Factors predictive of complete resection of operable esophageal cancer: review of 746 patients

OBJECTIVE: Surgery is the treatment of reference for early-stage esophageal cancer, but 5-year survival is only 20% to 25%. After complete resection (R0), survival is significantly longer than after incomplete resection, with microscopic (R1) or macroscopic (R2) penetration. The purpose of this work was to identify retrospectively the factors predictive of complete resection of operable esophageal cancers.PATIENTS AND METHODS: Between January 1982 and March 2001, 746 patients with esophageal cancer underwent curative surgery. R0 resection was performed in 585 patients (78.4%), R1 in 61 (8.2%) and R2 in 100 (13.4%). Univariate and multivariate analysis included 28 preoperative, clinical, tumor and therapeutic parameters.RESULTS: Multivariate analysis showed that factors predictive of complete resection R0 were: absence of any modification of the esophageal axis on the barium swallow (P=0.054), a partial or complete response to preoperative radio-chemotherapy (P=0.042), tumor height<10 cm (P=0.1) and tumor diameter<30 mm (P=0.01). Three groups of patients were identified from the 2 most significant variables. Group 1: no deviation of the axis on the barium swallow (n=501). Group 2: deviation of the axis on the barium swallow and partial or complete response to radiochemotherapy (n=91). Group 3: deviation of the axis on the barium swallow and no response to radiochemotherapy or no preoperative treatment (n=126). For the three groups, rate of R0 resection was 82.6%, 80.1% and 61.1% and 5-year actuarial survival 36%, 27% and 14%, respectively. These rates were significantly different between groups (P<10(- 4)) and two by two (P<0.04).CONCLUSION: Complete resection of esophageal cancer is predictable. After validation with an independent population the findings presented here could be used to establish stratification criteria for future therapeutic trials.     

Myocardial asynchronism is a determinant of changes in functional mitral regurgitation severity during dynamic exercise in patients with chronic heart failure due to severe left ventricular systolic dysfunction.

AIMS: Functional mitral regurgitation (MR) and myocardial asynchronism occur commonly in patients with dilated cardiomyopathy and affect adversely their prognosis and symptoms. The aim of this study was to evaluate the mechanisms of changes in MR severity during dynamic exercise in patients with chronic heart failure (CHF). METHODS AND RESULTS: Seventy patients with CHF due to left ventricular (LV) systolic dysfunction [LV ejection fraction (EF) <40%] and functional MR were studied. All were in sinus rhythm. Medications were left unchanged for the study. Each patient performed a maximal symptom-limited exercise test with continuous 2D-Doppler echocardiography. Mitral regurgitant volume (RV) and effective regurgitant orifice (ERO) were determined at rest and during exercise. LV asynchrony using Doppler tissue imaging and interventricular asynchrony using conventional pulsed-Doppler were evaluated at rest. Resting LV EF averaged 25+/-8%. Mean resting LV and interventricular mechanical delays were 56+/-50 and 43+/-37 ms, respectively. The overall median values for mitral ERO and RV did not significantly change during dynamic exercise (11 [7-16] vs. 11 [6-21] mm2 and 14 [10-22] vs. 12 [9-23] mL, respectively). However, changes in mitral ERO and RV were individually variable and significantly correlated with the degree of LV asynchronism (r=0.66, P<0.0001 and r=0.66, P<0.0001, respectively). CONCLUSION: Changes in MR are variable during dynamic exercise. LV asynchronism at rest substantially contributes to worsening of functional MR during dynamic exercise in patients with CHF due to LV systolic dysfunction.     

Flt3-ligand induces adhesion of haematopoietic progenitor cells via a very late antigen (VLA)-4- and VLA-5-dependent mechanism

The adhesion of haematopoietic progenitor cells (HPC) to the bone marrow microenvironment is a process regulated by cytokines. In this study, we have shown that flt3-ligand (FL), a growth factor that controls early haematopoiesis, regulated the function and expression of the beta-1 integrins, very late antigen (VLA)-4 and VLA-5 on HPC. The modulation of the adhesiveness of HPC by FL was studied by adhesion assays on umbilical vein endothelial cells (HUVEC). Stimulation by FL induced two peaks of increased adhesiveness of HPC. The first peak was at around 30 min and was mechanistically related to an activation of the beta-1 integrins, mainly VLA-4 and VLA-5. The second peak was at around 12 h and was related to increased expression of VLA-4 and VLA-5. The control of HPC adhesiveness by FL is a previously unreported property of FL that may be important for the homing and the retention of flt3-expressing HPC within the bone marrow microenvironment.     

Electrophysiologically guided pulmonary vein isolation during sustained atrial fibrillation

INTRODUCTION: Sustained atrial fibrillation (AF) is frequently encountered during pulmonary vein (PV) isolation. The aim of this study was to evaluate the feasibility and safety of PV isolation during sustained AF. METHODS AND RESULTS: Thirty-seven patients (30 men, age 54 +/- 10 years) underwent Lasso-guided isolation of 87 PVs during sustained AF. Baseline PV electrogram patterns were classified into one of two types: organized, with consistent PV activation sequence; or disorganized, with constant variation of PV activation sequence. In disorganized activity, radiofrequency ablation was performed circumferentially around the Lasso while the earliest PV potential was targeted during organized activity. Complete left atrial (LA) to PV block during AF was identified by abolition or dissociation of all sharp potentials recorded within the vein. PV isolation then was verified during sinus rhythm. Baseline activation patterns of PV potential were organized in 32 PVs (37%) [more frequently in inferior veins than superior veins (53% vs 26%, P = 0.01)] and disorganized in 55 PVs (63%). In 59 of 87 PVs, isolation was begun and completed during AF. Radiofrequency ablation organized PV activation sequence in 75% prior to isolation. LA-PV block was confirmed during sinus rhythm in 54 (92%) of 59 PVs. In 28 of 87 PVs, sinus rhythm was restored before complete LA-PV block. Complete isolation was achieved in all 87 PVs without complications. CONCLUSION: PV isolation can be effectively and safely performed during sustained AF, preceded in most cases by organization of PV electrogram activity. This strategy may be the preferred alternative to multiple intraprocedural cardioversions.     

Results of ileal J-pouch-anal anastomosis in familial adenomatous polyposis complicated by rectal carcinoma

PURPOSE: Rectal cancer frequently occurs in patients with familial adenomatous polyposis (FAP) and, in some cases, proctocolectomy and ileal pouch-anal anastomosis (IPAA) can be proposed as an alternative to end ileostomy. This study aimed to assess the results of IPAA for familial adenomatous polyposis complicated by rectal carcinoma. PATIENTS AND METHODS: Postoperative morbidity and bowel function following IPAA were assessed in six patients who had a mesorectal excision for rectal cancer. The functional results were compared with those obtained after IPAA in 134 FAP patients without bowel cancer. RESULTS: Carcinomas were located at a mean of 11 cm from the dentate line. There were no postoperative complications. One patient with synchronous hepatic metastases died 6 months after operation and the 5 others were alive without recurrence after a mean follow-up of 29 months. Mean frequency of defecation was 6.5/day (vs. 4.2/day in patients without carcinoma), 86 percent of patients had nocturnal defecation (vs. 50 percent), day and night continence were normal in 66 percent and 33 percent of patients, respectively, compared with 90 percent and 85 percent for IPAA without cancer. Pouch excision was required in one patient for unsatisfactory functional result. CONCLUSION: IPAA can be safely performed for cancer of the upper rectum complicating FAP, but a poor functional outcome related to mesorectal excision has to be expected.     

Report on a novel emerging class of highly potent benzimidazole NPS opioids: Chemical and in vitro functional characterization of isotonitazene

This paper reports on the identification and full chemical characterization of isotonitazene (N,N‐diethyl‐2‐[5‐nitro‐2‐({4‐[(propan‐2‐yl)oxy]phenyl}methyl)‐1H‐benzimidazol‐1‐yl]ethan‐1‐amine), a potent NPS opioid and the first member of the benzimidazole class of compounds to be available on online markets. Interestingly, this compound was sold under the name etonitazene, a structural analog. Identification of isotonitazene was performed by gas chromatography mass spectrometry (GC–MS) and liquid chromatography time‐of‐flight mass spectrometry (LC‐QTOF‐MS), the latter identifying an exact‐mass m/z value of 411.2398. All chromatographic data indicated the presence of a single, highly pure compound. Confirmation of the specific benzimidazole regio‐isomer was performed using ¹H and ¹³C NMR spectroscopy, after which the chemical characterization was finalized by recording Fourier‐transform (FT‐IR) spectra. A live cell‐based reporter assay to assess the in vitro biological activity at the μ‐opioid receptor (MOR) revealed that isotonitazene has a high potency (EC₅₀ of 11.1 nM) and efficacy (E_max 180% of that of hydromorphone), thus confirming that this substance is a strong opioid. Isotonitazene has not been previously detected, either in powder form, or in biological fluids. The high potency and efficacy of isotonitazene, combined with the fact that this compound was being sold undiluted, represents an imminent danger to anyone aiming to use this powder.     

Effects of Fecal Microbiota Transplantation on Composition in Mice with CKD

Background: Chronic kidney disease (CKD) is a renal disorder characterized by the accumulation of uremic toxins with limited strategies to reduce their concentrations. A large amount of data supports the pivotal role of intestinal microbiota in CKD complications and as a major source of uremic toxins production. Here, we explored whether fecal microbiota transplantation (FMT) could be attenuated in metabolic complication and uremic toxin accumulation in mice with CKD. Methods: Kidney failure was chemically induced by a diet containing 0.25% (w/w) of adenine for four weeks. Mice were randomized into three groups: control, CKD and CKD + FMT groups. After four weeks, CKD mice underwent fecal microbiota transplantation (FMT) from healthy mice or phosphate buffered saline as control. The gut microbiota structure, uremic toxins plasmatic concentrations, and metabolic profiles were explored three weeks after transplantation. Results: Associated with the increase of alpha diversity, we observed a noticeable improvement of gut microbiota disturbance, after FMT treatment. FMT further decreased p-cresyl sulfate accumulation and improved glucose tolerance. There was no change in kidney function. Conclusions: These data indicate that FMT limited the accumulation of uremic toxins issued from intestinal cresol pathway by a beneficial effect on gut microbiota diversity. Further studies are needed to investigate the FMT efficiency, the timing and feces amount for the transplantation before, to become a therapeutic option in CKD patients.     

Melanocortin 4 receptor signals at the neuronal primary cilium to control food intake and body weight

The melanocortin 4 receptor (MC4R) plays a critical role in the long-term regulation of energy homeostasis, and mutations in the MC4R are the most common cause of monogenic obesity. However, the precise molecular and cellular mechanisms underlying the maintenance of energy balance within MC4R-expressing neurons are unknown. We recently reported that the MC4R localizes to the primary cilium, a cellular organelle that allows for partitioning of incoming cellular signals, raising the question of whether the MC4R functions in this organelle. Here, using mouse genetic approaches, we found that cilia were required specifically on MC4R-expressing neurons for the control of energy homeostasis. Moreover, these cilia were critical for pharmacological activators of the MC4R to exert an anorexigenic effect. The MC4R is expressed in multiple brain regions. Using targeted deletion of primary cilia, we found that cilia in the paraventricular nucleus of the hypothalamus (PVN) were essential to restrict food intake. MC4R activation increased adenylyl cyclase (AC) activity. As with the removal of cilia, inhibition of AC activity in the cilia of MC4R-expressing neurons of the PVN caused hyperphagia and obesity. Thus, the MC4R signaled via PVN neuron cilia to control food intake and body weight. We propose that defects in ciliary localization of the MC4R cause obesity in human inherited obesity syndromes and ciliopathies.     

Depression,anxiety and loss of resilience after multiple traumas: an illustration of a mediated moderation model of sensitization in a group of children who survived the Nazi Holocaust

Background

Depressive and anxiety disorders (DAD) have become a major public health problem. Multiple trauma is known to increase the risk of DAD through a sensitization mechanism. We investigate the hypothesis that resilience is a mediator of this mechanism.

Methods

Former Hidden Children (FHC), the Jewish youths who spent World War II in various hideaway shelters across Nazi-occupied Europe, were compared with a control group. In each group, we measured the presence of multiple traumas, the resilience with the Resilience Scale for Adults, which has a six factors solution, and the DAD with the Hopkins Symptoms Checklist. We test a mediated moderation model with childhood trauma as the predictor; Later trauma as the moderator; Resilience as the mediator; and DAD as the outcome variable.

Results

Results are consistent with a sensitization model of DAD mediated by resilience: confrontation with a primary trauma during childhood followed by secondary trauma(s) after childhood damages resilience, which, in turn, results in higher level of DAD.

Limitations

We are unable to differentiate if the sensitization process is a consequence of the nature of the trauma endured by FHC (long-standing exposure to extreme external events) or a consequence of the fact that this first trauma occurred during childhood.

Conclusions

Resilience construct is multi-factorial and a limited damaging of some of the factors is sufficient to lead to DAD even if other factors remain unaltered. Resilience can be altered by multiple traumas and, therefore, needs to be bolstered in therapy sessions.     

HLA-G haplotype structure shows good conservation between different populations and good correlation with high,normal and low soluble HLA-G expression

HLA-G molecule has considerable impact in various clinical fields, therefore many studies attempted to predict its expression based on HLA-G genotype. These studies have focused on polymorphisms in either the coding region or in one of the two untranslated regions (UTR) of the gene. The aim of our study was to determine if HLA-G haplotype defined based on SNPs 5′ and 3′UTR could be used to predict soluble HLA-G expression in unstimulated individuals. Our findings showed that HLA-G haplotype structure was well conserved between distant populations and that the defined haplotypes were correlated with high, normal and low HLA-G soluble secretors. In conclusion, we showed that this genotyping strategy based on the use of a few selected SNPs rather than isolated SNP analysis allows reliable HLA-G expression in all populations. This strategy could be useful in a number of clinical settings, e.g., predicting graft compatibility immunogenetic laboratories.