Synthesis of sp(3)-rich scaffolds for molecular libraries through complexity-generating cascade reactions.

An efficient strategy for the synthesis of complex small molecules from simple building blocks is presented. Key steps of the strategy include tandem Petasis and Diels-Alder reactions, and divergent complexity-generating cyclization cascades from a key dialdehyde intermediate. The methodology is validated through the synthesis of a representative compound set, which has been used in the production of 1617 molecules for the European Lead Factory.

Vaginal mesh erosion after transvaginal repair of cystocele using Gynemesh or Gynemesh-Soft in 138 women: a comparative study.

The objective of this study was to compare mesh erosion after transvaginal repair of cystocele using Gynemesh or Gynemesh-Soft mesh. We retrospectively analyzed 138 consecutive cases of transvaginal repair of cystocele using synthetic mesh. The study endpoint was the pathological evidence of vaginal erosion. Multiple logistic regression was used to determine independent predictors of vaginal erosion. One hundred and thirty eight women (ages 30-83 years) with cystocele between October 1999 and October 2004, from a French University Hospital, participated in this study. Cystocele repair was performed in all patients according to the technique of tension-free polypropylene mesh. The median follow-up was 32.1 months (range 7.5-59.9) in the Gynemesh group and 7.1 months (range 1-21.9) in the Gynemesh-Soft group. Vaginal erosion was reported in 27 (20%) of the patients. Anatomically, the success rate was 95% (131/138). There was no statistically significant difference between the Gynemesh and the Gynemesh-Soft meshes [the rate of vaginal erosion of the mesh was 16% (15/89) vs 24% (12/49), respectively, p=0.39]. Univariate analysis only identified age class as factor significantly associated with the probability of vaginal erosion. Multivariate analysis revealed that age class is an independent predictive factor of vaginal erosion (age > 70 years, odds ratio (OR) 3.6, 95% confidence interval (CI) 1.3-9.7, p=0.010). Furthermore cystocele stage > 2 (Baden and Walker classification) is a protective factor against vaginal erosion (OR 0.3, 95% CI 0.1-0.8, p=0.016). Thirteen symptomatic patients (13/27, 48%) necessitated a partial excision of the mesh, associated with a vaginal mucosal closure. Two patients (2/27, 7%) underwent a complete excision of the mesh. The incidence of de novo dyspareunia was 9% in patients with vaginal erosion and 11% in patient without mesh erosion (p=0.85). There was no occurrence of bladder or urethral erosion and no vaginal or pelvic infection. Isolated vaginal erosion of the mesh did not prove to be problematic. Gynemesh-Soft mesh does not decrease the incidence of vaginal erosion. Age > 70 years is an independent predictive factor of vaginal erosion. We recommend that mesh placement by vaginal route should be avoided by women with moderate cystocele. Where possible, total hysterectomy and vertical incision should also be avoided. Management of vaginal erosion is simple and is associated with a low rate of morbidity. However, patients should be informed that vaginal erosion of the mesh can occur. A multivariate analysis reveals that the incidence of vaginal erosion is not significantly different between Gynemesh and Gynemesh-Soft meshes. Other factors of erosion are analyzed.

[Vaginal mesh extrusion after transvaginal repair of cystocele using a prosthetic mesh: Treatment and functional outcomes]. / Exposition prothétique après mise en place d'une prothèse par voie vaginale pour cure de cystocèle: traitement et conséquences fonctionnelles.

OBJECTIVE: To describe management of vaginal mesh erosion following transvaginal repair of acystocele by placement of a polypropylene mesh. MATERIALS AND METHOD: Retrospective analysis of 34 consecutive cases of vaginal mesh erosion following transvaginal repair of cystocele using synthetic mesh (Gynemesh or Gynemesh-Soft). We have analyzed the results of both medical and surgical management of this complication. Furthermore, we also assessed sexual and urinary morbidity in women with mesh erosion (n = 34) and in women who had undergone the same procedure but without mesh erosion (n = 111). RESULTS: Among the 34 patients with vaginal mesh erosion, 23 (68%) have undergone local therapy using Colposeptine (Chlorquinaldol + Promestriène). In 12 (52%) cases no modification of the surface of the erosion was observed. In 6 (26%) cases, a decrease of the surface of the mesh erosion was observed. In 5 (22%) cases the mesh erosion had completely disappeared, with a follow-up of 2 to 9 months. Nineteen symptomatic patients (19/32, 59%) required partial (n = 18) or complete (n = 1) excision of the mesh, associated with vaginal mucosal closure, under general anaesthesia. Duration of operation ranged from 15 to 40 minutes for partial excision of the mesh. This procedure was successful in 14 cases (77%). Four women required repeated resection of the mesh because of recurrence. The incidence of de novo dyspareunia was 12% in patients with vaginal mesh erosion, and 11% in patients without mesh erosion (p = 0.81). The incidence of urge urinary symptoms and voiding dysfunction symptoms was respectively 8% versus 9% (p = 0.95), and 8% versus 10% (p = 0.81) in the 2 groups. CONCLUSION: Management of vaginal mesh erosion is simple and is associated with a low rate of morbidity. However, patients should be informed that vaginal erosion of the mesh can occur.

[Transvaginal cervico-isthmic cerclage using polypropylene tape: surgical procedure and pregnancy outcome: Fernandez's procedure]. / Technique de cerclage cervico-isthmique par voie vaginale avec bandelette de polypropylène: technique de Fernandez.

OBJECTIVE: To assess the efficacy of performing transvaginal cervico-isthmic cerclage using synthetic tape in prevention of preterm labor in high-risk women. PATIENTS AND METHODS: A retrospective analysis of 24 transvaginal cerclages using polypropylene tape performed in women presenting with high risk of preterm delivery: prior histories of pregnancy losses in the second trimester, prior failure of Mac Donald's cerclage and/or absent portio vaginalis of the cervix. Cerclage was performed between 12 and 16 weeks of gestation. A polypropylene tape was placed at the cervicoisthmic junction by vaginal route. RESULTS: The median age of the patients in this series was 32.1 years (range 22-39 years). No intra-operative complication occurred. The median operating time was 34.9 minutes (+/-5.1) (range 30-45 min). Cesarean delivery was systematically performed in all patients since the cerclage was considered to be definitive. Mean gestational age and birth weight at delivery were respectively 37.1 weeks (+/-1.8) and 2850 g (+/-745). Preterm birth rate was 19% (4/21). Birth at less than 32 weeks occurred in only one patient (4%). In one case, the tape has been removed later because symptomatic vaginal erosion was noted. One neonatal death occurred following amniotic fluid infection at 34 weeks. At the present time, 3 women are at 22, 26 and 26 weeks of gestation with no preterm labor. CONCLUSION: Transvaginal cerclage using polypropylene tape may be considered as an effective and minimally invasive alternative to transabdominal cervico-isthmic cerclage in women presenting with high risk of preterm delivery.

[Subtotal hysterectomy: evolving concepts with implications for practice]. / Hystérectomie sub-totale: données récentes et implications pratiques.

INTRODUCTION: The advantages and drawbacks of total and sub-total hysterectomy remain a topic of debate. Our study reviews the literature concerning recent comparative and prospective studies regarding the options of total and subtotal hysterectomy. RESULTS: Subtotal hysterectomy may be useful in preventing severe complications when total hysterectomy is technically difficult. Furthermore, conservation of the uterine cervix may decrease vaginal erosion in genital prolapse repair when synthetic meshes are used. The type of technique does not appear to determine the persistence or development of problems related to sexual activity (frequency of intercourse, sexual desire, and achievement of orgasm). There are no apparent advantages to subtotal hysterectomy compared with total hysterectomy with respect to bowel or bladder function. Some women (5-20%) who had the subtotal procedure continued to have genital bleeding, although this can be avoided with endocervical electro-coagulation or resection. Cervical stump prolapse is uncommon (1.5-2%), 12 months after subtotal hysterectomy. The risk of carcinoma of the cervical stump is low, and treatment results are similar in both patients with carcinoma of the cervical stump and in patients with carcinoma of the intact uterus. CONCLUSION: When subtotal hysterectomy is necessary, it can be performed with a low rate of long term complications. Furthermore, for women undergoing hysterectomy for benign disease, it should be reasonable to discuss advantages and drawbacks of both procedures and offer a choice. Nevertheless, sub-total hysterectomy should be avoided in populations with restricted access to screening programs for cancer of the uterine cervix.

[Urinary complications in sub-urethral sling procedures]. / Complications urinaires des soutènements sous-urétraux.

INTRODUCTION: Urinary complications following sub urethral sling procedures are common, and management of these complications continue to be discussed. METHODS: The literature available on Medline/PubMed, relating to urinary complications associated with suburethral sling procedures, was reviewed. RESULTS: Bladder perforation, which occurs with an incidence of 5.7% in tension-free vaginal tape procedure, requires repositioning of the sling, but does not cause any increase in postoperative morbidity. The trans-obturator approach appears to decrease this risk. Urethral perforation, which is uncommon (0.4-1%), is a contraindication to maintenance of the sling. Bladder erosion is rare, requiring resection of the mesh with a combined abdominal and cystoscopic approach. Urethral mesh erosion (0.07% to 1.5%) also requires surgical sling removal, but few patients remain continent because this removal requires a large urethrolysis (recurrence rate of incontinence is 66% following removal of the sling). Bladder outlet obstruction occurs frequently after sub-urethral procedures. When complete obstruction is clinically evident 2 days after a sub-urethral sling procedure, immediate reintervention is performed with a rapid return to normal voiding. Recurrence rate of stress incontinence is less than 30% following reintervention.

Survival in cervix cancer patients treated with radiotherapy followed by radical surgery.

AIM: To determine the incidence and predictive value of residual disease in the hysterectomy specimens of cervical cancer patients treated with primary radiotherapy, with or without chemotherapy, followed by surgery and to determine whether pathologically confirmed residual disease is a surrogate marker of outcome. METHODS: The medical records of patients treated for stage IB/II carcinoma of the cervix in a single institution between 1985 and 2000 were retrospectively analysed into two different groups, depending on whether they had received radiotherapy or concurrent chemo-radiotherapy. Six to 8 weeks after irradiation, all patients underwent radical or extrafascial hysterectomy and pelvic and para-aortic lymphadenectomy. RESULTS: A total of 403 patients were included in the study (360 in the radiotherapy only group and 43 in the chemo-radiotherapy group). One hundred and seventy-eight patients had residual disease on hysterectomy specimens in the radiotherapy group. Considering only the stages IB2 and II, 126 (52%) and 16 (37%) patients had residual disease on hysterectomy specimens in the radiotherapy group and in the chemo-radiotherapy group, respectively (P=0.08). Residual disease was associated with pelvic and para-aortic nodal metastases. The 5-year local control and overall survival rates were 88 and 86%, respectively, in the patients with complete pathologic response and 73 and 62%, respectively, in the patients with residual disease (P<0.001). In multivariate analysis, FIGO stage, residual disease, and pathologic nodal involvement were independent predictive factors of both local recurrence and overall survival. CONCLUSION: Pathologically confirmed residual disease on hysterectomy specimen is an independent and strong predictive factor of both local recurrence and overall survival.

A parametric study of the N40 auditory evoked response in rats.

BACKGROUND: The N40 auditory evoked potential (EP) in rats is used to study "sensory gating." Our first goal was to compare the effects of systematically varying the characteristics of the pairs of clicks (S1-S2), on the degree of attenuation of the responses to S2 stimuli. A second goal was to examine the effects of changing S2 stimuli on the degree of attenuation of the responses to the deviant stimulus. METHODS: The N40 EP was recorded from 10 rats in eight identical-pair conditions and from 11 rats in two paradigms: nonidentical pairs and short trains of identical stimuli followed by a deviant stimulus. RESULTS: In eight identical-pair conditions changing stimulus duration, intensity, or frequency had no effect on the degree of attenuation of S2 responses. Changing S2 stimulus or presenting a deviant stimulus following a train of identical stimuli had a significant effect on the degree of attenuation of the response to the deviant stimulus. CONCLUSIONS: We conclude that the rat N40 EP is sensitive to stimulus change and can contribute to the study of both habituation and dishabituation mechanisms of "sensory gating."

The utility of topographic EEG mapping in obstructive sleep apnea syndrome.

A study was undertaken to determine whether topographic brain mapping of standard EEG and cognitive evoked potentials would provide additional information for the detection of subtle brain abnormalities associated with obstructive sleep apnea. During nocturnal sleep, significant brain activity was detected in frontal regions not usually monitored with standard sleep recordings. Moreover, preliminary results suggest that total brain activity decreased in association with apneic events and depth of O2 desaturation. Also, component asymmetry in the P300 waveform observed in brain areas not typically recorded improved with treatment. We conclude that the use of topographic mapping adds important information to the study of brain function during sleep and sleep apnea.

Autonomic control of heart rate in the adult, aquatic Notophthalmus viridescens viridescens.

1. We investigated the role of the autonomic nervous system in the control of the heart rate using an isolated heart preparation. 2. Addition of the parasympathetic blocker, atropine, to the organ bath resulted in an increase in heart rate as expected. 3. Addition of the sympathetic blocker, ergotamine, to the organ bath showed no change in the heart rate. 4. Addition of the sympathetic blocker, propranolol, to the organ bath resulted in the expected decrease in heart rate. 5. Both the sympathetic and parasympathetic nervous systems appear to play a role in the control of the heart rate.

The effect of hyperthyroidism on opiate receptor binding and pain sensitivity.

This study was conducted to determine the effect of thyroid hormone on opiate receptor ligand-binding and pain sensitivity. Specific opiate receptor-binding was performed on brain homogenates of Swiss-Webster mice. There was a significant increase in 3H-naloxone-binding in thyroxine-fed subjects (hyperthyroid). Scatchard analysis revealed that the number of opiate receptors was increased in hyperthyroid mice (Bmax = 0.238 nM for hyperthyroid samples vs. 0.174 nM for controls). Binding affinity was unaffected (Kd = 1.54 nM for hyperthyroid and 1.58 nM for control samples). When mice were subjected to hotplate stimulation, the hyperthyroid mice were noted to be more sensitive as judged by pain aversion response latencies which were half that of control animals. After morphine administration, the hyperthyroid animals demonstrated a shorter duration of analgesia. These findings demonstrate that thyroxine increases opiate receptor number and native pain sensitivity but decreases the duration of analgesia from morphine.

Dopaminergic supersensitivity follows ferric chloride-induced limbic seizures.

Injection of ferric chloride (FC) into the left amygdala of rats produced limbic seizures that lasted at least 3 weeks. In addition, FC-injected animals demonstrated motor impairment, decreased protesting vocalizations, and spontaneous stereotypies during a behavioral examination. An increase in apomorphine-induced stereotypies was also noted, and weekly administration of apomorphine for 3 weeks potentiated the increase in stereotypies produced by FC injection. These behavioral changes were associated with changes in postsynaptic dopamine D2 receptors. In animals injected only with FC, an increase in the [3H]-spiperone Bmax in the left nucleus accumbens and an increase in Kd in the right nucleus accumbens were noted. In FC-injected animals challenged weekly with apomorphine for 3 weeks, increases in the [3H]-spiperone Bmax in both amygdalae, the left nucleus accumbens, and the right nucleus caudatus and increases in Kd in the left amygdala and right nucleus accumbens were noted. Severance of the anterior commissure at the time of FC injection reversed most of these changes in behavior and dopamine receptor binding. Possible mechanisms for these changes are discussed, as well as the implications of these results for research on limbic dysfunction and psychopathology.

Dopaminergic supersensitivity at distant sites following induced epileptic foci.

Injection of ferric chloride (FeCl3) into the left amygdaloid nucleus of the rat produced partial complex seizures. Subsequent repeated apomorphine challenges revealed steady development of behavioral dopaminergic supersensitivity, above that observed in saline-injected controls. The behavioral supersensitivity observed in FeCl3-injected animals was accompanied by increases in 3H-spiroperidol binding in contralateral amygdala, striatum and ipsilateral nucleus accumbens. In contrast, saline-injected controls demonstrated bilateral decreases in 3H-spiroperidol binding in amygdala and striatum. The effects of FeCl3 injection on the behavioral dopaminergic supersensitivity and 3H-spiroperidol binding were eliminated when the anterior commissure was severed.

Calmodulin increases in selective brain regions with opioid dependence.

Acute challenge of thalamic membranes with opioid agonists displaces calcium and prevents isoproterenol stimulation of adenylate cyclase. Chronic morphine administration for three days or three weeks results in significant increases in the level of calmodulin in membranes of thalamus, but not in periaqueductal gray, striatum, amygdala or hypothalamus.

Brain cyclic AMP and memory in mice.

A phosphodiesterase inhibitor 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (Rolipram, 10 mg/kg IP) administered immediately, but not 3 hr post-training, reversed an amnesia for an inhibitory avoidance response induced by the protein synthesis inhibitor anisomycin. Immediate post-training administration of Rolipram also enhanced retention for a weakly learned avoidance response. Unshocked animals did not show increased test latencies thus ruling out conditioned aversion as an explanation for the enhanced avoidance. Mice treated with Rolipram (10 mg/kg after training showed elevated cyclic AMP but not cyclic GMP in frontal cortex, thalamus, and hypothalamus. These results support the suggestion that cyclic AMP may play a role in memory processes.

Mu and kappa opioid agonists elevate brain stimulation threshold for escape by inhibiting aversion.

Rats were trained to press a lever to escape electrical stimulation of the nucleus reticularis gigantocellularis and to obtain stimulation of the lateral hypothalamus. Morphine sulfate and ethylketocyclazocine (EKC) both elevated the intensity of stimulation required to sustain escape at doses which did not affect self-stimulation. Parallel dose-response lines were obtained for the two opioid agonists but the effect of EKC was more resistant to naloxone antagonism. These results suggest that both mu-and chi-sub-types of opiate receptor mediate the inhibition of supraspinally-elicited aversion.