Vástagos modulares de anclaje diafisario con tornillos de bloqueo en la revisión de cadera con defectos femorales masivos / Modular diaphyseal anchor stems with locking screws in the hip revision with massive femoral defects

INTRODUCCIÓN: Los defectos femorales complejos con istmo insuficiente (Paprosky III y IV) y fracturas periprotésicas B3 de Vancouver condicionan la fijación de los vástagos de revisión. El objetivo es evaluar los resultados de los vástagos de revisión modular de anclaje diafisario con bloqueo distal (Sistema Revitan Zimmer Biomet GmbH, Winterthur, Suiza). Nuestra hipótesis es que ofrecen una fijación primaria estable en casos de afectación del istmo femoral. MATERIAL Y MÉTODOS: Estudio de cohortes retrospectivo de 38 pacientes, seguimiento mínimo de 12 meses (12-94) y defectos femorales severos tratados con vástagos Revitan encerrojados. Realizamos una vía endofemoral o una transfemoral. Valoramos el hundimiento según el método de Callahan y la neoformación ósea según Barnett y Nordin. Se utilizó la escala Merle d'Aubigné-Postel y se recogieron las complicaciones y reintervenciones. Se realizó un análisis estadístico con SPSS y un nivel de significación p < 0,05. RESULTADOS: Entre 2009 y 2017 se realizaron 147 revisiones con vástago Revitan, 38 encerrojados, 23 hombres y 15 mujeres, edad media de 74 años y seguimiento medio de 64 meses. Las causas de revisión fueron: 15 aflojamientos sépticos, 14 asépticos, dos fracturas y siete fijaciones fibrosas estables. Obtuvimos una correcta fijación en 27 casos; hubo cuatro aflojamientos, tres roturas de tornillos, tres infecciones, una luxación y una lesión del nervio femoral. El MDP mejoró de forma significativa de 11,26 a 14,98. CONCLUSIONES: Los vástagos modulares cónicos encerrojados son una buena alternativa en los defectos femorales con afectación ístmica si se consigue un correcto relleno del canal y una fijación bicortical de los tornillos

INTRODUCTION: Complex femoral defects with insufficient isthmus (Paprosky III and IV) and Vancouver B3 periprosthetic fractures determines the fixation of the revision stems. The objective is to evaluate the results of the modular revision stems with diaphyseal anchor and distal block (Revitan Zimmer Biomet GmbH, Winterthur, Switzerland). Our hypothesis is that this procedure offers a stable primary fixation in cases of alteration of the femoral isthmus. MATERIAL AND METHODS: Retrospective cohort study of 38 patients, minimum follow-up of 12 months (12-94) with severe femoral defects treated with Revitan stems distally blocked. An endofemoral or transfemoral approach was used. The subsidence was assessed according to Callahan's method and bone neoformation according to Nordin. Merle d'Aubigné-Postel was used and complications and reoperations were collected. A statistical analysis was performed with SPSS and a significance level p < 0.05 was considered. RESULTS: Between 2009 and 2017, 147 revisions were carried out with Revitan stem, 38 locked, 23 men and 15 women, with an average age of 74 years and an average follow-up of 64 months. The cause of the review was: 15 septic loosenings, 14 aseptic, two fractures and seven stable fibrous unions. Right fixation was obtained in 27 cases, there were four loosenings, three screw breakages, three infections, one of dislocation and one of femoral nerve injury. The MDP increased significantly from 11.26 to 14.98. CONCLUSIONS: Distally locked conical modular stems are a good alternative in femoral defects with isthmus involvement if proper canal filling and bicortical screw fixation are achieved

Modular diaphyseal anchor stems with locking screws in the hip revision with massive femoral defects. / Vástagos modulares de anclaje diafisario con tornillos de bloqueo en la revisión de cadera con defectos femorales masivos.

INTRODUCTION: Complex femoral defects with insufficient isthmus (Paprosky III and IV) and Vancouver B3 periprosthetic fractures determines the fixation of the revision stems. The objective is to evaluate the results of the modular revision stems with diaphyseal anchor and distal block (Revitan Zimmer Biomet GmbH, Winterthur, Switzerland). Our hypothesis is that this procedure offers a stable primary fixation in cases of alteration of the femoral isthmus. MATERIAL AND METHODS: Retrospective cohort study of 38 patients, minimum follow-up of 12 months (12-94) with severe femoral defects treated with Revitan stems distally blocked. An endofemoral or transfemoral approach was used. The subsidence was assessed according to Callahan's method and bone neoformation according to Nordin. Merle d'Aubigné-Postel was used and complications and reoperations were collected. A statistical analysis was performed with SPSS and a significance level p < 0.05 was considered. RESULTS: Between 2009 and 2017, 147 revisions were carried out with Revitan stem, 38 locked, 23 men and 15 women, with an average age of 74 years and an average follow-up of 64 months. The cause of the review was: 15 septic loosenings, 14 aseptic, two fractures and seven stable fibrous unions. Right fixation was obtained in 27 cases, there were four loosenings, three screw breakages, three infections, one of dislocation and one of femoral nerve injury. The MDP increased significantly from 11.26 to 14.98. CONCLUSIONS: Distally locked conical modular stems are a good alternative in femoral defects with isthmus involvement if proper canal filling and bicortical screw fixation are achieved.

Do regional brain volumes and major depressive disorder share genetic architecture? A study of Generation Scotland (n=19 762), UK Biobank (n=24 048) and the English Longitudinal Study of Ageing (n=5766).

Major depressive disorder (MDD) is a heritable and highly debilitating condition. It is commonly associated with subcortical volumetric abnormalities, the most replicated of these being reduced hippocampal volume. Using the most recent published data from Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium's genome-wide association study of regional brain volume, we sought to test whether there is shared genetic architecture between seven subcortical brain volumes and intracranial volume (ICV) and MDD. We explored this using linkage disequilibrium score regression, polygenic risk scoring (PRS) techniques, Mendelian randomisation (MR) analysis and BUHMBOX. Utilising summary statistics from ENIGMA and Psychiatric Genomics Consortium, we demonstrated that hippocampal volume was positively genetically correlated with MDD (rG=0.46, P=0.02), although this did not survive multiple comparison testing. None of the other six brain regions studied were genetically correlated and amygdala volume heritability was too low for analysis. Using PRS analysis, no regional volumetric PRS demonstrated a significant association with MDD or recurrent MDD. MR analysis in hippocampal volume and MDD identified no causal association, however, BUHMBOX analysis identified genetic subgrouping in GS:SFHS MDD cases only (P=0.00281). In this study, we provide some evidence that hippocampal volume and MDD may share genetic architecture in a subgroup of individuals, albeit the genetic correlation did not survive multiple testing correction and genetic subgroup heterogeneity was not replicated. In contrast, we found no evidence to support a shared genetic architecture between MDD and other regional subcortical volumes or ICV.

Assessing the presence of shared genetic architecture between Alzheimer's disease and major depressive disorder using genome-wide association data.

Major depressive disorder (MDD) and Alzheimer's disease (AD) are both common in older age and frequently co-occur. Numerous phenotypic studies based on clinical diagnoses suggest that a history of depression increases risk of subsequent AD, although the basis of this relationship is uncertain. Both illnesses are polygenic, and shared genetic risk factors could explain some of the observed association. We used genotype data to test whether MDD and AD have an overlapping polygenic architecture in two large population-based cohorts, Generation Scotland's Scottish Family Health Study (GS:SFHS; N=19 889) and UK Biobank (N=25 118), and whether age of depression onset influences any relationship. Using two complementary techniques, we found no evidence that the disorders are influenced by common genetic variants. Using linkage disequilibrium score regression with genome-wide association study (GWAS) summary statistics from the International Genomics of Alzheimer's Project, we report no significant genetic correlation between AD and MDD (rG=-0.103, P=0.59). Polygenic risk scores (PRS) generated using summary data from International Genomics of Alzheimer's Project (IGAP) and the Psychiatric Genomics Consortium were used to assess potential pleiotropy between the disorders. PRS for MDD were nominally associated with participant-recalled AD family history in GS:SFHS, although this association did not survive multiple comparison testing. AD PRS were not associated with depression status or late-onset depression, and a survival analysis showed no association between age of depression onset and genetic risk for AD. This study found no evidence to support a common polygenic structure for AD and MDD, suggesting that the comorbidity of these disorders is not explained by common genetic variants.

[Lung adenocarcinoma with concomitant EGFR mutation and ALK rearrangement]. / Adénocarcinome bronchique avec mutation de l'EGFR et réarrangement ALK concomitants.

INTRODUCTION: Among patients with non-small-cell lung cancer, coexistence of EGFR mutation and ALK rearrangement is rare. We describe the clinical features of two patients with this double anomaly. CASE REPORTS: A 62-year-old Caucasian non-smoking woman was diagnosed with cT4N0M0 lung adenocarcinoma. Initial biopsy showed EGFR mutation and ALK rearrangement. She received cisplatin-gemcitabine, followed by 17 months of gemcitabine. Owing to progression, she received erlotinib for 14 months, then paclitaxel for 6 months and finally crizotinib. A partial response was achieved and maintained for 24 months. A 45-year-old Caucasian woman, light smoker, was diagnosed with cT2N3M0 lung adenocarcinoma. Only EGFR mutation was found on initial analysis. She underwent treatment with cisplatin-gemcitabine and thoracic radiotherapy. Progression occurred after 8 months and afatinbib was started. Eight months later, progression was observed with a neoplasic pleural effusion in which tumor cells expressing ALK rearrangement were found. A new FISH analysis was performed on the initial tumor but did not find this rearrangement. Despite a third line of crizotinib, the patient died one month later. DISCUSSION: The literature shows 45 other cases of these two abnormalities, observed either from the start or during follow-up. EGFR's TKI were almost always given before ALK's TKI. CONCLUSIONS: Therapeutic strategy needs to be clarified in cases of double alteration. With regard to the second patient, appearance of ALK rearrangement may constitute a resistance mechanism to EGFR's TKI.

Dissection of major depressive disorder using polygenic risk scores for schizophrenia in two independent cohorts.

Major depressive disorder (MDD) is known for its substantial clinical and suspected causal heterogeneity. It is characterized by low mood, psychomotor slowing and increased levels of the personality trait neuroticism; factors also associated with schizophrenia (SCZ). It is possible that some cases of MDD may have a substantial genetic loading for SCZ. The presence of SCZ-like MDD subgroups would be indicated by an interaction between MDD status and polygenic risk of SCZ on cognitive, personality and mood measures. Here, we hypothesized that higher SCZ polygenic risk would define larger MDD case-control differences in cognitive ability, and smaller differences in distress and neuroticism. Polygenic risk scores (PRSs) for SCZ and their association with cognitive variables, neuroticism, mood and psychological distress were estimated in a large population-based cohort (Generation Scotland: Scottish Family Health Study, GS:SFHS). The individuals were divided into those with, and without, depression (n=2587 and n=16 764, respectively) to test for the interactions between MDD status and schizophrenia risk. Replication was sought in UK Biobank (UKB; n=6049 and n=27 476 cases and controls, respectively). In both the cohorts, we found significant interactions between SCZ-PRS and MDD status for measures of psychological distress (ßGS=-0.04, PGS=0.014 and ßUKB=-0.09, PUKB⩽0.001 for GS:SFHS and UKB, respectively) and neuroticism (ßGS=-0.04, PGS=0.002 and ßUKB=-0.06, PUKB=0.023). In both the cohorts, there was a reduction of case-control differences on a background of higher genetic risk of SCZ. These findings suggest that depression on a background of high genetic risk for SCZ may show attenuated associations with distress and neuroticism. This may represent a causally distinct form of MDD more closely related to SCZ.

Common polygenic risk for autism spectrum disorder (ASD) is associated with cognitive ability in the general population.

Cognitive impairment is common among individuals diagnosed with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). It has been suggested that some aspects of intelligence are preserved or even superior in people with ASD compared with controls, but consistent evidence is lacking. Few studies have examined the genetic overlap between cognitive ability and ASD/ADHD. The aim of this study was to examine the polygenic overlap between ASD/ADHD and cognitive ability in individuals from the general population. Polygenic risk for ADHD and ASD was calculated from genome-wide association studies of ASD and ADHD conducted by the Psychiatric Genetics Consortium. Risk scores were created in three independent cohorts: Generation Scotland Scottish Family Health Study (GS:SFHS) (n=9863), the Lothian Birth Cohorts 1936 and 1921 (n=1522), and the Brisbane Adolescent Twin Sample (BATS) (n=921). We report that polygenic risk for ASD is positively correlated with general cognitive ability (beta=0.07, P=6 × 10(-7), r(2)=0.003), logical memory and verbal intelligence in GS:SFHS. This was replicated in BATS as a positive association with full-scale intelligent quotient (IQ) (beta=0.07, P=0.03, r(2)=0.005). We did not find consistent evidence that polygenic risk for ADHD was associated with cognitive function; however, a negative correlation with IQ at age 11 years (beta=-0.08, Z=-3.3, P=0.001) was observed in the Lothian Birth Cohorts. These findings are in individuals from the general population, suggesting that the relationship between genetic risk for ASD and intelligence is partly independent of clinical state. These data suggest that common genetic variation relevant for ASD influences general cognitive ability.

Major depressive disorder and current psychological distress moderate the effect of polygenic risk for obesity on body mass index.

Major depressive disorder (MDD) and obesity are frequently co-morbid and this correlation is partly due to genetic factors. Although specific genetic risk variants are associated with body mass index (BMI) and with larger effect sizes in depressed individuals, the genetic overlap and interaction with depression has not been addressed using whole-genome data. Polygenic profile scores for MDD and BMI were created in 13,921 members of Generation Scotland: the Scottish Family Health Study and tested for their association with BMI, MDD, neuroticism and scores on the General Health Questionnaire (GHQ) (current psychological distress). The association between BMI polygenic profile scores and BMI was tested fitting GHQ, neuroticism or MDD status as an interaction term to test for a moderating effect of mood disorder. BMI polygenic profile scores were not associated with lifetime MDD status or neuroticism although a significant positive association with GHQ scores was found (P = 0.0001, ß = 0.034, r(2) = 0.001). Polygenic risk for MDD was not associated with BMI. A significant interaction between BMI polygenic profile scores and MDD (P = 0.0003, ß = 0.064), GHQ (P = 0.0005, ß = 0.027) and neuroticism (P = 0.003, ß = 0.023) was found when BMI was the dependent variable. The effect of BMI-increasing alleles was greater in those with MDD, high neuroticism or current psychological distress. MDD, neuroticism and current psychological distress amplify the effect of BMI polygenic profile scores on BMI. Depressed individuals with a greater polygenic load for obesity are at greater risk of becoming obese than control individuals.

Treatment with a BH3 mimetic overcomes the resistance of latency III EBV (+) cells to p53-mediated apoptosis.

P53 inactivation is often observed in Burkitt's lymphoma (BL) cells due to mutations in the p53 gene or overexpression of its negative regulator, murine double minute-2 (MDM2). This event is now considered an essential part of the oncogenic process. Epstein-Barr virus (EBV) is strongly associated with BL and is a cofactor in its development. We previously showed that nutlin-3, an antagonist of MDM2, activates the p53 pathway in BL cell lines harboring wild-type p53. However, nutlin-3 strongly induced apoptosis in EBV (-) or latency I EBV (+) cells, whereas latency III EBV (+) cells were much more resistant. We show here that this resistance to apoptosis is also observed in latency III EBV (+) lymphoblastoid cell lines. We also show that, in latency III EBV (+) cells, B-cell lymphona 2 (Bcl-2) is selectively overproduced and interacts with Bcl-2-associated X protein (Bax), preventing its activation. The treatment of these cells with the Bcl-2-homology domain 3 mimetic ABT-737 disrupts Bax/Bcl-2 interaction and allows Bax activation by nutlin-3. Furthermore, treatment with these two compounds strongly induces apoptosis. Thus, a combination of Mdm2 and Bcl-2 inhibitors might be a useful anti-cancer strategy for diseases linked to EBV infection.

Activation of p53 by MDM2 antagonists has differential apoptotic effects on Epstein-Barr virus (EBV)-positive and EBV-negative Burkitt's lymphoma cells.

p53 inactivation is often observed in Burkitt's lymphoma (BL) cells, because of either mutations in p53 gene or an overexpression of the p53-negative regulator MDM2. Epstein-Barr virus (EBV) is present in virtually 100% of BL cases occurring in endemic areas, but in only 10-20% of sporadic cases. In EBV(-) BL cells, reactivation of p53, induced by reducing MDM2 protein level, led to apoptosis. We show here that nutlin-3, a potent antagonist of MDM2, activates the p53 pathway in all BL cell lines harboring wild-type p53, regardless of EBV status. However, nutlin-3 strongly induced apoptosis in EBV(-) or latency I EBV(+) cells, whereas latency III EBV(+) cells were much more resistant. Prior treatment with sublethal doses of nutlin-3 sensitizes EBV(-) or latency I EBV(+) cells to apoptosis induced by etoposide or melphalan, but protects latency III EBV(+) cells. p21(WAF1) which is overexpressed in the latter, is involved in this protective effect, as siRNA-mediated inhibition of p21(WAF1) restores sensitivity to etoposide. Nutlin-3 protects latency III BL cells by inducing a p21(WAF1)-mediated G1 arrest. Most BL patients with wild-type p53 tumors could therefore benefit from treatment with nutlin-3, after a careful determination of the latency pattern of EBV in infected patients.

Trocar arrangement for HALS.

The appropriate position of the hand-access device and trocars for hand-assisted laparoscopic surgery depends on several factors, including the surgeon's preference, physical stature, and handedness; the patient's anatomy; and the type of procedure being performed. This article reviews the options, including measures for special circumstances such as patient obesity.