La esclerosis múltiple (EM) es una enfermedad degenerativa progresiva y autoinmune que se caracteriza por la neuroinflamación del sistema nervioso central. Fingolimod es un medicamento comercializado en la Unión Europea en marzo de 2011 como primer tratamiento oral para la esclerosis múltiple remitente recurrente (EMRR) muy activa o de rápida evolución. Se recomienda el protocolo de primera dosis por el efecto de bradicardia o posibles bloqueos cardiacos, monitorizando al paciente las 6 horas tras la primera dosis de fingolimod, realizando electrocardiograma (ECG) basal y posterior a las 6 horas; con la toma de frecuencia cardiaca (FC) y tensión arterial (TA) horaria. Valorar la seguridad cardiológica inmediata de fingolimod. A través de los registros ECG, la gráfica de constantes y el registro de pacientes de EM desde agosto 2011 hasta octubre 2013, hemos recogido tratamiento anterior a fingolimod, ECG normal o no, bradicardia medicada o no, prolongación de las 6 h de protocolo e interrupción de tratamiento. En total han comenzado tratamiento con fingolimod en nuestra unidad 42 pacientes. Quince pacientes habían sido tratados con natalizumab previamente (motivo del cambio: 8 por virus JC+, 3 por reacción de hipersensibilidad, 4 por respuesta inadecuada). Cuarenta de cuarenta y dos presentaron bradicardia asintomática, ninguno precisó tratamiento. Cinco de cuarenta y dos precisaron prolongar el tiempo de monitorización. Se suspendió el tratamiento con fingolimod durante su seguimiento a 3 pacientes, 2 lo reanudaron y uno de ellos restableció interferón beta. La seguridad cardiológica inmediata de fingolimod es muy buena. Multiple Sclerosis (M.S.) is a progressive, autoimmune degenerative disease that is characterized by central nervous system neuro-inflammation. Fingolimod is a medicinal product that has been marketed in the European Union since March 2011, as the first oral treatment for very active and rapidly evolving Relapsing Remitting Multiple Sclerosis. A first dose 6 hour protocol is recommended, due to the effect of bradycardia or heart blockages. This includes monitoring the patient for 6 hours after the first dose of Fingolimod, with an electrocardiogram being performed at baseline and at 6 hours, as well as monitoring the heart rate and blood pressure. To assess the immediate cardiac safety of Fingolimod. A record was made of the electrocardiograms, the vital constants graph, and records from the MS patient register from August 2011 to October 2013, as well as those recorded prior to Fingolimod treatment (normal or abnormal electrocardiogram, or medicated or non-medicated bradycardia, prolongation of the 6 h of Protocol, and interruption of treatment). A total 42 patients have started treatment with Fingolimod in our unit. Of this total, 15 patients had been treated with Natalizumab previously (reason for the change: 8 by JC Virus, 3 by hypersensitivity reaction, and inadequate response 4). Asymptomatic bradycardia was observed in 40/42 patients, with none needing treatment. A longer monitoring time was required in 5/42. Treatment was suspended with Fingolimod during follow-up in 3 patients, resumed in 2, and 1 of them re-established with Interferon beta. The immediate cardiac safety of Fingolimod is very good.

Abstract Aims: This study reports the changes in patterns of fetal breathing movements recorded with a photogrammetric method in three successive periods of gestation. Methods: Respiratory movements were studied in fetuses of 28 healthy women with uncomplicated pregnancies of 30–38 weeks of gestation. Women were divided into three groups according to gestational age of the fetus: 30–32 weeks, 7 fetuses; 33–36 weeks, 9 fetuses; and 37–38 weeks, 12 fetuses. Sonographic images of the fetuses were recorded on videotape, digitized (1 image per 0.12 s) and analyzed with specially developed software. Results: The proportion of fetuses in each age group for which movements were detectable was similar in all three groups, as was the frequency of movements. Duration of a complete respiratory cycle, the inspiratory phase and the expiratory phase tended to be shorter at 33–36 weeks of gestation than in younger and older fetuses. Fetuses in the 30–32-week group had slower breathing rates than fetuses in the two older groups. Conclusions: The photogrammetric technique revealed differences in some patterns of fetal breathing movements between weeks 30–32, 33–36 and 37–38 of gestation. The data provide a sound basis for relating changes in fetal breathing movements with physiological and anatomical changes that occur as the respiratory system matures.

Objective: Studies in animals and human muscle have demonstrated differential splicing of the insulin-like growth factor-1 gene in response to mechanical strain and damage. We conducted a study on the expression of insulin-like growth factor-1 splice variants in the levator am muscle after the first vaginal delivery.Study design: Ten women were recruited after the first vaginal delivery. Biopsy specimens were taken vaginally of the pubovisceral component of the levator am muscle. Five nonpregnant women were recruited as control subjects. Samples were processed with real-time quantitative polymerase chain reaction, with specific primers for the insulin-like growth factor-1 splice variants.Results: Insulin-like growth factor splice variants mechano growth factor and insulin-like growth factor-1Ea were significantly up-regulated (100- and 1000-fold) in the delivery population, compared with control subjects (P = .012 and .04, respectively). Statistical analysis indicated a correlation between the expression of the insulin-like growth factor-1 splice variants and the length of the second stage.Conclusion: These results show that damaged levator am muscle results from stretch and overload after the first vaginal delivery. (c) 2005 Elsevier Inc. All rights reserved.

OBJECTIVE: To estimate the role of dynamic magnetic resonance imaging MRI as a diagnostic tool in die evaluation of vaginal apex prolapse in women with previous hysterectomy.METHODS: Clinical examinations were performed on 51 women presenting with symptoms of prolapse. A preoperative dynamic MRI assessment was performed. The mid pubic line was the reference level used for prolapse grading. The parameters of analysis included 1) correlation by compartments of clinical and MRI grading of prolapse, 2) assessment of the accuracy of clinical examination of the middle compartment, and 3) identification of any additional information provided by MRI. All MRI films were analyzed and validated by the same two observers.RESULTS: Analysis of each compartment separately revealed poor correlation between clinical and MRI assessment. Of the 51 cases with clinical vault prolapse, 27 (52.9%) cases were clinically overdiagnosed, 3 (6%) were underdiagnosed, and there was agreement in 21 (41.1%) when compared with MRI findings. Postoperative follow-up of the 18 (85%) patients who underwent colposacropexy after intraoperative assessment revealed the presence of cystocele in 4 (26.6%) occasions and rectocele in 3 (20%), which had been detected on MRI but not confirmed intraoperatively.CONCLUSION: There is poor correlation between clinical and MRI findings when assessing vaginal apex prolapse. Magnetic resonance imaging allows the identification of other prolapsing compartments and may be a complementary diagnostic tool for the diagnosis of complex vaginal apex prolapse. (C) 2004 by The American College of Obstetricians and Gynecologists.

Pelvic floor dysfunction in women with eating disorders is an underexplored area. We present a case of pelvic floor dysfunction in a nulliparous woman with anorexia nervosa.

OBJECTIVE: To study the anatomic and functional efficacy and assess long-term success of the fascial technique in the repair of rectocele.METHODS: Forty-two women with symptomatic posterior vaginal wall prolapse of at least stage 11 underwent a surgical repair using the technique of reconstruction of the rectovaginal septum. These women were evaluated at 6 weeks and 18 months postoperatively for anatomic improvement in the grade of their rectocele and a functional improvement in their vaginal, bowel, and sexual symptoms.RESULTS: Ninety-five percent (40 of 42) were assessed at 6 weeks and 78.5% (33 of 42) attended follow-up at 18 months. Preoperative symptoms included 1) vaginal protrusion (78%); 2) defecation symptoms (76%), which included fecal incontinence alone in 9.5%, evacuation difficulties in 57%, and both fecal incontinence and evacuation difficulties in 9.5%; and 3) sexual dysfunction (33%). At 6-week follow-up there was resolution of vaginal protrusion in 87.5%, and bowel symptoms in 87%. At 18 months there was anatomic cure in 92%, improvement in defecation in 81%, and improvement of sexual dysfunction in 35%. No major complications were seen.CONCLUSION: This technique is effective in providing relatively long anatomic cure of the rectoccle and resolution of its symptoms. (C) 2003 by The American College of Obstetricians and Gynecologists.

Glycoprotein 5 (GP(5)) is the major glycoprotein of porcine reproductive and respiratory syndrome virus (PRRSV). Expression of GP(5) has been improved by removing the transmembrane regions. Vectors were constructed encoding complete GP(5) plus three mutants: GP(5) Ns (residues 28--201), GP(5)[30--67] (residues 30--67) and GP(5)[30--201] (residues 30--67/130--201). The three deletion mutants were expressed at levels 20--30 times higher than complete GP(5). GP(5)[30--201] was well recognized in ELISA or immunoblotting by a collection of pig sera. All the fragments were tested for the generation of MAbs, but only the polyhistidine-tagged fragment GP(5)[30--201]H elicited an antibody response sufficient to produce MABS: The two MAbs were positive for PRRSV in ELISA and immunoblotting, but negative for virus neutralization. MAb 4BE12 reacted with residues 130--170 and MAb 3AH9 recognized residues 170--201. This region was recognized strongly in immunoblotting by a collection of infected-pig sera. These results indicate diagnostic potential for this epitope.

Organic cation transporters (OCTs) are polyspecific facilitated diffusion transporters that contribute to the absorption and clearance of various physiological compounds and xenobiotics in mammals, by mediating their vectorial transport in kidney, liver or placenta cells. Unexpectedly, a corpus of studies within the last decade has revealed that these transporters also fulfill important functions within the brain. The high-affinity monoamine reuptake transporters (SERT, NET and DAT) exert a crucial role in the control of aminergic transmission by ensuring the rapid clearance of the released transmitters from the synaptic cleft and their recycling into the nerve endings. Substantiated evidence indicate that OCTs may serve in the brain as a compensatory clearance system in case of monoamine spillover after high-affinity transporter blockade by antidepressants or psychostimulants, and in areas of lower high-affinity transporter density at distance from the aminergic varicosities. In spite of similar anatomical profiles, the two brain OCTs, OCT2 and OCT3, show subtle differences in their distribution in the brain and their functional properties. These transporters contribute to shape a variety of central functions related to mood such as anxiety, response to stress and antidepressant efficacy, but are also implicated in other processes like osmoregulation and neurotoxicity. In this review, we discuss the recent knowledge and emerging concepts on the role of OCTs in the uptake of aminergic neurotransmitters in the brain and in these various physiological functions, focusing on the implications for mental health.

Objectives: Increased uterine artery pulsatility index (PI) is associated with lower implantation rates in women undergoing in-vitro fertilization. There are no comparable studies in women undergoing conventional ovulation induction therapy, although there is evidence that clomiphene citrate (CC) increases uterine artery PI in women with unexplained infertility. The aim of the present study is to assess uterine artery PI in clomiphene-stimulated cycles in relation to outcome. Design: A prospective cross-sectional study of women with anovulatory infertility, treated with CC between July 1999–January 2000. Materials and Methods: 40 subjects (mean age of the patients was 31.1 ± 4.4 years) received CC (dose 50–100 mg) from days 2–6 during 54 cycles. Transvaginal ultrasound was performed by the same operator (KL) between days 12 and 14 using a TOSHIBA 'Powervision 6000' with a 7.5 MHz transvaginal probe and color Doppler facility. The uterine artery PI were measured and the highest value (left or right artery) used for analysis. Results: Pregnancy, confirmed by ultrasound was achieved in 7 cycles; conception failed to occur in the remaining 47 cycles. The mean uterine artery PI in the conception cycles was significantly (P=0.04) lower than in the nonconception cycles (2.38 ± 0.3 and 2.75 ± 0.85 respectively, CI for the difference 0.02–0.71). Conclusion: This is the first demonstration that uterine artery PI is predictive of cycle outcome in women receiving CC. The mechanism responsible for the lower PI in the conception cycles is not known but is suggestive of improved uterine and/or endometrial perfusion in these women. Further studies are planned to identify an effective intervention for women receiving CC and who have an elevated uterine artery PI.

OBJECTIVE:In most recent studies, fetal respiratory movements have been measured with real-time and Doppler echography. We describe an alternative approach using photogrammetry that provides more objective measurements. METHODS:Respiratory movements were studied in 28 women with uncomplicated pregnancies of 30-38 weeks' gestation. Fetal echographic images were recorded on videotape and digitized to obtain coordinates of the reference point (midpoint on the anterior abdominal wall of the fetus between the xiphoid process and the insertion of the umbilical vessels) and generate graphic representations of fetal movements in the anterior abdomen. RESULTS:The mean duration of a complete respiratory cycle was 1.194 s, the mean distance representing the extent of movement was 2.92 mm, the mean inspiratory velocity was 5.52 mm/s and the mean expiratory velocity was 5.06 mm/s. CONCLUSIONS:Photogrammetric analysis of images obtained with real-time echography provided accurate measurements of fetal breathing movements.

The combination of inhaled nitric oxide with almitrine bismesylate has been proposed for the management of acute respiratory distress syndrome in order to divert pulmonary blood flow away from poorly ventilated toward well-ventilated areas. The aims of this prospective and comparative study were to: 1) confirm the beneficial effects on oxygenation of this association; 2) evaluate the haemodynamic effects of this association; and 3) evaluate the influence of noradrenaline (a nonspecific vasoconstrictor) on the modification of gas exchange related to inhaled NO and/or almitrine bismesylate.Forty-one sedated paralysed and ventilated patients were investigated. Haemodynamic and blood gas measurements were performed in a fixed order: baseline; inhalation of NO for 30 min.; intravenous infusion of almitrine bismesylate; and concomitant administration of inhaled NO and almitrine bismesylate.Inhaled NO and almitrine bismesylate increased arterial oxygen tension (Pa,O-2)/inspiratory oxygen fraction (FI,O-2) (p<0.001). The association of inhaled NO with almitrine bismesylate resulted in a dramatic improvement in Pa,O-2/FI,O-2 (p<0.0001 versus almitrine bismesylate, p<0.05 versus inhaled NO). In patients receiving noradrenalin (n=19), almitrine bismesylate had no effect on oxygenation.The present study confirmed that the combination of inhaled NO with almitrine bismesylate improved oxygenation, and demonstrated that almitrine bismesylate has no effect on oxygenation in patients receiving noradrenalin.

Rabbit haemorrhagic disease virus (RHDV) causes an important disease in rabbits. The virus capsid is composed of a single 60 kDa protein. The capsid protein gene was cloned in Escherichia coli using the pET3 system, and the antigenic structure of RHDV VP60 was dissected using 11 monoclonal antibodies (MAbs) and 12 overlapping fragments of the protein expressed in E, coli, Two antigenic regions were found. Ten out of the 11 MAbs recognized different discontinuous epitopes in the most immunodominant region of the viral capsid, This domain was located between residues 31 and 250 of the VP60 N terminus. The other MAb revealed the presence of an antigenic site within 102 aa of the C terminus. This MAb did not recognize the major cleavage product of the full-length 60 kDa protein. These results indicate that, in contrast to other caliciviruses such as Norwalk virus (NV), the 36 kDa cleavage product probably forms the N-terminal region of VP60. However, as in NV, the cleavage region appears to be the most immunodominant region.

La réalisation d'une anesthésie locorégionale expose à un risque de lésion nerveuse qui peut être essentiellement de trois types: ischémique, traumatique et toxique. Divers mécanismes peuvent être impliqués, seuls ou en association. Au cours d'une anesthésie périmédullaire (anesthésie péridurale ou rachianesthésie), deux principaux facteurs contribuent à une ischémie médullaire: une hypotension artérielle majeure et prolongée ou une compression médullaire par un hématome, dont le principal facteur causal est l'administration périopératoire d'anticoagulants. Au niveau du système nerveux périphérique, une ischémie peut également se produire en cas d'injection intranerveuse, et elle-même engendrer une agression nerveuse traumatique directe par le biseau de l'aiguille, notamment lors de la recherche de paresthésies. Enfin les anesthésiques locaux ont une neurotoxicité locale, concentration et dose-dépendante. La connaissance de ces mécanismes permet de proposer de nouvelles attitudes préventives raisonnées.Neurol damage is a possible complication of central nerve blockade and regional anaesthesia. Damage may be caused by ischaemic, mechanical or chemical mechanisms, which may occur either alone or in combination. Neurol ischaemia may be caused by 1) prolonged and severe arterial hypotension, which compromises blood supply to the cord, 2) a spinal haematoma whose main etiological factor is a coagulation abnormality and 3) an intraneural injection. Mechanical trauma by the needle bevel is an important factor of neuropathy, particularly when searching for paraesthesiae. Neurological complications may also result from a direct neurotoxic effect of local anaesthetic agents which is concentration and dose-dependent. Better understanding of these mechanisms will permit the establishment of reliable bases for new preventive strategies.

Rabbit hemorrhagic disease virus (RHDV) causes more than 90% mortality in adult rabbits. In this study, the cDNA of the VP60 coding sequence of RHDV was cloned under the control of the polyhedrin and p10 promoters of baculovirus to be expressed in insect cells. The expression of RHDV VP60 under the control of the p10 promoter was 5–10 times higher than using the polyhedrin promoter. The p10-derived VP60 was able to assemble into virus-like particles (VLPs). RHDV VLPs were successfully used to protect rabbits against the disease even at doses as low as 0.5 µg when injected intramuscularly or sub-cutaneously. The ability to elicit an immune response was independent of the adjuvant or the route of immunization. Remarkably, oral administration of RHDV VLPs efficiently induced protecting antibodies to RHD at doses as low as 3 µg. The use of binary ethylenimine for the stabilization of the VLPs was decisive for eliciting a good oral immunity. This report demonstrates the potential use of these procapsids in obtaining RHD oral vaccines and opens the door to the use of these capsids for the prevention of the disease in wild animals. Therefore, a new, and potentially important application of recombinant VLPs in the induction of protective immunity by the oral route is foreseen.

The N-terminal domain of the major capsid protein VP2 of canine parvovirus was shown to be an excellent target for development of a synthetic peptide vaccine, but detailed information about number of epitopes, optimal length, sequence choice, and site of coupling to the carrier protein was lacking. Therefore, several overlapping peptides based on this N terminus were synthesized to establish conditions for optimal and reproducible induction of neutralizing antibodies in rabbits. The specificity and neutralizing ability of the antibody response for these peptides were determined. Within the N-terminal 23 residues of VP2, two subsites able to induce neutralizing antibodies and which overlapped by only two glycine residues at positions 10 and 11 could be discriminated. The shortest sequence sufficient for neutralization induction was nine residues. Peptides longer than 13 residues consistently induced neutralization, provided that their N termini were located between positions 1 and 11 of VP2. The orientation of the peptides at the carrier protein was also of importance, being more effective when coupled through the N terminus than through the C terminus to keyhole limpet hemocyanin. The results suggest that the presence of amino acid residues 2 to 21 (and probably 3 to 17) of VP2 in a single peptide is preferable for a synthetic peptide vaccine.