Risk Factors for Postrepair Elevated Mitral Gradient: A Post-hoc Analysis of a Randomized Trial.

BACKGROUND: Predischarge elevated mean mitral gradients (>5 mm Hg) may occur after repair for degenerative mitral regurgitation. We sought to identify risk factors associated with elevated gradients and to evaluate its impact on functional outcomes at 12 months in this subanalysis of the Canadian Mitral Research Alliance CardioLink-2 trial. METHODS: One hundred four patients with degenerative mitral regurgitation undergoing mitral repair were randomized to either a leaflet resection or preservation strategy. Logistic regression was used to identify risk factors associated with an elevated gradient. Functional outcomes at 12 months were compared between participants with and without elevated gradients. RESULTS: Elevated gradients was identified in 15 participants (14.4%), which was not significantly different based on allocation to each repair strategy (P = .10). Patients with elevated gradients were more likely to be women (odds ratio [OR], 4.28; 95% confidence interval [CI], 1.29-14.19; P = .02) and to have a lower preoperative hemoglobin level (OR, 0.93; 95% CI, 0.89-0.98; P = .01) and smaller intercommissural diameter (OR, 0.86; 95% CI, 0.76-0.97; P = .02) and mitral annuloplasty size (OR, 0.71; 95% CI, 0.57-0.87; P = .001). The ratio of intercommissural diameter-to-annuloplasty size was similar between those with and without elevated gradients (both 0.8 ± 0.1, P = .69). At 12 months those with elevated gradients had a worse New York Heart Association functional status (P = .0001), lower peak oxygen saturation in exercise test (P = .01), smaller body weight-walk distance product (P = .02), and higher Borg scale (P = .01) in the 6-minute walk test. CONCLUSIONS: Female gender, smaller mitral anatomy sizes, and lower preoperative hemoglobin levels were associated with postoperative elevated mitral gradients, which was in turn were associated with reduced functional status. Further research is warranted to investigate these potential risk factors.

Toward Community Empowerment: The Puerto Rican Ganchero.

People who inject drugs (PWID) who migrate from Puerto Rico (PR) to New York City (NYC) are at elevated risk for hepatitis C (HCV), HIV and drug overdose. There is an urgent need to identify a sustainable path toward improving the health outcomes of this population. Peer-driven HIV/HCV prevention interventions for PWID are effective in reducing risk behaviors. Additionally, the concept of intravention-naturally occurring disease prevention activities among PWID (Friedman, 2004)-is a suitable theoretical framework to cast and bolster PWID-indigenous risk reduction norms and practices to achieve positive health outcomes. From 2017-2019, we conducted an ethnographic study in the Bronx, NYC to identify the injection risks of migrant Puerto Rican PWID, institutional barriers to risk reduction and solutions to these barriers. Study components included a longitudinal ethnography with 40 migrant PWID (e.g., baseline and exit interviews and monthly face-to-face follow-ups for 12 months), two institutional ethnographies (IEs) with 10 migrants and six service providers, and three focus groups (FGs) with another 15 migrant PWID. Data were analyzed using a grounded theory approach. In this article, we present findings from the IEs and FGs, specifically regarding a promising intravention pathway to promote health empowerment among these migrants that leverages an existing social role within their networks: the PR-indigenous ganchero. A ganchero is a vein-finding expert who is paid with drugs or cash for providing injection services. Ethnographic evidence from this study suggests that gancheros can occupy harm reduction leadership roles among migrant Puerto Rican PWID, adapting standard overdose and HIV/HCV prevention education to the specific experiences of their community. We conclude by noting the culturally appropriate risk reduction service delivery improvements needed to mitigate the health vulnerabilities of migrants and provide a roadmap for improving service delivery and identifying future research avenues.

Predictors of recurrence after durable pulmonary vein isolation for paroxysmal atrial fibrillation.

AIMS: Catheter ablation of paroxysmal atrial fibrillation (AF) reduces AF recurrence, AF burden, and improves quality of life. Data on clinical and procedural predictors of arrhythmia recurrence are scarce and are flawed by the high rate of pulmonary vein reconnection evidenced during repeat procedures after pulmonary vein isolation (PVI). In this study, we identified clinical and procedural predictors for AF recurrence 1 year after CLOSE-guided PVI, as this strategy has been associated with an increased PVI durability. METHODS AND RESULTS: Patients with paroxysmal AF, who received CLOSE-guided PVI and who participated in a prospective trial in our centre, were included in this study. Uni- and multivariate models were plotted to find clinical and procedural predictors for AF recurrence within 1 year. Three hundred twenty-five patients with a mean age of 63 years (CHA2DS2VASc 1 [1-3], left atrium diameter 41 ± 6 mm) were included. About 60.9% were male individuals. After 1 year, AF recurrence occurred in 10.5% of patients. In a binary logistic regression analysis, the diagnosis-to-ablation time (DAT) was found to be the strongest predictor of AF recurrence (P = 0.011). Diagnosis-to-ablation time ≥1 year was associated with a nearly two-fold increased risk for developing AF recurrence. CONCLUSION: The DAT is the most important predictor of arrhythmia recurrence in low-risk patients treated with durable pulmonary vein isolation for paroxysmal AF. Whether reducing the DAT could improve long-term outcomes should be investigated in another trial.

Randomized, Controlled Trial Comparing Mitral Valve Repair With Leaflet Resection Versus Leaflet Preservation on Functional Mitral Stenosis: The CAMRA CardioLink-2 Study.

BACKGROUND: Equipoise exists between the use of leaflet resection and preservation for surgical repair of mitral regurgitation caused by prolapse. We therefore performed a randomized, controlled trial comparing these 2 techniques, particularly in regard to functional mitral stenosis. METHODS: One hundred four patients with degenerative mitral regurgitation surgically amenable to either leaflet resection or preservation were randomized at 7 specialized cardiac surgical centers. Exclusion criteria included anterior leaflet or commissural prolapse, as well as a mixed cause for mitral valve disease. Using previous data, we determined that a sample size of 88 subjects would provide 90% power to detect a 5-mm Hg difference in mean mitral valve gradient at peak exercise, assuming an SD of 6.7 mm with a 2-sided test with α=5% and 10% patient attrition. The primary end point was the mean mitral gradient at peak exercise 12 months after repair. RESULTS: Patient age, proportion who were female, and Society of Thoracic Surgeons risk score were 63.9±10.4 years, 19%, and 1.4±2.8% for those who were assigned to leaflet resection (n=54), and 66.3±10.8 years, 16%, and 1.9±2.6% for those who underwent leaflet preservation (n=50). There were no perioperative deaths or conversions to replacement. At 12 months, moderate mitral regurgitation was observed in 3 subjects in the leaflet resection group and 2 in the leaflet preservation group. The mean transmitral gradient at 12 months during peak exercise was 9.1±5.2 mm Hg after leaflet resection and 8.3±3.3 mm Hg after leaflet preservation (P=0.43). The participants had similar resting peak (8.3±4.4 mm Hg versus 8.4±2.6 mm Hg; P=0.96) and mean resting (3.2±1.9 mm Hg versus 3.1±1.1 mm Hg; P=0.67) mitral gradients after leaflet resection and leaflet preservation, respectively. The 6-minute walking distance was 451±147 m for those in the leaflet resection versus 481±95 m for the leaflet preservation group (P=0.27). CONCLUSIONS: In this adequately powered randomized trial, repair of mitral prolapse with either leaflet resection or leaflet preservation was associated with similar transmitral gradients at peak exercise at 12 months postoperatively. These data do not support the hypothesis that a strategy of leaflet resection (versus preservation) is associated with a risk of functional mitral stenosis. Registration: URL: https://www.clinicaltrials.gov; Unique identifier NCT02552771.

A dimensional investigation of error-related negativity (ERN) and self-reported psychiatric symptoms.

Alterations in error processing are implicated in a range of DSM-defined psychiatric disorders. For instance, obsessive-compulsive disorder (OCD) and generalised anxiety disorder show enhanced electrophysiological responses to errors-i.e. error-related negativity (ERN)-while others like schizophrenia have an attenuated ERN. However, as diagnostic categories in psychiatry are heterogeneous and also highly intercorrelated, the precise mapping of ERN enhancements/impairments is unclear. To address this, we recorded electroencephalograms (EEG) from 196 participants who performed the Flanker task and collected scores on 9 questionnaires assessing psychiatric symptoms to test if a dimensional framework could reveal specific transdiagnostic clinical manifestations of error processing dysfunctions. Contrary to our hypothesis, we found non-significant associations between ERN amplitude and symptom severity of OCD, trait anxiety, depression, social anxiety, impulsivity, eating disorders, alcohol addiction, schizotypy and apathy. A transdiagnostic approach did nothing to improve signal; there were non-significant associations between all three transdiagnostic dimensions (anxious-depression, compulsive behaviour and intrusive thought, and social withdrawal) and ERN magnitude. In these same individuals, we replicated a previously published transdiagnostic association between goal-directed learning and compulsive behaviour and intrusive thought. Possible explanations discussed are (i) that associations between the ERN and psychopathology might be smaller than previously assumed, (ii) that these associations might depend on a greater level of symptom severity than other transdiagnostic cognitive biomarkers, or (iii) that task parameters, such as the ratio of compatible to incompatible trials, might be crucial for ensuring the sensitivity of the ERN to clinical phenomena.

Orientation Matters: Polarization Dependent IR Spectroscopy of Collagen from Intact Tendon Down to the Single Fibril Level.

Infrared (IR) spectroscopy has been used for decades to study collagen in mammalian tissues. While many changes in the spectral profiles appear under polarized IR light, the absorption bands are naturally broad because of tissue heterogeneity. A better understanding of the spectra of ordered collagen will aid in the evaluation of disorder in damaged collagen and in scar tissue. To that end, collagen spectra have been acquired with polarized far-field (FF) Fourier Transform Infrared (FTIR) imaging with a Focal Plane Array detector, with the relatively new method of FF optical photothermal IR (O-PTIR), and with nano-FTIR spectroscopy based on scattering-type scanning near-field optical microscopy (s-SNOM). The FF methods were applied to sections of intact tendon with fibers aligned parallel and perpendicular to the polarized light. The O-PTIR and nano-FTIR methods were applied to individual fibrils of 100-500 nm diameter, yielding the first confirmatory and complementary results on a biopolymer. We observed that the Amide I and II bands from the fibrils were narrower than those from the intact tendon, and that both relative intensities and band shapes were altered. These spectra represent reliable profiles for normal collagen type I fibrils of this dimension, under polarized IR light, and can serve as a benchmark for the study of collagenous tissues.

Injection risk norms and practices among migrant Puerto Rican people who inject drugs in New York City: The limits of acculturation theory.

BACKGROUND: Among people who inject drugs (PWID) in New York City (NYC), racial minorities are disproportionately infected with HIV and hepatitis C (HCV). Prior research has shown that PWID who started injecting drugs in Puerto Rico (P.R.) tend to maintain the risky injection behaviors learned there. This study identifies the P.R.-native norms supporting the continued injection risk behavior of migrant Puerto Rican PWID in NYC to inform a culturally appropriate risk-reduction intervention. METHODS: 40 migrant Puerto Rican PWID were recruited in NYC for a longitudinal qualitative study. The sample was stratified to include 20 migrants with <3 years in NYC and 20 migrants with >3-6 years in NYC. Time-location sampling was used to curb possible network bias in recruitment. Over 12 months, migrants completed semi-structured interviews at baseline, monthly follow-ups, and study exit. Analyses were guided by grounded theory. RESULTS: Most participants (90%) reported having had chronic HCV, and 22.5% reported being HIV-positive. Syringe- and cooker-/cotton-sharing were widespread in both P.R. and NYC. The ubiquitous practice of cleaning used syringes by "water-rinsing and air-blowing" was guided by a normative belief, learned in P.R., that "water and air kill HIV." Sterile syringe use was not a priority. HCV was not a concern. P.R.-native abstinence-only narratives discouraged opioid agonist treatment (OAT) enrollment among recent migrants (≤3 years). Experiences with drug dealers, prison-power groups, and injection doctors ("Gancheros") in P.R. influenced migrants' injection risk behavior in NYC. Those who were Gancheros in P.R. continued working as Gancheros in NYC. CONCLUSIONS: Injection risks make migrant Puerto Rican PWID in NYC vulnerable to HIV/HCV. Harm reduction programs should pay closer attention to the rationales behind these injection risks. A risk-reduction intervention that incorporates the Ganchero figure may be a credible way to help migrants reduce injection risk and accept OAT and syringe exchange programs (SEP).

Ultrastructural and SINS analysis of the cell wall integrity response of Aspergillus nidulans to the absence of galactofuranose.

With lethal opportunistic fungal infections on the rise, it is imperative to explore new methods to examine virulence mechanisms. The fungal cell wall is crucial for both the virulence and viability of Aspergillus nidulans. One wall component, Galf, has been shown to contribute to important fungal processes, integrity of the cell wall and pathogenesis. Here, we explore gene deletion strains lacking the penultimate enzyme in Galf biosynthesis (ugmAΔ) and the protein that transports Galf for incorporation into the cell wall (ugtAΔ). In applying gene deletion technology to the problem of cell wall integrity, we have employed multiple micro- and nano-scale imaging tools, including confocal fluorescence microscopy, electron microscopy, X-Ray fluorescence and atomic force microscopy. Atomic force microscopy allows quantification of ultrastructural cell wall architecture while near-field infrared spectroscopy provides spatially resolved chemical signatures, both at the nanoscale. Here, for the first time, we demonstrate correlative data collection with these two emerging modalities for the multiplexed in situ study of the nanoscale architecture and chemical composition of fungal cell walls.

Randomised trial of mitral valve repair with leaflet resection versus leaflet preservation on functional mitral stenosis (The CAMRA CardioLink-2 Trial).

BACKGROUND: The gold-standard treatment of severe mitral regurgitation (MR) due to degenerative disease is valve repair, which is surgically performed with either a leaflet resection or leaflet preservation approach. Recent data suggest that functional mitral stenosis (MS) may occur following valve repair using a leaflet resection strategy, which adversely affects patient prognosis. A randomised comparison of these two approaches to mitral repair on functional MS has not been conducted. METHODS AND ANALYSIS: This is a prospective, multicentre randomised controlled trial designed to test the hypothesis that leaflet preservation leads to better preservation of mitral valve geometry, and therefore, will be superior to leaflet resection for the primary outcome of functional MS as assessed by 12-month mean mitral valve gradient at peak exercise. Eighty-eight patients with posterior leaflet prolapse will be randomised intraoperatively once deemed by the operating surgeon to feasibly undergo mitral repair using either a leaflet resection or leaflet preservation approach. Secondary end points include comparison of repair strategies with regard to mitral valve orifice area, leaflet coaptation height, 6 min walk test and a composite major adverse event end point consisting of recurrent MR ≥2+, death or hospital readmission for congestive heart failure within 12 months of surgery. ETHICS AND DISSEMINATION: Institutional ethics approval has been obtained from all enrolling sites. Overall, there remains clinical equipoise regarding the mitral valve repair strategy that is associated with the least likelihood of functional MS. This trial hopes to introduce high-quality evidence to help surgical decision making in this context. TRIAL REGISTRATION NUMBER: NCT02552771.

Coumatetralyl resistance of Rattus tanezumi infesting oil palm plantations in Indonesia.

Rodent control is an important issue in human health and agriculture. Oil palm plantations are rapidly expanding in Indonesia and this is having a major economic and ecological impact. Rodent control in oil palm plantations is based principally on the use of anti-vitamin K (AVK), the main anticoagulant used being coumatetralyl, a first-generation AVK. We conducted a comparative study in two well established oil palm plantations in Indonesia: (1) one without chemical control in Riau and (2) another with intensive coumatetralyl use on Bangka Island. Rat species were identified by the molecular barcoding method. Susceptibility to coumatetralyl was then assessed within the two populations and we screened for mutations in vkorc1, which encodes the molecular target of AVK. Different species were found in the two areas: Rattus tiomanicus in Riau, and a mix of R. tanezumi and a close relative one in Bangka. The rats in Riau were much more susceptible to coumatetralyl than those in Bangka. This study is the first to demonstrate physiological tolerance to AVK in these species. vkorc1 displayed low levels of polymorphism, and no SNP was associated with the high-tolerance phenotypes of R. tanezumi clade, even those exposed to very high concentrations (32 × the effective dose of 0.36 mg kg(-1)). The biochemical basis of this tolerance remains unknown, but may involve the vkorc1 promoter and/or cytochrome P450 metabolism. We discuss our results and the selective role of anticoagulant use in the occurrence of phenotypic tolerance.

VKORC1 mutations detected in patients resistant to vitamin K antagonists are not all associated with a resistant VKOR activity.

BACKGROUND: The VKORC1 gene codes for the VKORC1 enzyme, which is responsible for the reduction of vitamin K epoxide into vitamin K. VKORC1 enzyme is the target of vitamin K antagonists (VKA). Twenty-eight rare single mutations in the VKORC1 coding sequence have been reported from resistant patients receiving unusually high doses of VKA to achieve therapeutic anticoagulation. OBJECTIVES: It has been suggested that these mutations are responsible for the resistant phenotype, while biochemical consequences of these mutations on the VKORC1 enzyme have not yet been evaluated. Therefore, the aim of this study was to investigate the causality of the VKORC1 mutations in the resistance phenotype. METHODS: Wild-type VKORC1 and its spontaneous mutants were expressed in Pichia pastoris and susceptibility to VKA was assessed by the in vitro determination of kinetic and inhibition constants. RESULTS AND CONCLUSIONS: The in vitro analysis revealed that six mutations only (A26P, A41S, V54L, H68Y, I123N and Y139H) were associated with increase in K(i) , suggesting their involvement in the resistance phenotype observed in patients. A41S and H68Y led to selective resistance, respectively, to indane-1,3-dione and 4-hydroxycoumarine derivatives. The other mutations did not increase the K(i). Furthermore, 10 mutations (S52L, S52W, W59L, W59R, V66M, V66G, G71A, N77S, N77T and L128R) led to an almost complete loss of activity. These results suggest the existence of other resistance mechanisms.

Streamlining the medication process improves safety in the intensive care unit.

BACKGROUND: Multiple interventions were made to optimize the medication process in our intensive care unit (ICU). 1 Transcriptions from the medical order form to the administration plan were eliminated by merging both into a single document; 2 the new form was built in a logical sequence and was highly structured to promote completeness and standardization of information; 3 frequently used drug names, approved units, and fixed routes were pre-printed; 4 physicians and nurses were trained with regard to the correct use of the new form. This study was aimed at evaluating the impact of these interventions on clinically significant types of medication errors. METHODS: Eight types of medication errors were measured by a prospective chart review before and after the interventions in the ICU of a public tertiary care hospital. We used an interrupted time-series design to control the secular trends. RESULTS: Over 85 days, 9298 lines of drug prescription and/or administration to 294 patients, corresponding to 754 patient-days were collected and analysed for the three series before and three series following the intervention. Global error rate decreased from 4.95 to 2.14% (-56.8%, P < 0.001). CONCLUSIONS: The safety of the medication process in our ICU was improved by simple and inexpensive interventions. In addition to the optimization of the prescription writing process, the documentation of intravenous preparation, and the scheduling of administration, the elimination of the transcription in combination with the training of users contributed to reducing errors and carried an interesting potential to increase safety.

[Medication errors on intensive care units: don't underestimate the risks due to transcription]. / Erreurs médicamenteuses aux soins intensifs: ne pas sous-estimer les risques dôs aux transcriptions.

UNLABELLED: INTRODUCTION; Medication errors [ME] can harm patients and increase costs. ME are frequent in the intensive care units (ICU], where patients are critically ill and therefore more vulnerable. Publications about ME in the critical care setting are rare. The differences between settings, the lack of standardized definitions and the use of different methods do not allow transposing published results to a specific ICU. The goal of this observational study is to analyse our local situation in relation to the literature findings and determine improvement opportunities. OUTCOMES: Rates of actual medication error [AME] and potential medication error [PME] per line of drug, and per patient-day. Distribution of errors among eight types considered clinically significant. CONTEXT: Intensive care unit, in a tertiary care hospital. METHOD: Error detection was based on the comparison between the prescriptions, the scheduling of the administrations [PME] and the actual medication administrations [AME). RESULTS: 229 lines with an AME were detected in 4636 lines of drugs administered to 144 patients during 373 patient-days. AME rate per line of drug was 5%. PME rate per line of drug was 17%. AME rate per patient-day was 61%. Dose omissions and not discontinued administrations accounted altogether for more than 50% of the total of AME. CONCLUSIONS: The literature does not consider the transcription stage as a priority target for error reduction, but this work shows that, depending on the context, transcriptions can significantly increase opportunities for errors. As transcription does not add any value, its suppression seems therefore to be an interesting target for medication safety improvement.

[Elements of completeness and results of the first year of registration of the "Registre général des cancers de Lille et de sa région"]. / Éléments d'exhaustivité et résultats pour la première année d'enregistrement du Registre général des cancers de Lille et de sa région.

BACKGROUND: In 2005, following the first cancer plan of the national health authorities, a general cancer registry was established in northern France, in a territory designated as a "zone in proximity to the city of Lille" (ZPL). The aim of the present work was to evaluate the completeness of the registry's first year of incident cancer registration (2005) and to compare the observed cancer incidence in the "ZPL" with the estimated incidence in France. METHODS: Completeness was assessed using the average number of sources per case, the percentage of histological verification and a method of independent case ascertainment (mortality/incidence ratio). A direct standardization on the world population was used to calculate the ZPL/France ratios of standardized incidence rates. Analyses were conducted for 21 cancer sites. RESULTS: In 2005, 3635 cases of invasive cancer were recorded by the registry. The average number of sources per case was 2.7 and histological proof was available for 91.4% of cases. Mortality/incidence ratios showed satisfactory completeness of the data for men for most cancer sites. For women however, for cancer sites for which the number of cases was low, data will have to be confirmed during the subsequent years of observation. A lack of completeness was found for cutaneous melanoma. In men, an overincidence was identified for cancers of lip-mouth-pharynx, larynx, esophagus, lung, liver, bladder, kidney and colon-rectum. In women, an overincidence has been identified for cancers of lip-mouth-pharynx, liver, bladder, colon-rectum, corpus uteri and ovaries. CONCLUSION: The first year of incidence validated at the "Registre général des cancers de Lille et de sa région" shows a completeness of records with regards to studied criteria. The comparison with national data shows an overincidence of cancers related to tobacco and alcohol consumption in the geographical area covered by the registry. The incidence of lip-mouth-pharynx cancer in men is the highest of all French registries.

Fishing destabilizes the biomass flow in the marine size spectrum.

Fishing impacts on marine food webs are predicted by simulations of a size spectrum community model. In this model, predation is determined by predator and prey size and abundance, and drives predator growth and prey mortality. Fishing amplifies temporal oscillations in the biomass flow. Oscillations appear at lower fishing intensity and have wider amplitude when fishing is selective (removes a narrow size range) and/or when large fish are targeted, than when fishing is more balanced (catching a larger size range) or when small fish are targeted. A novel index of size diversity is developed, and is shown to be sensitive to both fishing intensity and selectivity. To avoid unstable food web dynamics with potential harmful consequences for fisheries, limiting both fishing intensity and selectivity might be an appropriate exploitation strategy.

[Can new technologies reduce the rate of medications errors in adult intensive care?]. / Les nouvelles technologies permettent-elles de réduire les erreurs médicamenteuses en soins intensifs adultes?

In the intensive care environment, technology is omnipresent to ensure the monitoring and the administration of critical drugs to unstable patients. Since the early 2000's computerized physician order entry (CPOE), bar code assisted medication administration (BCMA), "smart" infusion pumps (SIP), electronic medication administration record (eMAR) and automated dispensing systems (ADS) have been recommended to reduce medication errors. About ten years later, their implementation rises but remains modest. The objective of this study is to determine the impact of these technologies on the rate of medication errors (ME) in adult intensive care. CPOE allows a strong and significant reduction of ME, especially the least critical ones. Only when adding a clinical decision support system (CDSS), CPOE could allow a reduction of serious errors. Used alone, it could even increase them. The available studies do not have the sufficient power to demonstrate the benefits of SIP or BCMA on ME. However, these devices, reveal practices, such as overriding of alerts. Power or methodology problems and conflicting results do not allow to determine the ability of ADS to reduce the incidence of ME in the intensive care. The studies, investigating these technologies, are not very recent, of limited number and present lacks in their methodology, which does not allow to determine whether they can reduce the incidence of MEs in the adult intensive care. Currently, the benefits appear to be limited which may be explained by the complexity of their integration into the care process. Special attention should be given to the communication between caregivers, the human-computer interface and the caregivers' training.

[A reminder of the structure and function of the skeletal neuromuscular junction]. / Rappels structuraux et fonctionnels de la jonction neuromusculaire squelettique.

The skeletal neuromuscular junction has been considered as a model of chemical synapses due to its relatively simple organization. It is made up of three cellular partners including the motoneuron nerve terminals, the peri-synaptic Schwann cells and a specialized region of skeletal muscle fibers. It has been extensively studied revealing its ultrastructural complexity involving many molecular actors. The neuromuscular junction is a highly specialized structure, optimized for the rapid transmission of information from the presynaptic nerve terminal to the post-synaptic muscle fiber. This rapid transmission requires a very close apposition of plasmic membranes of pre- and post-synaptic partners, and a strict structural and molecular arrangement on both sides of the narrow synaptic cleft separating nerve terminal and muscle membranes. In this short review, we summarize the knowledge regarding pre- and post-synaptic ultrastructural specializations and give an overview of some functional aspects of neuromuscular transmission, including the quantal acetylcholine release process, which will help to better understand the pharmacological actions of botulinum toxins in esthetic and corrective dermatology.

Subclinical doses of T-2 toxin impair acquired immune response and liver cytochrome P450 in pigs.

This study was designed to investigate the effect of subclinical doses of T-2 toxin on liver drug-metabolizing enzymes and the immune response. Pigs were offered over a 28-day period either a control diet or diets contaminated with 540, 1324 or 2102microg pure T-2toxin/kg feed. Pigs were immunized with ovalbumin and subsequent humoral and cellular immune responses measured. Monooxygenase and transferase enzyme activities and protein expression were investigated in liver tissue samples. Pigs fed 1324 or 2102microg T-2toxin/kg feed exhibited reduced anti-ovalbumin antibody production without significant alteration to specific lymphocyte proliferation. The livers of pigs exposed to T-2 toxin presented normal cytochrome P450 content, UGT 1A and P450 2B, 2C or 3A protein expression, and glutathione- and UDP glucuronosyl-transferase activities. However, P450 1A related activities (ethoxyresorufin O-deethylation and benzo-(a)-pyrene hydroxylation) were reduced for all pigs given T-2 toxin, with P450 1A protein expression decreased in pigs fed the highest dose. In addition T-2 toxin exposure reduced certain N-demethylase activities. The results of this study confirm the immunotoxic properties of T-2 toxin, in particular toward the humoral immune response. The reduction of monooxygenase activities, even though the liver presented no tissue lesion or lipid peroxidation, suggests possible deleterious interactions of T-2 toxin with these enzymes.

Oxaliplatin, an anticancer agent that affects both Na+ and K+ channels in frog peripheral myelinated axons.

The use of oxaliplatin, a relatively new chemotherapeutic agent, is somewhat limited since it produces a specific peripheral neuropathy regarding other neurotoxic anticancer platinum analogues. In order to investigate the mechanism of such a peripheral neuropathy, the effects of 1-100 micromol/l oxaliplatin were assessed on the nodal ionic currents of single frog myelinated axons as a model of peripheral excitable membranes. Oxaliplatin decreased both Na(+) and K(+) currents in a dose-dependent manner and within 5-10 min, without producing any marked changes in the current kinetics. It was about three to eight times more effective in reducing the Na(+) than the K(+) current. In addition, it shifted the voltage-dependence of both Na(+) and K(+) conductances towards negative membrane potentials. A negative shift in the steady-state inactivation-voltage curve of the peak Na(+) current was also observed in the presence of oxaliplatin. These effects were not reversed by washing the myelinated axons with an oxaliplatin-free solution for at least 30 min. It is concluded that oxaliplatin modifies the voltage-dependent ionic channels mainly by altering the external surface membrane potential. The knowledge of such a mechanism may help to counteract the neurotoxic action of this anticancer agent.