Evidence of lowest brain penetration of an antiemetic drug, metopimazine, compared to domperidone, metoclopramide and chlorpromazine, using an in vitro model of the blood-brain barrier.

PURPOSE: The objective of the current study was to determine the ability of some antiemetic compounds to cross the blood-brain barrier (BBB) and thereby to determine possible side effects of compounds for the central nervous system (CNS). METHODS: We compared the brain penetration of some antiemetic compounds using an in vitro BBB model consisting in brain capillary endothelial cells co-cultured with primary rat glial cells. RESULTS: This study clearly demonstrated that the metopimazine metabolite, metopimazine acid, has a very low brain penetration, lower than metopimazine and even less than the other antiemetic compounds tested in this study. CONCLUSIONS: The poor brain penetration of metopimazine acid, metopimazine biodisponible form, seems very likely related to the clinically observed difference in therapeutic and safety profile.     

Retrospective analysis of fetal vertebral defects: Associated anomalies,etiologies, and outcome

Our objectives were to describe fetal cases of vertebral defects (VD), assess the diagnostic yield of fetal chromosomal analysis for VD and determine which investigations should be performed when evaluating fetal VD. We performed a retrospective chart review for fetuses with VD seen between 2006 and 2015. Cases were identified from CHU Sainte‐Justine's prenatal clinic visits, postmortem fetal skeletal surveys, and medical records. Cases with neural tube defects were excluded. Sixty‐six fetuses with VD were identified at a mean gestational age of 20 weeks. Forty‐seven (71.2%) had associated antenatal anomalies, most commonly genitourinary, skeletal/limb, and cardiac anomalies. Thirteen mothers (19.7%) had pregestational diabetes (95% CI [10.1%–29.3%]). Fifty‐three cases had chromosomal analysis. Three had abnormal results (5.6%): trisomy 13, trisomy 22, and 9q33.1q34.11 deletion. Thirty‐four (51.5%) pregnancies were terminated, one led to intrauterine fetal demise and 31 (46.9%) continued to term. Of 27 children who survived the neonatal period, 21 had congenital scoliosis and 3 had spondylocostal dysostosis. Seven had developmental delay. In conclusion, prenatal evaluation of fetuses with VD should include detailed morphological assessment (including fetal echocardiogram), maternal diabetes screening, and chromosomal microarray if non‐isolated. Our findings provide guidance about management and counseling after a diagnosis of fetal VD.     

The role of disconnected and extremely insensitive parenting in the development of disorganized attachment: validation of a new measure

Early adverse caregiving experiences constitute an important risk factor for the development of disorganized attachment in infancy, especially extreme insensitivity and frightening behavior associated with an unresolved loss or trauma. Using existing measures for frightening parenting and disrupted communication, we developed a new measure assessing Disconnected and extremely Insensitive Parenting (DIP), in order to investigate the unique contribution of disconnected and extremely insensitive parenting behaviors to infant disorganization. Maternal behavior was assessed during a laboratory session in a low-risk sample of 202 mothers and their infants. Construct and discriminant validity of the DIP was established for both types of parental behavior. Disconnected parental behavior predicted infant disorganization but not organized attachment security, whereas extreme insensitivity was marginally related to organized attachment insecurity in boys but not to attachment disorganization.     

Palliative Resection for Advanced Gastric and Junctional Adenocarcinoma: Which Patients will Benefit from Surgery?

Background

Whereas palliative chemotherapy offers a median survival of approximately 10 months in advanced gastric and junctional adenocarcinoma (AGJA), the survival impact of primary tumor resection is controversial. Our purpose was to identify which AGJA patients benefit from palliative resection.

Methods

In 3,202 AGJA patients scheduled for surgery in 21 French centers between 1997 and 2010, prognostic factors were identified in palliative group and the impact of each combination of these factors on survival was studied.

Results

Surgery was defined as palliative due to solid organ metastasis (5.6 %), localized (4.6 %) or diffuse (2.3 %) peritoneal carcinomatosis (PC), or incomplete tumoral resection (12.8 %). Median survival of AGJA patients resected with a palliative intent (n = 677) was longer than in nonresected patients (n = 532; 11.9 vs. 8.5 months, P < 0.001). Multivariable analyses identified ASA score III-IV (P < 0.001) as a predictor of postoperative mortality and solid organ metastasis (P = 0.009), localized PC (P = 0.004), diffuse PC (P = 0.046), and signet ring cell histology (SRC; P = 0.02) as predictors of survival. Only ASA I–II patients with incomplete resection without metastasis or PC, one site solid organ metastasis without PC, or localized PC without SRC had a survival benefit after palliative surgery with median survivals from 12.0 to 18.3 months. Nonresected ASA I–II patients with same risk factors had median survivals from 3.5 to 8.8 months (P < 0.05 for each).

Conclusions

In AGJA, patient and tumor-related factors should be used to select candidates for palliative surgery in association with chemotherapy.     

Sequential behavior in the rat: role of skill and attention

The serial reaction time task (SRTT) is a well-established experimental tool to study cognitive and neural mechanisms of sequential performance in humans. We have recently developed a rodent version of the human serial reaction time task, in which rats have to respond to visual stimuli by nose-poking into one of four spatial locations in order to obtain food reward. In this task, rats display superior performance under sequential as compared to random conditions of stimulus presentation. Specifically, the subjects are able to profit from sequential regularities in terms of faster reaction times and higher response accuracy. Here, we studied the effects of violating a single stimulus in rats, which had been intensively trained under sequential conditions, and we asked whether these subjects, when confronted with sequence violations, still attend to the actual stimulus order (that is, show correct responses), or whether their behavior has become fully automated (leading to specific incorrect responses to violated stimulus positions). In two independent experiments using partly differing instrumental set-ups, we found that the responses to non-cued violations of single stimulus positions were mostly correct, that is, the animals were apparently attending to the stimuli. Nevertheless, these reaction times were slowed, which probably reflects cognitive resources necessary to respond correctly to the unexpected irregularities. When quantifying the minority of responses, which were incorrect, we found that most of them were directed to the position, where the stimulus would have appeared if the sequence had not been violated. These responses were faster than the correct ones (to the violated stimulus), which indicates that sequential responding had become partly automated. Together, our data show that both, attention and skill play a role for sequential performance in our SRT task, and that they can be dissected by quantification of specific response types. In future work, the neural correlates underlying these functional mechanisms will have to be addressed.     

Effects of high- vs low-dose native vitamin D on albuminuria and the renin–angiotensin–aldosterone system: a randomized pilot study

International Urology and Nephrology - Residual albuminuria is associated with an increased risk of progression to ESKD. We tested whether a supplementation with native vitamin D could reduce...     

Drug specific cytotoxic T-cells in the skin lesions of a patient with toxic epidermal necrolysis

Toxic epidermal necrolysis is an extremely severe drug reaction, manifesting itself by widespread apoptosis of keratinocytes, generally considered to result from Fas/CD95-FasLigand interaction, but of unknown primary mechanism. We looked at the role of cells present in the skin blisters as probable effectors of this immune reaction. In a patient suffering from cotrimoxazole-induced toxic epidermal necrolysis, blister fluid cells were phenotyped by FACS and tested without prior restimulation for cytotoxicity on autologous and allogeneic cells in the presence of the drug. Blister fluid lymphocytes were predominantly CD8+, DR+, CLA+, CD56+ T lymphocytes, perforin positive and expressing preferentially two Vbeta chains of the T cell receptor repertoire. These lymphocytes were cytotoxic only in the presence of the drug towards autologous EBV transformed lymphocytes and towards allogeneic cells sharing HLA-Cw4. Cytotoxicity occurred in the presence of either cotrimoxazole, sulfamethoxazole, or the nitroso metabolite of sulfamethoxazole, but not with the hydroxylamine metabolite of sulfamethoxazole. The lysis was blocked by an anti-MHC class I monoclonal antibody. It was abolished by EGTA and CMA, but neither by anti-fas, brefeldin A, nor by anti-TRAIL receptor monoclonal antibodies, strongly suggesting perforin/granzyme-mediated cytotoxicity, without implication of Fas or TRAIL at this stage. This is direct evidence that T lymphocytes present within the lesions of toxic epidermal necrolysis may exhibit, without any re-stimulation, a drug-specific cytotoxicity against autologous cells. Harboring the markers of classical CTL and MHC class I restriction these lymphocytes reacted against the parent drug and one of its reactive metabolites. These results challenge several current concepts and could support new therapeutic approaches.     

Levetiracetam: preliminary efficacy in generalized seizures

Levetiracetam is a novel antiepileptic drug (AED) with proven efficacy against partial seizures, but there is limited information about its effectiveness against generalized seizures. In animal models, levetiracetam protects against seizures in audiogenic susceptible rodents, and it is effective in the Genetic Absence Epilepsy Rat from Strasbourg, a model of absence seizures. In these models, levetiracetam has a therapeutic index that is higher than those of other AEDs. A number of small open-label studies suggest that levetiracetam reduces seizure frequency in patients with generalized seizures, including primarily generalized seizures and myoclonic seizures. Case reports provide additional information regarding the potential efficacy of levetiracetam in postanoxic, post-encephalitic and progressive myoclonus. Although random-ized controlled studies of patients with generalized seizures have not yet been conducted, on the basis of available information, levetiracetam may be prom-ising in the treatment of generalized seizures.