Pharmacological Characterization of Low Molecular Weight Biased Agonists at the Follicle Stimulating Hormone Receptor.

Follicle-stimulating hormone receptor (FSHR) plays a key role in reproduction through the activation of multiple signaling pathways. Low molecular weight (LMW) ligands composed of biased agonist properties are highly valuable tools to decipher complex signaling mechanisms as they allow selective activation of discrete signaling cascades. However, available LMW FSHR ligands have not been fully characterized yet. In this context, we explored the pharmacological diversity of three benzamide and two thiazolidinone derivatives compared to FSH. Concentration/activity curves were generated for Gαs, Gαq, Gαi, ß-arrestin 2 recruitment, and cAMP production, using BRET assays in living cells. ERK phosphorylation was analyzed by Western blotting, and CRE-dependent transcription was assessed using a luciferase reporter assay. All assays were done in either wild-type, Gαs or ß-arrestin 1/2 CRISPR knockout HEK293 cells. Bias factors were calculated for each pair of read-outs by using the operational model. Our results show that each ligand presented a discrete pharmacological efficacy compared to FSH, ranging from super-agonist for ß-arrestin 2 recruitment to pure Gαs bias. Interestingly, LMW ligands generated kinetic profiles distinct from FSH (i.e., faster, slower or transient, depending on the ligand) and correlated with CRE-dependent transcription. In addition, clear system biases were observed in cells depleted of either Gαs or ß-arrestin genes. Such LMW properties are useful pharmacological tools to better dissect the multiple signaling pathways activated by FSHR and assess their relative contributions at the cellular and physio-pathological levels.

Influence of social cognition as a mediator between cognitive reserve and psychosocial functioning in patients with first episode psychosis.

BACKGROUND: Social cognition has been associated with functional outcome in patients with first episode psychosis (FEP). Social cognition has also been associated with neurocognition and cognitive reserve. Although cognitive reserve, neurocognitive functioning, social cognition, and functional outcome are related, the direction of their associations is not clear. Therefore, the main aim of this study was to analyze the influence of social cognition as a mediator between cognitive reserve and cognitive domains on functioning in FEP both at baseline and at 2 years. METHODS: The sample of the study was composed of 282 FEP patients followed up for 2 years. To analyze whether social cognition mediates the influence of cognitive reserve and cognitive domains on functioning, a path analysis was performed. The statistical significance of any mediation effects was evaluated by bootstrap analysis. RESULTS: At baseline, as neither cognitive reserve nor the cognitive domains studied were related to functioning, the conditions for mediation were not satisfied. Nevertheless, at 2 years of follow-up, social cognition acted as a mediator between cognitive reserve and functioning. Likewise, social cognition was a mediator between verbal memory and functional outcome. The results of the bootstrap analysis confirmed these significant mediations (95% bootstrapped CI (-10.215 to -0.337) and (-4.731 to -0.605) respectively). CONCLUSIONS: Cognitive reserve and neurocognition are related to functioning, and social cognition mediates in this relationship.

Leukemia inhibitory factor induces cumulus expansion in immature human and mouse oocytes and improves mouse two-cell rate and delivery rates when it is present during mouse in vitro oocyte maturation.

OBJECTIVE: To examine the role of leukemia inhibitory factor (LIF) during in vitro maturation (IVM) on human and mice cumulus expansion and mice oocyte competence by in vitro fertilization (IVF), culture, and embryo transfer (ET). DESIGN: Prospective animal and human study. SETTING: Serono laboratories and IVF clinic. PATIENT(S): Healthy women volunteers and 8-week-old female mice. INTERVENTION(S): Cumulus compacted human and mice oocytes were matured in IVM media with and without recombinant follicle-stimulating hormone (FSH) and with and without LIF. Mice IVM oocytes with and without 0.2 IU/mL of recombinant FSH; or with and without recombinant FSH + LIF (0.1, 1.0, 1000.0 ng/mL) and ovulated oocytes were in vitro fertilized and cultured. We transferred 395 blastocysts to the uterine horn of 2.5-day pseudopregnant female mice. MAIN OUTCOME MEASURE(S): Cumulus expansion in human and mice oocytes, and two-cell rate, blastocyst rate, and delivered rate of live pups in mice. RESULT(S): In human and mouse oocytes, LIF induced cumulus expansion. When 1000 ng/mL of LIF was added in combination with recombinant FSH, a statistically significant increase in cleavage rate, embryo development rate, and birth rate was observed when compared with oocytes matured with FSH alone. CONCLUSION(S): Leukemia inhibitory factor induced cumulus expansion similarly in human and mouse cumulus-oocyte complexes, and recombinant FSH plus LIF supplementation during mouse IVM significantly improved oocyte competence as measured by cleavage rate, blastocyst development, and birth rate.

Variations in genes regulating neuronal migration predict reduced prefrontal cognition in schizophrenia and bipolar subjects from mediterranean Spain: a preliminary study.

Both neural development and prefrontal cortex function are known to be abnormal in schizophrenia and bipolar disorder. In order to test the hypothesis that these features may be related with genes that regulate neuronal migration, we analyzed two genomic regions: the lissencephaly critical region (chromosome 17p) encompassing the LIS1 gene and which is involved in human lissencephaly; and the genes related to the platelet-activating-factor, functionally related to LIS1, in 52 schizophrenic patients, 36 bipolar I patients and 65 normal control subjects. In addition, all patients and the 25 control subjects completed a neuropsychological battery. Thirteen (14.8%) patients showed genetic variations in either two markers related with lissencephaly or in the platelet-activating-factor receptor gene. These patients performed significantly worse in the Wisconsin Card Sorting Test-Perseverative Errors in comparison with patients with no lissencephaly critical region/platelet-activating-factor receptor variations. The presence of lissencephaly critical region/platelet-activating-factor receptor variations was parametrically related to perseverative errors, and this accounted for 17% of the variance (P = 0.0001). Finally, logistic regression showed that poor Wisconsin Card Sorting Test-Perseverative Errors performance was the only predictor of belonging to the positive lissencephaly critical region/platelet-activating-factor receptor group. These preliminary findings suggest that the variations in genes involved in neuronal migration predict the severity of the prefrontal cognitive deficits in both disorders.

Similar effect of family history of psychosis on Sylvian fissure size and auditory P200 amplitude in schizophrenic and bipolar subjects.

Several cerebral studies point to the non-specificity of structural and functional changes described in schizophrenia and bipolar disorders. Furthermore, the origin of these changes is still unclear. The present study investigated the effect of a family history (FH) of psychotic disorders in first-degree relatives on computed tomographic (CT) measures (ventricular, cerebral and Sylvian fissure size) and auditory event-related potentials (amplitudes and latencies of peak components in oddball paradigms) in 30 schizophrenic patients and 24 bipolar type I patients. We found a significant correlation between FH and the size of the right Sylvian fissure, and between FH and auditory P200 amplitude. More specifically, the schizophrenic and bipolar patients with negative FH (n=36) had larger right Sylvian fissures and smaller P200 amplitude than patients with positive FH (n=18). These findings were independent of the specific diagnosis, gender, and age of subjects. Our results suggest some underlying process common to schizophrenia and bipolar I disorder, and they provide support for the continuum view of the nosologic structure of psychotic illness.

[CT in findings intestinal carcinoids]. / Aspetti TC dei carcinoidi intestinali.

CT findings in intestinal carcinoids are various. While recognition of the primary tumour is a rare event, the contribution of CT in evaluating patients with suspected intestinal carcinoid is relevant, both for loco-regional staging and during long-term follow-up. Moreover, in the relatively frequent cases with an aspecific clinical onset, CT may be findings useful to direct diagnosis.

¿Inespecificidad de los hallazgos neurocognitivos en las psicosis? / No specific differences in neurocognitive performance in psychotic disorders

Introducción: En los últimos años se ha multiplicado el interés por el estudio del funcionamiento neurocognitivo no sólo en la esquizofrenia, sino también en otras psicosis y trastornos psiquiátricos. Los déficits de atención, memoria y procesamiento de la información pueden tener una gran relevancia como predictores del ajuste social y calidad de vida en los pacientes psicóticos. Objetivo y métodos: Se revisa la literatura que ha comparado el rendimiento neuropsicológico de los pacientes esquizofrénicos y afectivos, principalmente bipolares. Resultados: Los estudios analizados ofrecen resultados contradictorios. De una parte, algunos autores encuentran una mayor disfunción cognitiva global o de algunas funciones en la esquizofrenia. Sin embargo, la mayoría de los estudios, en especial aquellos que utilizan muestras homogéneas de pacientes afectivos con síntomas psicóticos, no encuentran diferencias en la afectación neurocognitiva entre los pacientes esquizofrénicos y los bipolares. Discusión: Aunque diversos factores como la selección de la muestra, el estado clínico o el tiempo de evolución de la enfermedad dificultan la interpretación de los resultados, no existirían déficits específicos en ninguno de los grupos diagnósticos estudiados (AU)

[Non-specific differences in neurocognitive performance in psychotic disorders?]. / Inespecificidad de los hallazgos neurocognitivos en las psicosis?

INTRODUCTION: In the last years, there has been a growing interest in the study of cognitive functioning, not only in schizophrenia but also in other psychoses and psychiatric disorders. Attention, memory and information processing deficits may have great relevance as predictors of social adjustment and quality of life. OBJECTIVE AND METHODS: [corrected] We revised literature concerning comparative studies of neuropsychological performance in schizophrenia and affective disorders, mainly bipolar disorders. RESULTS: Studies analyzed show contradictory results. Some authors report a more global dysfunction or a more limited and concrete dysfunction in schizophrenia. However, most of the studies, especially those with homogeneous samples of psychotic affective disorders do not find any difference in cognitive functioning between schizophrenic and bipolar patients. DISCUSSION: Although some factors as sample selection, clinical state, course of the disorder, make difficult the interpretation of results, it would not exist specific deficits in any of the diagnostic groups studied.

[Computerized tomography-guided drainage of postoperative abdominal fluid collections]. / Drenaggio guidato con tomografia computerizzata delle raccolte addominali post-operatorie.

INTRODUCTION: We report our personal technique and the results of CT-guided percutaneous drainage of postoperative abdominal fluid collections. MATERIAL AND METHODS: January 1990 to March 1998, eighty-three patients were treated for postoperative abdominal fluid collections. Forty-eight patients had undergone bowel resection, 11 laparoscopic cholecystectomy, 3 cholecystectomy, 5 splenectomy, 3 cephalopancreasectomy, 6 hepaticojejunal anastomosis, 4 hepatic resection, 2 laparocele, 1 hysterectomy. The complications had developed few days to about one year postoperatively. The suspicion of abdominal fluid collection was supported by clinical and laboratory findings. All patients were submitted to a preliminary CT scan to locate the fluid collection, assess its morphology and relationships with surrounding structures, and plan the safest access route. After local anesthesia, a trial fine needle (Chiba 20-22 G) aspiration was performed and then the draining tube was inserted into the collection under CT guidance; the tube caliber depended on the fluid amount and viscosity. After drainage, the tube was removed if CT showed complete resolution of the fluid collection; otherwise it was left in place for subsequent washing of the cavity. Based on clinical, laboratory and CT findings, another CT-guided percutaneous drainage was judged necessary in 30 patients, 2-9 days after the first one. Drainage was considered successful when sepsis resolved and no further percutaneous/surgical drainages were needed. RESULTS: CT-guided percutaneous drainage was successful in 61 of 83 patients (73.5%); the fluid collection resolved after one drainage in 26/61 patients, in 2-9 days in 18/61, and after a second CT-guided drainage in 17/61. Drainage was not resolutive in 22 of 83 patients, because major postoperative complications required laparotomic surgery; these complications were fistulas (anastomotic in 12 cases; pancreatic in 5 and biliary in 3) and segmentary bowel necrosis in 2 cases. Intracavitary bleeding as a catheter-related complication occurred only in one patient with an anterior abdominal wall abscess. CONCLUSIONS: CT-guided percutaneous drainage offers many advantages over surgery: it is less invasive, can be repeated and requires no anesthesia; there are no surgery-related risks and lower morbidity and mortality rates. Moreover, subsequent hospitalization is shorter and costs are consequently reduced. We conclude that CT-guided percutaneous drainage is the method of choice in the treatment of postoperative abdominal fluid collections.

[P300 and neuropsychological tests in schizophrenia and bipolar patients]. / P300 en esquizofrenia y trastorno bipolar. Correlatos neuropsicológicos y clínicos.

INTRODUCTION: A smaller P300 amplitude has been found in schizophrenic patients in the majority of the studies done. And this occur in spite of treatment, sex, clinical stage and evolution time of the illness. It has been already described an association between this amplitude reduction and a poor result on the neuropsychological tests. But these changes in the P300 amplitude are not specific of the schizophrenic patients and they can be found in affective patients. OBJECTIVES: This study try to value the influence of the clinical stage and the cognitive results on the P300 values in the bipolar patients and to compare these results with the schizophrenic patients. PATIENTS AND METHODS: It has been evaluated the evoked potentials and the results of a neuropsychological battery of tests in three patient groups: schizophrenics in patients with acute symptomatology (n = 18), schizophrenic out patients without acute symptomatology (n = 15) and bipolar in patients during a maniac period (n = 16). RESULTS: It has not been found any differences between schizophrenic and maniac patients nor in the amplitude or in the latency of the P300. The results of the neuropsychological tests have not any relation with P300 amplitude and latency except for the verbal fluidity (VF) which has a good correlation with a longer P300 latency. At the same time this was the only test in which schizophrenic patients have smaller results than affective patients with a good correlation. CONCLUSIONS: These results suggest a similar pattern of neuropsychological and neurophysiological damage in schizophrenic and affective patients in acute period of mania.

Native myosin from adult rabbit skeletal muscle: isoenzymes and states of aggregation.

The globular heads of skeletal muscle myosin have been shown to exist as isoenzymes S1 (A1) and S1 (A2), and there are also isoforms of the heavy chains. Using capillary electrophoresis, we found two dominant isoenzymes of the whole native myosin molecule, in agreement with what has previously been found by various techniques for native and nondenatured myosin from adult rabbits. Findings about possible states of aggregation of myosin and its heads are contradictory. By analytical ultracentrifugation, we confirmed the existence of a tail-tail dimer. By laser light scattering, we found a head-head dimer in the presence of MgATP. Capillary electrophoresis coupled with analytical ultracentrifugation and laser light scattering led us to refine these results. We found tail-tail dimers in a conventional buffer. We found tail-tail and head-head dimers in the presence of 0.5 mM MgATP and pure head-head dimers in the presence of 6 mM MgATP. All the dimers were homodimers. Naming the dominant isoenzymes of myosin a and b, we observed tail-tail dimers with isoenzyme a (TaTa) and with isoenzyme b (TbTb) and also head-head dimers with isoenzyme a (HaHa) and with isoenzyme b (HbHb).

Anterior hip dislocation in children with cerebral palsy.

This is a report of 27 hips with anterior dislocation in 17 children with cerebral palsy. Type 1 consists of patients with extension-external rotation and adduction contracture of the hip and extension contracture of the knee; type 2 consists of patients with extension-external rotation and abduction contracture of the hip and flexion contracture of the knee; and type 3 consists of patients without contractures. All children with types 1 and 2 were unable to sit and were forced into an almost full-time lying position. No child with type 3 pattern had sitting troubles. Hip pain was present in 50% of patients. All children with type 1 pattern and half of children with types 2 and 3 developed a thoracolumbar kyphosis. Standard radiographic hip measurements were inconsistent, and only three-dimensional computed tomography scans were useful in fully assessing the deformity. Indications for hip surgery were inability to sit or hip pain or both. Reconstruction was performed by anterior superior acetabular reconstruction and varus-shortening femoral osteotomy or proximal femur resection as a salvage procedure. Although three of the 13 children required two procedures, 11 of 13 children who underwent 16 hip procedures had stable and painless hips at the time of follow-up.

Tolerability of nimesulide and ketoprofen in paediatric patients with traumatic or surgical fractures.

The anti-inflammatory and analgesic activities of orally administered nimesulide and ketoprofen were assessed in a group of 71 paediatric patients (aged 7 to 14 years) with orthopaedic disorders. Both drugs had similar efficacy. The greatest advantage of nimesulide was its better tolerability: only 3 nimesulide-treated patients (8.6%) experienced side effects related to the drug, compared with 12 (33%) of the ketoprofen-treated children.