA risk assessment of III or IV. Fifty complications arose in 37 (29%) of the 26 patients, which required 12 surgical re-interventions (all in total gastrectomy cases). Four anastomosis dehiscence were diagnosed and 4 intra-abdominal abscesses with no evidence of anastomosis dehiscence which were resolved with drainage. Two (1.6%) of the 126 patients died, both after total gastrectomy and with no evidence of intra-abdominal complications. CONCLUSIONS: Patients with gastric cancer, even with associated risk factors, can be treated by gastrectomy and D2 lymphadenectomy with similar morbidity and mortality rates to those centres with more experience, due to a great extent to sub-specialising in this surgery.

Morbilidad y mortalidad de la gastrectomía con linfadenectomía D2 en una unidad especializada / Morbidity and mortality in gastrectomy with D2 lymphadenectomy in a specialised unit

Introducción. La asociación de gastrectomía y linfadenectomía D2 no es todavía una opción terapéutica ampliamente aceptada por los cirujanos occidentales debido a que la morbilidad y la mortalidad postoperatorias son elevadas. Objetivo. Evaluar la morbilidad y la mortalidad en una serie de pacientes con cáncer gástrico tratados con gastrectomía y linfadenectomía D2, y comparar estos resultados con los publicados por centros con experiencia relevante. Pacientes y método. Estudio descriptivo y prospectivo de una serie de 126 pacientes consecutivos con cáncer gástrico tratados con gastrectomía y linfadenectomía D2. Se registraron todas las complicaciones, agrupadas en abdominales y no abdominales, así como las reintervenciones quirúrgicas. Resultados. Se realizó gastrectomía total en 95 (75,4%) de los 126 pacientes. Se asoció esplenectomía en 22 (17,5%) casos y pancreatectomía izquierda en 9 (7,1%). Los estadios, según la AJCC, fueron: estadio 0, el 4,8%; IA, el 17,5%; IB, el 22,2%; II, el 10,3%; IIIA, el 16,7%; IIIB, el 9,5%, y IV, el 19%. El 52,4% de los pacientes tenían sobrepeso y más del 60%, una valoración del riesgo ASA III o IV. Se produjeron 50 complicaciones en 37 (29%) de los 126 pacientes, que precisaron 12 reintervenciones quirúrgicas (todas en casos de gastrectomía total). Se diagnosticaron 4 dehiscencias de anastomosis y 4 abscesos intraabdominales sin evidencia de dehiscencia anastomótica que se solucionaron con drenaje. De los 126 pacientes, 2 (1,6%) fallecieron, ambos tras una gastrectomía total y sin evidencia de complicaciones intraabdominales. Conclusiones. A los pacientes con cáncer gástrico, incluso con factores de riesgo asociados, se puede tratarlos con gastrectomía y linfadenectomía D2, con cifras de morbilidad y mortalidad semejantes a las de los centros de mayor experiencia, en gran parte debido a la subespecialización en esta cirugía (AU)

Introduction. The combination of gastrectomy and D2 lymphadenectomy is still not a widely accepted therapeutic option by Western surgeons, due to its high post-operative morbidity and mortality. Objective. To evaluate the morbidity and mortality in a series of patients with gastric cancer treated by gastrectomy and D2 lymphadenectomy, and compare these results with those published by centres with notable experience. Patients and method. A descriptive and prospective study on a series of 126 consecutive patients with gastric cancer treated by gastrectomy and D2 lymphadenectomy. All complications were recorded, grouped into abdominal and non-abdominal, as well as surgical re-interventions. Results. Total gastrectomy was performed on 95 (75.4%) of the 126 patients. It was combined with splenectomy in 22 cases (17.5%) and left pancreatectomy in 9 (7.1%). The stages, according to the AJCC, were: stage 0: 4.8%, IA: 17.5%, IB: 22.2%, II: 10.3%, IIIA: 16.7%, IIIB: 9.5%, and stage IV: 19%. Of these patients 52.4% were overweight and more than 60% had an ASA risk assessment of III or IV. Fifty complications arose in 37 (29%) of the 26 patients, which required 12 surgical re-interventions (all in total gastrectomy cases). Four anastomosis dehiscence were diagnosed and 4 intra-abdominal abscesses with no evidence of anastomosis dehiscence which were resolved with drainage. Two (1.6%) of the 126 patients died, both after total gastrectomy and with no evidence of intra-abdominal complications. Conclusions. Patients with gastric cancer, even with associated risk factors, can be treated by gastrectomy and D2 lymphadenectomy with similar morbidity and mortality rates to those centres with more experience, due to a great extent to sub-specialising in this surgery (AU)

Epsin N-terminal homology domains perform an essential function regulating Cdc42 through binding Cdc42 GTPase-activating proteins.

Epsins are endocytic proteins with a structured epsin N-terminal homology (ENTH) domain that binds phosphoinositides and a poorly structured C-terminal region that interacts with ubiquitin and endocytic machinery, including clathrin and endocytic scaffolding proteins. Yeast has two redundant genes encoding epsins, ENT1 and ENT2; deleting both genes is lethal. We demonstrate that the ENTH domain is both necessary and sufficient for viability of ent1Deltaent2Delta cells. Mutational analysis of the ENTH domain revealed a surface patch that is essential for viability and that binds guanine nucleotide triphosphatase-activating proteins for Cdc42, a critical regulator of cell polarity in all eukaryotes. Furthermore, the epsins contribute to regulation of specific Cdc42 signaling pathways in yeast cells. These data support a model in which the epsins function as spatial and temporal coordinators of endocytosis and cell polarity.