Impact of music therapy before first-trimester instrumental termination of pregnancy: a randomised controlled trial.

OBJECTIVES: To evaluate the impact of preoperative Music Therapy (MT) on pain in first-trimester termination of pregnancy (TOP) under local anaesthesia. DESIGN: Randomised controlled trial comparing women undergoing a first-trimester TOP under local anaesthesia with or without a preoperative MT session. SETTING: University Hospital of Angers from November 2016 to August 2017. POPULATION: Women who underwent first-trimester TOP under local anaesthesia. METHODS: Women allocated to the MT group underwent a preoperative 20-minute session of MT. MAIN OUTCOME MEASURES: Pain was assessed using a visual analogue scale (VAS) just before the procedure, during the procedure, at the end of the procedure and upon returning to the ward. RESULTS: A total of 159 women were randomised (80 in the MT group, and 79 in the control group). Two women were excluded from the control group and six from the MT group. Therefore, 77 women were analysed in the control group and 74 in the MT group. The intensity of pain was similar in the two groups just before the procedure (VAS 4.0 ± 2.9 versus 3.6 ± 2.5; P = 0.78), during the procedure (VAS 5.3 ± 2.5 versus 4.9 ± 2.9; P = 0.78), at the end of the procedure (VAS 2.7 ± 2.4 versus 2.6 ± 2.4; P = 0.43) and upon returning to the ward (VAS 1.8 ± 2.0 versus 1.5 ± 2.0; P = 0.84). The difference in pain between entering the department and returning to the room after the procedure was similar between the MT and control groups (difference in VAS 0.3 ± 2.5 versus 0.3 ± 2.4; P = 0.92). CONCLUSION: An MT session before a TOP under local anaesthesia procedure resulted in no improvement in patient perception of pain during a first-trimester TOP. TWEETABLE ABSTRACT: Music therapy before first-trimester termination of pregnancy under local anaesthesia did not improve the perception of pain.

Reduced-intensity and non-myeloablative allogeneic stem cell transplantation from alternative HLA-mismatched donors for Hodgkin lymphoma: a study by the French Society of Bone Marrow Transplantation and Cellular Therapy.

Allogeneic stem cell transplantation (allo-SCT) following a non-myeloablative (NMA) or reduced-intensity conditioning (RIC) is considered a valid approach to treat patients with refractory/relapsed Hodgkin lymphoma (HL). When an HLA-matched donor is lacking a graft from a familial haploidentical (HAPLO) donor, a mismatched unrelated donor (MMUD) or cord blood (CB) might be considered. In this retrospective study, we compared the outcome of patients with HL undergoing a RIC or NMA allo-SCT from HAPLO, MMUD or CB. Ninety-eight patients were included. Median follow-up was 31 months for the whole cohort. All patients in the HAPLO group (N=34) received a T-cell replete allo-SCT after a NMA (FLU-CY-TBI, N=31, 91%) or a RIC (N=3, 9%) followed by post-transplant cyclophosphamide. After adjustment for significant covariates, MMUD and CB were associated with significantly lower GvHD-free relapse-free survival (GRFS; hazard ratio (HR)=2.02, P=0.03 and HR=2.43, P=0.009, respectively) compared with HAPLO donors. In conclusion, higher GRFS was observed in Hodgkin lymphoma patients receiving a RIC or NMA allo-SCT with post-transplant cyclophosphamide from HAPLO donors. Our findings suggest they should be favoured over MMUD and CB in this setting.

Randomized phase II study of axitinib versus physicians best alternative choice of therapy in patients with recurrent glioblastoma.

We conducted a randomized, non-comparative, multi center, phase II clinical trial in order to investigate the efficacy of axitinib, an oral small molecule tyrosine kinase inhibitor with high affinity and specificity for the vascular endothelial growth factor receptors, in patients with recurrent glioblastoma following prior treatment with radiation and temozolomide. Forty-four patients were randomly assigned to receive treatment with axitinib (5 mg BID starting dose; N = 22) or "physicians best alternative choice of therapy" that consisted of bevacizumab (N = 20) or lomustine (N = 2). Six-month progression-free survival served as the primary endpoint. The estimated 6-month progression-free survival rate was 34 % (95 % CI 14-54) for patients treated with axitinib and 28 % (95 % CI 8-48) with best alternative treatment; median overall survival was 29 and 17 weeks, respectively. Objective responses according to RANO criteria were documented in 28 % of patients treated with axitinib and 23 % of patients treated with best alternative therapy. A decrease in maximal uptake of 18F-fluoro-ethyL-tyrosine (18F-FET) by the glioblastoma on PET imaging was documented in 85 % of patients at the time of response on axitinib. Corticosteroid treatment could be stopped in four and tapered in seven out of the 15 patients who were treated with steroids at baseline in the axitinib cohort. Most frequent axitinib related grade ≥3 adverse events consisted of fatigue (9 %), diarrhea (9 %), and oral hyperesthesia (4.5 %). We conclude that axitinib has single-agent clinical activity and a manageable toxicity profile in patients with recurrent glioblastoma.

Troubleshooting the rabbit ferric chloride-induced arterial model of thrombosis to assess in vivo efficacy of antithrombotic drugs.

INTRODUCTION: The FeCl3-induced arterial model of thrombosis is one of the most widely used animal models to assess arterial efficacy of new antithrombotic drug candidates. This model is well-established in rodents but in a less extent in the rabbit. In this work, we present a methodology for a rabbit FeCl3-induced arterial model of thrombosis derived from our troubleshooting which allows the generation of reliable efficacy data for new antithrombotic drug candidates. METHODS: Rabbits were administered with heparin 4.5U/kg/min, argatroban 10µg/kg/min or saline by intravenous infusion. The blood flow was monitored using a Doppler flow probe. The time from the application of FeCl3 to the recorded zero blood flow was defined as the time to occlusion, with a maximum recording time of 60min post-FeCl3 application. After 30min of infusion, thrombosis was induced by wrapping a FeCl3-saturated filter paper around the carotid artery caudal to the flow probe. Animals were subject to exclusion criteria based on the visual aspect of the artery FeCl3-induced injury and based on changes in blood flow upon FeCl3 application. RESULTS: Following the application of FeCl3, a mean time to occlusion for saline, heparin and argatroban of 24.3±1.8, 52.5±4.8 and 53.5±4.5min was obtained, respectively. Mean time to occlusion for heparin and argatroban administered groups was significantly different when compared to the saline-treated group (p<0.05). These results for the test compounds represent approximately 80% of the maximum possible prolongation. DISCUSSION: The rabbit FeCl3-induced arterial model of thrombosis presented in this paper derived from our troubleshooting is sensitive and reproducible for the generation of accurate and reliable efficacy data in the assessment of new antithrombotic agents in preclinical drug development.

Cannabidivarin is anticonvulsant in mouse and rat.

BACKGROUND AND PURPOSE: Phytocannabinoids in Cannabis sativa have diverse pharmacological targets extending beyond cannabinoid receptors and several exert notable anticonvulsant effects. For the first time, we investigated the anticonvulsant profile of the phytocannabinoid cannabidivarin (CBDV) in vitro and in in vivo seizure models. EXPERIMENTAL APPROACH: The effect of CBDV (1-100 µM) on epileptiform local field potentials (LFPs) induced in rat hippocampal brain slices by 4-aminopyridine (4-AP) application or Mg(2+) -free conditions was assessed by in vitro multi-electrode array recordings. Additionally, the anticonvulsant profile of CBDV (50-200 mg·kg(-1) ) in vivo was investigated in four rodent seizure models: maximal electroshock (mES) and audiogenic seizures in mice, and pentylenetetrazole (PTZ) and pilocarpine-induced seizures in rats. The effects of CBDV in combination with commonly used antiepileptic drugs on rat seizures were investigated. Finally, the motor side effect profile of CBDV was investigated using static beam and grip strength assays. KEY RESULTS: CBDV significantly attenuated status epilepticus-like epileptiform LFPs induced by 4-AP and Mg(2+) -free conditions. CBDV had significant anticonvulsant effects on the mES (≥100 mg·kg(-1) ), audiogenic (≥50 mg·kg(-1) ) and PTZ-induced seizures (≥100 mg·kg(-1) ). CBDV (200 mg·kg(-1) ) alone had no effect against pilocarpine-induced seizures, but significantly attenuated these seizures when administered with valproate or phenobarbital at this dose. CBDV had no effect on motor function. CONCLUSIONS AND IMPLICATIONS: These results indicate that CBDV is an effective anticonvulsant in a broad range of seizure models. Also it did not significantly affect normal motor function and, therefore, merits further investigation as a novel anti-epileptic in chronic epilepsy models. LINKED ARTICLES: This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8.

[Anaesthesia without anaesthetist?]. / L'anesthésie sans anesthésiste?

The continuing decline in the number of anaesthetists-intensive care physicians means that certain operations need to be performed under the responsibility of urologists alone. These procedures can be performed perfectly safely in selected patients, provided the urologist is aware of the inherent risks of each local and regional anaesthesia or sedation technique.

Estrogen-sensitive oxytocin binding sites are differently regulated by progesterone in the telencephalon and the hypothalamus of the rat.

The localization at the cellular level and the regulation by progesterone of the estrogen-sensitive oxytocin binding sites was studied in the rat telencephalon and the hypothalamus by using quantitative film-autoradiography and histoautoradiography. Male rats (castrated or not) and ovariectomized females (estradiol supplemented or not) were used to characterize these sites and to precise their localization. They were detected in the striatal cell bridges, the olfactory tubercle, the principal nucleus of the bed nucleus of the stria terminalis and the medial nucleus of the amygdala of the telencephalon and in the medial preoptic, the ventromedial and the ventral premammillary nuclei of the hypothalamus. Estrogen administration in addition induced expression of oxytocin binding sites in the major island of Calleja, the anterior hypothalamic area and the terete nucleus. The density of the estrogen-sensitive oxytocin binding sites varied during the estrous cycle, but differently in the telencephalon and the hypothalamus. In the telencephalon it peaked at proestrus 9 h and was already decreased at proestrus 21 h, whereas in the hypothalamus it was similarly high at proestrus 9 h and proestrus 21 h, suggesting the intervention of progesterone in the regulation of the hypothalamic estrogen-sensitive oxytocin binding sites.

Oxytocin and vasopressin binding sites in the hypothalamus of the rat: histoautoradiographic detection.

Localization of oxytocin and vasopressin binding sites has so far been studied in the rat brain by means of film autoradiographs. The availability of selective iodinated ligands with high specific activity allowed us to develop the histoautoradiographical technique and to reinvestigate at the microscopic scale the distribution of these sites in the hypothalamus. Most oxytocin binding sites were localized in delimited nuclei, e.g., the medial preoptic, the ventromedial, the ventral premammillary, the supramammillary, and the medial mammillary nuclei. In addition, a weak diffuse specific labeling occurred in the medial preoptic and the anterior hypothalamic areas. The vasopressin binding sites (of the V1a type) were detected in delimited nuclei, e.g., the suprachiasmatic, the stigmoid, and the arcuate nuclei, but they were also diffusely distributed in the lateral hypothalamic and the dorsochiasmatic areas. The locations of neurohypophysial peptides binding sites detected by light microscopy are compared with those previously obtained by film autoradiography.

Oxytocin receptors on oxytocin neurones: histoautoradiographic detection in the lactating rat.

1. The purpose of the present study was the detection at the cellular scale of the oxytocin (OT) receptors involved in the facilitatory effect of this neuropeptide on its own release during the milk ejection reflex. 2. OT binding sites were demonstrated in brain sections by using a highly selective 125I-labelled OT antagonist detected by film- and histoautoradiography. 3. Film autoradiographs revealed the presence of OT binding sites in the hypothalamic magnocellular (supraoptic, paraventricular and anterior commissural) nuclei in lactating rats, suckled or not. This detection was only possible after acute i.c.v. injection of OT antagonist which probably induced an upregulation of the OT binding sites to autoradiographically detectable levels. 4. Combined application of histoautoradiographic and immunohistochemical techniques showed that the OT binding sites were concentrated on OT magnocellular neurones. Labelling concerned cell bodies and dendrites but not the axons and endings in the pituitary neural lobe. 5. The presently detected somatodendritic autoreceptors on OT neurones probably mediate the facilitatory effect of OT on its own release during the milk ejection reflex.

Correlation between oxytocin neuronal sensitivity and oxytocin-binding sites in the amygdala of the rat: electrophysiological and histoautoradiographic study.

Central nucleus (Ce), basomedial and medial nuclei of the amygdala (AMG), and some parts of the striato-pallidal system, present high densities of oxytocin (OT)-binding sites. In order to examine whether these OT-binding sites are functional receptors, the OT neuronal sensitivity and the presence of OT-binding sites were investigated using electrophysiological and autoradiographical techniques. To identify the AMG cells, electrical stimulation of the oval subnucleus of the bed nucleus of the stria terminalis (Ov) and of the parabrachial nucleus (Pb) were performed. Somatic and auditory sensory stimulations were also tested. OT was applied by iontophoresis during extracellular single unit recordings of cells which were localized in frontal brain sections subsequently used for histoautoradiographic detection of OT-binding sites. Cells responding to Ov nucleus stimulation were located in the AMG, mainly in the Ce nucleus, whereas those responding to Pb nucleus stimulation were distributed in the Ce nucleus and in the postero lateral part of the caudate putamen. Iontophoretic OT application excited 45% of the recorded cells (43/96) among which OT alone activated spontaneous firing rate of 30 and potentiated the L-Glutamate (GLU)-induced activation on 13. These OT-sensitive neurons were located mainly in the AMG and caudate putamen areas containing OT-binding sites. These results strongly suggest that OT-binding sites found in the AMG are functional receptors upon which OT could act as a neurotransmitter and as a neuromodulator to regulate autonomic functions.

Response to chemotherapy after relapse in patients with or without previous adjuvant chemotherapy for breast cancer. The French Epirubicin Study Group.

The French Epirubicin Study Group undertook a retrospective study to evaluate the response rate at relapse, time to treatment failure, and overall survival according to previous CMF-type adjuvant chemotherapy in patients who had taken part in two successive clinical trials. The statistical significance of the comparisons was tested after adjustment for the factors that differed most between the two groups. Patients who had received previous adjuvant chemotherapy had a lower response rate (p = 0.03), a shorter time to treatment failure (p = 0.007), and shorter overall survival after relapse (p = 0.008); overall survival after initial diagnosis was not significantly different. With respect to patients with axillary node metastases at the time of diagnosis (N+ patients), those with previous adjuvant chemotherapy had a lower response rate (p = 0.01) and shorter time to treatment failure (p = 0.02), but overall survival after relapse and after initial diagnosis were not significantly different. This retrospective and descriptive study suggests that chemotherapy is less effective after relapse, as measured by response rate and time to treatment failure, in patients with previous adjuvant chemotherapy.

Premenopausal patients with node-positive resectable breast cancer. Preliminary results of a randomised trial comparing 3 adjuvant regimens: FEC 50 x 6 cycles vs FEC 50 x 3 cycles vs FEC 75 x 3 cycles. The French Adjuvant Study Group.

Anthracyclines are among the most active drugs for the treatment of advanced breast cancer. Epirubicin has been found to be as effective as doxorubicin at equimolar doses but significantly better tolerated, especially in terms of alopecia, leucopenia, and cardiac toxicity. The role of anthracycline-containing regimens in adjuvant treatment of breast cancer has been studied by only a few clinical trial teams. In 1986, the French Adjuvant Study Group (FASG) began a randomised trial aimed to investigate the concept of dose intensity as well as the optimal duration of treatment in patients with early breast cancer. Between 1986 and 1990, 621 patients were included in the trial, of whom 595 were evaluable. Patients were randomised to 1 of 3 treatment groups: Group A (n = 207) received FEC 50 (fluorouracil 500 mg/m2, epirubicin 50 mg/m2 plus cyclophosphamide 500 mg/m2) every 21 days for 6 cycles; Group B (n = 193) received FEC 50 every 21 days for 3 cycles; Group C (n = 195) received FEC 75 (fluorouracil 500 mg/m2, epirubicin 75 mg/m2 plus cyclophosphamide 500 mg/m2) every 21 days for 3 cycles. Locoregional radiotherapy was administered after the third cycle of chemotherapy in all treatment arms. Clinical prognostic factors were similar between treatment groups. Approximately 62% of all patients had 1 to 3 positive lymph nodes; 50% of patients were hormone receptor positive and 73% were Scarff-Bloom Richardson (SBR) grade 2 to 3. Toxicity was evaluated in 595 patients (207, 193 and 195 patients in Groups A, B and C, respectively), who received a total of 2301 chemotherapy cycles.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation from population registry data of health care expenditure during the 6 months after cancer diagnosis.

It is currently estimated in France, that the cost of cancer has risen to $3.8 billion, with an annual growth of 5-10%. This represents approximately 6% of all health expenditure. The data from the Registry of Tumors in the Doubs region have enabled us to make an evaluation of health expenditure, reimbursed by the French Securite Sociale (S.S.), and its distribution in relation to different activities (diagnosis, type of treatment, follow-up, transport), according to cancer site. In 1984, the average cost per patient within the first 6 months of the illness was evaluated at $4,000. The results show major differences for the cancer sites, care facilities and budget items. Diagnosis assessment represents 27% of all expenditure, surgery 37%, radiotherapy, chemotherapy and transport, 11% each. All kinds of expenses are fully reimbursed by the French S.S. and transportation, which at the beginning used to avoid hospitalization, is now used as a comfort system and represents a high cost to the S.S. The different costs for the same illness between private, general public and university hospitals do not reflect a difference in care, but rather different systems of calculating and functioning. Till now there has not been any logical evaluation of care in the French health system.

Characterization of oxytocin-binding sites in primary rat brain cell cultures.

Detection and characterization of oxytocin-binding sites in dissociated brain cell cultures were performed, using a highly selective iodinated oxytocin antagonist [( 125I]OTA). Dissociated cells derived from hypothalamus and extrahypothalamic forebrain of 16-day-old fetal rats were maintained in chemically defined medium in order to enrich the cultures in neuronal cells. Specific binding of [125I]OTA, demonstrated in both hypothalamic and forebrain cell cultures, was temperature- and time-dependent; maximal binding was obtained by incubating the iodinated ligand for 60 min at 37 degrees C. The binding parameter were shown to be identical in both cell type cultures. The Scatchard plot analysis suggested the presence of a single class of binding sites of high affinity (Kd about 0.06 nM) and low binding capacity (Bmax about 4 fmol/dish). The specificity of these binding sites tested in competition experiments revealed that the unlabelled OT antagonist was the most potent in inhibiting specific [125I]OTA binding (Ki = 0.1 nM). A lower affinity, of the nM range was demonstrated for oxytocin (OT), arginine-vasopressin (AVP) and the V1 antagonist, whereas the V2 AVP agonist poorly competed for [125I]OTA binding sites (Ki about 250 nM). In conclusion, the [125I]OTA binding characteristics, identical in both hypothalamic and forebrain cultures, fulfil the classical conditions required for the existence of receptor sites since the binding was reversible, saturable and specific. As these characteristics were similar to those already described in the adult rat, at the central level in hippocampus, and at the periphery in the mammary gland, it could be postulated that [125I]OTA binds to an OT receptor site.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological characteristics and anatomical distribution of [3H]oxytocin-binding sites in the Wistar rat brain studied by autoradiography.

Oxytocin-binding sites were detected by autoradiography on rat brain sections incubated in the presence of the [3H]oxytocin. These sites were characterized pharmacologically using quantitative autoradiography. High pressure liquid chromatography controls of the incubation media indicated that labelling was due to the intact [3H]oxytocin molecule. Pharmacological analysis of different locations (central amygdaloid nucleus, ventral subiculum and ventromedial hypothalamic nucleus) showed that the sites detected had a high affinity for oxytocin and also for arginine-vasopressin. In contrast, some areas known to bind vasopressin intensely, such as suprachiasmatic and lateral septum nuclei, had little or no affinity for oxytocin. Autoradiographs revealed [3H]oxytocin-binding sites in already known brain areas (olfactory centres, ventral subiculum, central amygdaloid nucleus, bed nucleus of the stria terminalis) albeit with more extensive labelling of some of these formations, in particular, the amygdaloid complex. In addition, specific [3H]oxytocin-binding sites were found in areas not yet reported to bind oxytocin, such as the paraventricular thalamic and caudate nuclei. In the hypothalamus, specific binding sites were not detected in the supraoptic and paraventricular nuclei: the only structure labelled was the ventrolateral part of the ventromedial nucleus. Discrepancies between the concentrations of [3H]oxytocin-binding sites, the known distribution of oxytocin-containing endings and electrophysiological data indicate that autoradiography, under our conditions, apparently only reveals some of the oxytocin receptors in the brain. Thus, in the hypothalamus, no relationship can be established between the known effect of oxytocin on oxytocinergic magnocellular neurons and detection of specific [3H]oxytocin-binding sites. Autoradiography may reveal mainly oxytocin-binding sites in areas receiving diverse "parasynaptic" information, where oxytocin might play a modulatory role rather than exerting rapid, short-term effects of the neurotransmitter type.

[Peptidergic control of electrical activities in the magnocellular neurons of the hypothalamus]. / Contrôle peptidergique des activités électriques des neurones magnocellulaires de l'hypothalamus.

Although many peptides have been reported in the vicinity of hypothalamic magnocellular nuclei, their role in the control of neurohypophysial hormone release was only studied for few peptides: opiates, angiotensin II, substance P, CRF, oxytocin and vasopressin. Their effects are briefly recalled and then compared to the more detailed study of their role in the firing pattern of oxytocin and vasopressin neurones. This technique, in some cases, revealed the action site and mechanism of these peptides in the hypothalamo-neurohypophysial system.

In vitro and in vivo studies on the potential mutagenicity of alclofenac, dihydroxyalclofenac and alclofenac epoxide.

Alclofenac (A) and two of its metabolites, dihydroxyalclofenac (DHA) and alclofenac epoxide (AE), were tested for their mutagenic potential. Alclofenac and DHA showed no mutagenic, transforming or clastogenic potential in any in vitro experiment. The addition of a supplementary metabolic activation system did not change the response of those two compounds in any test procedures in vitro. AE, an intermediary metabolite between A and DHA, was mutagenic by itself in the Ames test, but in the presence of a liver post-mitochondrial fraction its activity of Salmonella typhimurium was greatly decreased. Dominant lethal mutations were not induced in male rats given alclofenac, and AE had no effect in the micronucleus test. In human volunteers given alclofenac at therapeutic dose levels, no mutagenic activity was found in the urine and no significant increase in the incidence of structural chromosome aberrations was observed in peripheral blood lymphocytes.

Ultrastructural study of electrophysiologically identified neurones in the paraventricular nucleus of the rat.

The ultrastructural characterization of electrophysiologically identified neurones of the rat paraventricular hypothalamic nucleus was performed with extracellular labelling technique. The extracellularly recorded neurons are labelled with an electrophoretic deposit of alcian blue contained in the recording micropipette. The neurone thus labelled takes on a dark and shrunken appearance which enables its detection among neighbouring cells without, however, concealing its main morphological characteristics. 1) Spontaneously firing neurones, invaded by an antidromic action potential elicited by electrical stimulation of the neurohypophysis, were identified as magnocellular cells containing dense-cored vesicles of 200-250 nm in diameter. Dense-cored vesicles were not found in the antidromically activated neurones devoid of spontaneous activity. 2) Trans-synaptically activated neurones in the PVN or in its dorso-lateral edge were small cells devoid of dense secretory vesicles. 3) PV neurones in which neurohypophysial stimulation evoked no response, contained small, dense vesicles (100 nm in diameter) comparable with those found in parvocellular peptidergic neurones.