[Long-term effects of dibenzazepines on metabolic parameters: retrospective comparison of carbamazepine, oxcarbazepine and eslicarbazepine acetate in the real world]. / Efectos a largo plazo de las dibenzacepinas sobre los parámetros metabólicos: comparación retrospectiva de carbamacepina, oxcarbacepina y acetato de eslicarbacepina en el mundo real.

INTRODUCTION: Although carbamazepine (CBZ) has strong enzyme-inducing properties, oxcarbazepine (OXC) and eslicarbazepine acetate (ESL) are thought to have a milder effect. These drugs are known to have effects on lipid metabolism and may cause hyponatremia and changes in blood cell counts and liver function tests. AIM: To compare the long-term effects of three antiepileptic drugs (CBZ, OXC and ESL) on these variables. PATIENTS AND METHODS: Retrospective cohort study of consecutive patients treated with CBZ, OXC or ESL. Natremia, lipid concentrations, blood cell counts and liver function tests were compared before, during and at the end of the study period. RESULTS: A total of 292 patients were included. Of these, 143 were treated with CBZ, 55 with OXC and 94 with ESL. CBZ showed a greater impact on lipid metabolism, while OXC was correlated with lower mean sodium levels and a higher frequency of hyponatremia. Lifestyle recommendations related to diet, physical activity and water intake were helpful in overcoming these side effects. No other statistically significant differences were detected. CONCLUSIONS: While CBZ showed a greater impact on lipid metabolism, OXC displayed a higher frequency of hyponatremia. Lifestyle recommendations may be helpful in overcoming these side effects. No other statistically significant differences were found.

TITLE: Efectos a largo plazo de las dibenzacepinas sobre los parámetros metabólicos: comparación retrospectiva de carbamacepina, oxcarbacepina y acetato de eslicarbacepina en el mundo real.Introducción. Aunque la carbamacepina (CBZ) tiene fuertes propiedades de inducción enzimática, se cree que la oxcarbacepina (OXC) y el acetato de eslicarbacepina (ESL) ejercen un efecto más leve. Se sabe que estos fármacos tienen efectos sobre el metabolismo lipídico, pueden causar hiponatremia y cambios en el recuento de células sanguíneas y en las pruebas de función hepática. Objetivo. Comparar los efectos a largo plazo de tres medicamentos antiepilépticos (CBZ, OXC y ESL) en estas variables. Pacientes y métodos. Estudio de cohorte retrospectivo de pacientes consecutivos tratados con CBZ, OXC o ESL. La natremia, las concentraciones de lípidos, el recuento de células sanguíneas y las pruebas de función hepática se compararon antes, durante y al final del período de estudio. Resultados. Se incluyó a 292 pacientes. De ellos, 143 fueron tratados con CBZ, 55 con OXC y 94 con ESL. La CBZ mostró un mayor impacto en el metabolismo de los lípidos, mientras que la OXC se correlacionó con niveles medios de sodio más bajos y una frecuencia mayor de hiponatremia. Las recomendaciones de estilo de vida relacionadas con la dieta, la actividad física y la ingesta de agua fueron útiles para superar estos efectos secundarios. No se detectaron otras diferencias estadísticamente significativas. Conclusiones. Mientras que la CBZ mostró un mayor impacto en el metabolismo de los lípidos, la OXC mostró una mayor frecuencia de hiponatremia. Las recomendaciones de estilo de vida pueden ser útiles para superar estos efectos secundarios. No se encontraron otras diferencias estadísticamente significativas.

Coordinated representational reinstatement in the human hippocampus and lateral temporal cortex during episodic memory retrieval.

Theoretical models of episodic memory have proposed that retrieval depends on interactions between the hippocampus and neocortex, where hippocampal reinstatement of item-context associations drives neocortical reinstatement of item information. Here, we simultaneously recorded intracranial EEG from hippocampus and lateral temporal cortex (LTC) of epilepsy patients who performed a virtual reality spatial navigation task. We extracted stimulus-specific representations of both item and item-context associations from the time-frequency patterns of activity in hippocampus and LTC. Our results revealed a double dissociation of representational reinstatement across time and space: an early reinstatement of item-context associations in hippocampus preceded a later reinstatement of item information in LTC. Importantly, reinstatement levels in hippocampus and LTC were correlated across trials, and the quality of LTC reinstatement was predicted by the magnitude of phase synchronization between hippocampus and LTC. These findings confirm that episodic memory retrieval in humans relies on coordinated representational interactions within a hippocampal-neocortical network.

[Substance related disorder in emergency services: Which attitudes?] / Autoévaluation des attitudes soignantes aux urgences face aux conduites addictives. Étude exploratoire.

INTRODUCTION: Substance related disorders are more prevalent in emergency services than in the general population, about 20% of individuals in emergency care test positive for alcohol. Emergency services are strategic places to identify alcohol misuse. Attitudes to individuals presenting substance related disorders are important in developing therapeutic relationships and applying interventions. OBJECTIVE: This study explores the attitudes of an emergency staff to these individuals across a range of roles, and evolution in face of an addictology care improvement. METHOD: Data were gathered from an emergency service sample from the emergency department of a general hospital in Morlaix (France). We used a short questionnaire, adapted from previous similar French studies. RESULTS: Twenty-five persons answered the first questionnaire and 18 the second. A self-administrated attitudes questionnaire showed its interest in our study and helped us to identify attitudes and to initiate a reflection on behaviours in emergency care. Moreover, it helped to change attitudes towards individuals presenting substance related disorders. The daily setting of an addictive disorders specialized unit in emergency changed the point of view on addictive disorders of both physicians and nurses. We showed differences in addictive related disorders prevalence perception among patients attending emergency care between the two evaluations. But we also showed that physicians and nurses stressed that it was more difficult to ask patients in emergency care on the second evaluation, after and despite a daily addictive disorders specialized setting. We showed several limits in emergency staff care relationship with patients with substance related disorders. They identified difficulties to talk about addictive disorders, especially in younger and older patients. Regarding literature, we discuss our study limits and different ways of improving addictology care in emergency services.

Assessing long-term effects of eslicarbazepine acetate on lipid metabolism profile, sodium values and liver function tests.

INTRODUCTION: Older dibenzazepines with a carboxamide substitution have been demonstrated to cause deleterious effects on lipid metabolism profile, as well as frequent hyponatremia. The aim of our study is to assess the effects of eslicarbazepine acetate, a novel AED, on lipid metabolism profile, sodium values and liver function tests, as well as to compare them with previous effects of carbamazepine and oxcarbazepine. METHODS: This report describes a retrospective cohort study of 108 patients who were treated with eslicarbazepine. Of these patients, 52% had switched to eslicarbazepine from prior treatment with carbamazepine or oxcarbazepine. Laboratory values concerning lipid metabolism profile, liver function tests and sodium were assessed before and after beginning/switching treatment. Patients who began treatment or whose treatment for dyslipidemia was modified during the study period were excluded from the analysis. Co-medications that could impact lipid metabolism profile, sodium or hepatic function were kept stable during the study period. RESULTS: The mean total cholesterol of the entire group decreased significantly from prior pathological to normal values after beginning/switching treatment. The percentage of patients with pathological values decreased. Patients switching from prior carboxamides also showed significant reductions in mean LDL and triglycerides. Patients beginning treatment without prior carboxamides did not develop dyslipidemia after titration. A tendency for an increased percentage of patients with hyponatremia was detected in both groups. CONCLUSIONS: Compared with older carboxamides, eslicarbazepine acetate exhibits a safer profile related to lipid metabolism. No relevant changes were detected in liver function tests. Consequently, a vascular risk factor could be avoided in patients with chronic epilepsy, while hyponatremia still needs to be ruled out. Prospective studies are still needed.

Perfusion SPECT, SISCOM and PET (18)F-FDG in the assessment of drug- refractory epilepsy patients candidates for epilepsy surgery.

AIMS: Brain perfusion SPECT (ictal-interictal), SPECT images and subtraction ictal SPECT coregistered to MRI (SISCOM) and (18)F-FDG-PET (interictal), play an important role in the pre-surgical diagnosis of patients with medically refractory epilepsy. This study aimed to establish: the reproducibility of visual ictal-interictal SPECT and SISCOM analysis altogether with the capacity of SPECT, SISCOM and PET to determine the epileptogenic zone. MATERIAL AND METHODS: (99m)Tc-HMPAO SPECT ictal-interictal and SISCOM (Analyze 7.0) were performed on 47 refractory epilepsy patients (24 F, 19-60 yrs). In 13 patients, SISCOM was also performed using a new program (Focus DET). Ictal-interictal SPECT and SISCOM images were analysed independently by two nuclear medicine physicians (observer 1 and 2). Kappa concordance coefficient was used to evaluate the reproducibility. In sixteen patients, SPECT, SISCOM and PET findings were compared with the resected area during the surgery, and surgical outcome using Engel scale or with the stereo EEG-(SEEG). RESULTS: The ictal-interictal SPECT interobserver agreement was 91%, Kappa index 0.86, SISCOM (Analyze 7.0) interobserver agreement percentage was 82%, Kappa index 0.80, Analyze 7.0 showed a higher inconclusive results than visual SPECT analysis. SISCOM FocusDET interobserver agreement was 92%, Kappa index 0.87, with lower inconclusive results than Analyze 7.0. SPECT, SISCOM and PET combined findings identified 87% seizure onset zone: 79% temporal, 26% parieto-temporal and 7% frontal. CONCLUSIONS: Ictal-interictal SPECT and SISCOM showed a high reproducibility in this sample of patients with drug-refractory epilepsy. SPECT,SISCOM and PET combined findings improved detection of epileptogenic zone in comparison with the individual assessment.

The role of targeted BRCA1/BRCA2 mutation analysis in hereditary breast/ovarian cancer families of Portuguese ancestry.

We report the analysis of altogether 1050 suspected hereditary breast/ovarian cancer (HBOC) families, 524 fully screened for BRCA1/BRCA2 mutations and 526 tested only for the most common mutations. Of the 119 families with pathogenic mutations, 40 (33.6%) had the BRCA2 c.156_157insAlu rearrangement and 15 (12.6%) the BRCA1 c.3331_3334del mutation, the former being specific of Portuguese ancestry and the latter showing a founder effect in Portugal. Interestingly, the two most common mutations were found in a significant proportion of the HBOC families with an a priori BRCAPRO mutation probability <10%. We recommend that all suspected HBOC families from Portugal or with Portuguese ancestry, even those fulfilling moderately stringent clinical-criteria for genetic testing, should be specifically analyzed for the two most common BRCA1/BRCA2 founder mutations, and we here present a simple method for this first tier test. Screening of the entire coding regions of BRCA1 and BRCA2 should subsequently be offered to those families with a mutation probability ≥10% if none of those founder mutations are found.

Post-authorisation study of eslicarbazepine as treatment for drug-resistant epilepsy: preliminary results.

INTRODUCTION: Eslicarbazepine acetate (ESL) is a new antiepileptic drug (AED) and an analogue to carbamazepine (CBZ) and oxcarbazepine (OXC). In this study, we evaluate initial therapeutic response to ESL and events in the change from CBZ and OXC. METHODS: We evaluated 61 patients with a broad spectrum of drug-resistant epilepsies in a cross-sectional study. The switch from CBZ and OXC to ESL was carried out in a single night at ratios of 1:1.3 and 1:1mg respectively. RESULTS: The most common form of epilepsy was temporal lobe epilepsy (62.3%). The most common aetiology was mesial temporal sclerosis (26.2%). Mean follow-up time was 4.7±3.2 months. In 40 patients with a minimum follow-up period of 3 months, monthly median seizure frequency dropped by 63.6% (P<.001) and a reduction of 80% or more was recorded in 30%. Adverse events (AEs) occurred in 54%; all appeared during the titration phase. They were more frequent at doses in excess of 800mg (73.9% vs. 47.4%; P=.042). The most common AE was dizziness (34.4%), which was commonly associated with VPA, LTG and/or LCS consumption (19.2% vs. 45.7%; P=.031). The retention rate at 3 months was 75.4%. A total of 25 patients replaced CBZ or OXC treatment with ESL; any AEs were transient (69.2% for CBZ and 33% for OXC; P=.073). At 3 months after the treatment change, median seizure frequency had decreased by 20% (P<.075). CONCLUSIONS: ESL is effective in the treatment of focal epilepsies and its early retention rate is > 70%. AEs occurred during the titration phase and corresponded to associated AEDs. A rapid change from CBZ and OXC to ESL treatment can be safely performed.

The plant-associated Bacillus amyloliquefaciens strains MEP2 18 and ARP2 3 capable of producing the cyclic lipopeptides iturin or surfactin and fengycin are effective in biocontrol of sclerotinia stem rot disease.

AIMS: This work was conducted to identify the antifungal compounds produced by two previously isolated Bacillus sp. strains: ARP(2) 3 and MEP(2) 18. Both strains were subjected to further analysis to determine their taxonomic position and to identify the compounds responsible for their antifungal activity as well as to evaluate the efficiency of these strains to control sclerotinia stem rot in soybean. METHODS AND RESULTS: The antifungal compounds were isolated by acid precipitation of cell-free supernatants, purified by RP-HPLC and then tested for antagonistic activity against Sclerotinia sclerotiorum. Mass spectra from RP-HPLC eluted fractions showed the presence of surfactin C(15) , fengycins A (C(16) -C(17)) and B (C(16)) isoforms in supernatants from strain ARP(2) 3 cultures, whereas the major lipopeptide produced by strain MEP(2) 18 was iturin A C(15) . Alterations in mycelial morphology and sclerotial germination were observed in the presence of lipopeptides-containing supernatants from Bacillus strains cultures. Foliar application of Bacillus amyloliquefaciens strains on soybean plants prior to S. sclerotiorum infection resulted in significant protection against sclerotinia stem rot compared with noninoculated plants or plants inoculated with a nonlipopeptide-producing B. subtilis strain. CONCLUSIONS: Both strains, renamed as B. amyloliquefaciens ARP(2) 3 and MEP(2) 18, were able to produce antifungal compounds belonging to the cyclic lipopeptide family. Our data suggest that the foliar application of lipopeptide-producing B. amyloliquefaciens strains could be a promising strategy for the management of sclerotinia stem rot in soybean. SIGNIFICANCE AND IMPACT OF THE STUDY: Sclerotinia stem rot was ranked as one of the most severe soybean disease in Argentina and worldwide. The results of this study showed the potential of B. amyloliquefaciens strains ARP(2) 3 and MEP(2) 18 to control plant diseases caused by S. sclerotiorum.

High prevalence of the GSTM3*A/B polymorphism in sub-Sarahan African populations

A 3-bp insertion/deletion polymorphism in intron 6 of GSTM3 (rs1799735, GSTM3*A/*B) affects the activity of the phase 2 xenobiotic metabolizing enzyme GSTM3 and has been associated with increased cancer risk. The GSTM3*B allele is rare or absent in Southeast Asians, occurs in 5-20 percent of Europeans but was detected in 80 percent of Bantu from South Africa. The wide genetic diversity among Africans led us to investigate whether the high frequency of GSTM3*B prevailed in other sub-Saharan African populations. In 168 healthy individuals from Angola, Mozambique and the São Tomé e Príncipe islands, the GSTM3*B allele was three times more frequent (0.74-0.78) than the GSTM3*A allele (0.22-0.26), with no significant differences in allele frequency across the three groups. We combined these data with previously published results to carry out a multidimensional scaling analysis, which provided a visualization of the worldwide population affinities based on the GSTM3 *A/*B polymorphism.

High prevalence of the GSTM3*A/B polymorphism in sub-Sarahan African populations.

A 3-bp insertion/deletion polymorphism in intron 6 of GSTM3 (rs1799735, GSTM3*A/*B) affects the activity of the phase 2 xenobiotic metabolizing enzyme GSTM3 and has been associated with increased cancer risk. The GSTM3*B allele is rare or absent in Southeast Asians, occurs in 5-20% of Europeans but was detected in 80% of Bantu from South Africa. The wide genetic diversity among Africans led us to investigate whether the high frequency of GSTM3*B prevailed in other sub-Saharan African populations. In 168 healthy individuals from Angola, Mozambique and the São Tomé e Príncipe islands, the GSTM3*B allele was three times more frequent (0.74-0.78) than the GSTM3*A allele (0.22-0.26), with no significant differences in allele frequency across the three groups. We combined these data with previously published results to carry out a multidimensional scaling analysis, which provided a visualization of the worldwide population affinities based on the GSTM3 *A/*B polymorphism.

Antagonism of the cannabinoid CB-1 receptor protects rat liver against ischaemia-reperfusion injury complicated by endotoxaemia.

BACKGROUND/AIM: Endotoxaemia can complicate hepatic ischaemia-reperfusion (IR) injury. Endocannabinoids appear to modulate the haemodynamic alterations and cytokine response induced by lipopolysaccharide (LPS). Thus, we aimed to determine the effect of the endocannabinoid CB1-receptor antagonist Rimonabant in a model of hepatic IR injury complicated by endotoxaemia. METHODS: Sprague-Dawley rats pre-treated with Rimonabant 3 or 10 mg/kg or vehicle underwent partial hepatic IR and lipopolysaccharide (LPS) injection at reperfusion. Liver injury was evaluated by serum alanine aminotransferase (ALT) and necrotic-cell count. The inflammatory response was investigated by assessing hepatic neutrophil infiltration, tumour necrosis factor alpha (TNFalpha), interferon gamma (IFNgamma), interleukin 6 (IL6), and suppressor of cytokine signalling (SOCS) 1 and SOCS3 gene expression by real-time polymerase chain reaction (RT-PCR). Systolic blood pressure and hepatic blood flow were measured as haemodynamic parameters. Finally, lipid peroxidation, glutathione status, and immunoreactive CB1 receptor expression in the liver were also determined. RESULTS: Liver injury and neutrophil infiltration occurring in the late-phase of LPS-enhanced IR were significantly reduced by CB1-receptor antagonism. Rimonabant-treated rats showed significantly higher gene expression of IFNgamma, IL6, SOCS1 and SOCS3 in "early" reperfusion, while that of TNFalpha was reduced. These findings were associated with increased STAT3 phosphorylation. Furthermore, CB1-receptor antagonism significantly improved the oxidative injury and haemodynamic alterations occurring during reperfusion in untreated rats. Finally, CB1-receptor immunoreactivity was upregulated early after reperfusion. CONCLUSIONS: This study demonstrates that CB1-receptor antagonism protects the liver against LPS-enhanced IR injury by interfering with the inflammatory response that causes the late, neutrophil-dependent phase of reperfusion injury, although the prevention of the transient endotoxin-related hypotension occurring early during reperfusion may be also involved.

Effects of granulocyte colony stimulating-factor in a rat model of acute liver injury.

BACKGROUND/AIM: Controversial experimental observations suggest that granulocyte colony stimulating-factor may promote hepatic regeneration after hepatectomy and chemical injury either by directly stimulating adult liver cells or facilitating the mobilization of bone marrow cells and their homing to the liver. We investigated whether different schedules of granulocyte colony stimulating-factor administration protect against experimental acute liver injury. METHODS: Acute liver injury was induced in Sprague-Dawley fed rats by injecting a single intraperitoneal dose of carbon tetrachloride. Recombinant human granulocyte colony stimulating-factor or vehicle was given daily after intoxication (4 days) or before (7 days) and after carbon tetrachloride administration. Liver injury and regeneration were assessed 2 and 4 days after damage. Bone marrow cells mobilization was evaluated by the white blood cell count and the assessment of circulating clonogenic haematopoietic progenitors (colony forming unit-cells). RESULTS: In this experimental model, although granulocyte colony stimulating-factor induced the significant mobilization of colony forming unit-cells, the study cytokine had no effect on liver injury (serum alanine amino transaminase level and necrotic index) and liver regeneration (mitotic index and bromodeoxyuridine incorporation), regardless of the administration schedule. CONCLUSIONS: This study does not support the conclusion that: (1) granulocyte colony stimulating-factor exerts a protective effect against toxic-induced, non-lethal acute liver injury and (2) promotes hepatocyte regeneration.

Oxidative injury in rat fatty liver exposed to ischemia-reperfusion is modulated by nutritional status.

BACKGROUND AND AIMS: Oxidative stress contributes to ischemia-reperfusion injury in fatty livers. This study aimed to determine whether glycogen depletion influences this oxidative injury and whether the administration of glucose can be protective. METHODS: Rats with choline deficiency-induced fatty liver underwent hepatic ischemia-reperfusion. Experimental groups: (1) fed rats; (2) 18 h fasted rats; (3) 18 h fasted rats supplemented with glucose prior to surgery. The thiobarbituric acid-reactive substances, protein carbonyls and total glutathione concentrations were measured in liver tissue and isolated mitochondria as parameters of oxidative stress before and after ischemia and during reperfusion. The mitochondrial F1-ATPase content and the serum alanine transaminase were also determined. RESULTS: With respect to fed rats, fasted rats exhibited an increased oxidative injury in both liver tissue and isolated mitochondria throughout the experiment with the only exception of thiobarbituric acid-reactive substances, which were not affected by the nutritional status in liver tissue. Fasted rats showed a significantly lower F1-ATPase content and higher alanine transaminase levels. Glucose supplementation significantly reduced the fasting-associated exacerbation of oxidative stress and liver injury and the F1-ATPase exhaustion. CONCLUSIONS: These data indicate that the pre-existing hepatic glycogen content modulates the oxidative damage in rat fatty livers exposed to ischemia-reperfusion injury and that the energetic substrate supplementation may represent a clinically feasible protective strategy.

Diagnostic dilemmas in biliary strictures mimicking cholangiocarcinoma.

BACKGROUND/AIMS: Bile duct strictures may be malignant or benign. In the absence of previous biliary surgery a precise preoperative diagnosis is often difficult, in particular when a tumor mass is absent in the preoperative radiologic findings. METHODOLOGY: A review of 179 patients observed between 1982 and 2001 by the same surgical team with a preoperative diagnosis of malignant stricture of the biliary tree. A surgical procedure was performed in 153 of these cases. RESULTS: The presence of a malignant stricture was confirmed by final pathologic examination in 32 of 38 cases (96%) in which a curative resection was performed. A final diagnosis of inflammatory stricture secondary to choledocholithiasis was made in 3 of the remaining 6 cases (4%), along with one case each of sclerosing cholangitis, granular cell tumor and Mirizzi's syndrome, respectively. CONCLUSIONS: Precise preoperative evaluation of biliary structures can be very difficult when a tumor mass is absent. Despite the use of invasive procedures and new techniques such as magnetic resonance cholangiopancreatography, a false-positive rate of 4% may be expected. However, whenever a malignancy is not definitely excluded, biliary strictures should be treated as a cholangiocarcinoma.

Mirizzi syndrome with cholecysto-choledocal fistula with a high CA19-9 level mimicking biliary malignancies: a case report.

Mirizzi syndrome type II is a form of obstructive jaundice caused by a stone impacted in the gallbladder neck or the cystic duct that impinges on the common hepatic duct with a cholecysto-choledochal fistula. Preoperative recognition is necessary to prevent injury to the common duct during surgery. We present a patient with an operative diagnosis of type II Mirizzi syndrome, which was not originally indicated in the preoperative work-up; in particular endoscopic retrograde cholangiopancreatography showed stenosis of the middle third of the hepatic duct along with markedly elevated serum CA19-9 levels (up to 35,000 U/mL). Surgical specimen examination did not reveal the presence of neoplasia. We performed cholecystectomy and a jejunal loop was brought up and anastomosed to the common duct at the hilar level in a Roux-en-Y fashion. In cases such as ours with extensive fibrosis and inflamed tissue mimicking cholangiocarcinoma or gallbladder carcinoma, a wide hepaticojejunostomy is required to establish adequate biliary drainage.

Fifteen-year experience with pediatric renal transplantation at the Montefiore Medical Center.

At Montefiore Medical Center, 140 pediatric recipients have received 155 renal allografts over a 16-year period with an overall 6% mortality. Graft survival was not significantly different based upon race or sex of recipient. Graft survival was significantly better for first time transplants and the youngest recipients. Graft survival was significantly improved using Tacrolimus immunosuppression.