Search

Varicocele is the most common clini- cal finding in infertile men but controversy con- tinues to surround the utility of its treatment. An increased response of FSH to gonadotrophin-re- leasing hormone testing has been described in pa- tients with varicocele, while the co-influence of Yq chromosome microdeletions in the infertility as- sociated to this pathology is still under investiga- tion. We studied 30 patients with first- and sec- ond-grade varicocele, 15 idiopathic oligozoosper- mic men and 21 age-matched healthy controls. All subjects underwent testicular Doppler ultra- sonography, semen analysis, gonadotrophin-relea- sing hormone testing and baseline blood sampling for total and free testosterone, PRL, 17β-estradi- ol, SHBG evaluation and Yq chromosome analy- sis. Apart from FSH, no difference in baseline hor- monal levels was found between the groups. The patients with varicocele showed both an increased basal (p=0.007) and GnRH-induced FSH response (peak and AUC) (p=0.004) in comparison with the controls, while the idiopathic oligozoospermic men had only higher GnRH-induced FSH AUC (p=0.04). In the varicocele group, FSH peaks af- ter GnRH testing correlated positively with the grade of disease (r=0.42, p=0.02) and negatively with sperm count (r=-0.50, p=0.005) and bilateral testis volume (r=-0.52, p=0.005). Sperm count and sperm motility were similarly significantly reduced both in patients with varicocele and in patients with idiopathic oligozoospermia in comparison with healthy controls. Yq chromosome analysis by sequence-tagged site PCR revealed no micro- deletion in the AZF regions in any subject stud- ied. Given the quite small number of subjects stud- ied, our overall findings can only prompt us to sug- gest a possible causal role of varicocele in the im- pairment of spermatogenesis in our patients. Furthermore, although a genetic co-influence (i.e. Yq microdeletions) does not seem to be involved in the pathogenesis of infertility in men with varic- ocele and mild to moderate oligozoospermia, ge- netic screening seems to be advisable, especially in those patients who present a severe impairment of sperm count, as has been suggested by recent literature data. (J. Endocrinol. Invest. 24: 217-223, 2001) ©2001, Editrice Kurtis

The electrical resistance of Ni 50 Ti 30 Hf 20 and Ni 50 Ti 40.5 Hf 9.5 alloys during Stress Assisted Two Way Memory Effect was investigated with the aim to deduce the relationship between electrical resistance and deformation across the transformation range. Results show an almost linear relationship although a crossing point between increasing and decreasing deformation may compromise the use of these alloys actuators.

Pituitary apoplexy has been reported as a rare complication of dynamic testing used for the study of pituitary functional reserve. In 1993, a diagnosis of non-secreting macroadenoma with moderate functional hyperprolactinaemia was made in a 43-year-old woman. Soon after the start of therapy with bromocriptine up to 5 mg/die, the patient complained of nausea and postural hypotension. As the symptoms persisted even when the dose was reduced to 2.5 mg/die, the patient was transferred to therapy with quinagolide at the dosage of 37.5 microg/die. PRL levels quickly normalized (range 1.4-5.7 ng/ml) as well as menstrual cycles, and no side-effect was reported. In 1995 a sellar magnetic resonance imaging (MRI) showed no shrinkage of the known macroadenoma. In 1996, few hours after a gonadotropin-releasing-hormone (GnRH) test, which showed normal LH and FSH response and with baseline PRL levels in the normal range, the patient started complaining of severe frontal headache, nausea and vomiting. No gross visual defects were present. An emergency computed tomography (CT) showed no evident hemorrhagic infarction in the macroadenoma. The symptoms completely resolved in few days with steroidal and antiemetic therapy. A new MRI performed in 1998 showed a partial empty sella and PRL levels were in the normal range under dopaminergic treatment. The pituitary functional reserve proved normal on dynamic testing. The temporal association between the onset of symptoms and the GnRH test strongly suggests an association between the two events. No evident signs of pituitary apoplexy (either on emergency CT or hormonal evaluation) were detected. The authors suggest that GnRH can cause severe side-effects that mimic pituitary apoplexy without related morphological evidence and that, in our particular case, it can have caused the gradual disappearance of the non-secreting macroadenoma. Moreover, a causal role of the chronic dopaminergic treatment cannot be completely ruled out.

The pathogenetic role of varicocele in male infertility is still controversial. Although epidemiological data have clearly shown a higher incidence of varicocele in the population of subfertile and infertile patients, the real effectiveness of the surgical repair of varicocele, expressed as increase in the pregnancy rate, is still debated. The presurgical gonadotropin releasing hormone (GnRH) test is the most reliable predictive index of successful surgical outcome in terms of fertility. Only patients with an increased gonadotropin response (in particular FSH) to GnRH will benefit from the surgery. The aim of the present study was to evaluate the gonadotropin response to GnRH 50 micrograms i.v. in a group of patients with low-medium grade varicocele. At the beginning of the test, a fine needle was inserted into the forearm and kept patent by a saline solution. Blood samples were collected at the following experimental times: 0, +15, +30, +60, +90, +120 min. The stimulus was administered i.v. as bolus at time 0. The gonadotropin response to the stimulus and baseline levels of testosterone, PRL, 17 beta oestradiol and SHBG were compared with those of a control group. Moreover, all the patients underwent semen analysis after 3-7 days' abstinence and to ultrasound-doppler of the testis. Finally, we preliminarily looked for the presence of microdeletions on the Yq chromosome by polymerase chain reaction. No difference in baseline hormonal levels was found between the patients with varicocele and the controls; the LH response to GnRH was also similar in the two groups. The patients with varicocele showed a significantly (p = 0.03) higher FSH response (13.6 +/- 5.9 mUI/ml) to GnRH than controls (3.8 +/- 0.5 mUI/ml). A significant positive correlation (r = 0.6, p = 0.05) was found between LH peaks after GnRH testing and varicocele grade. Nine of 11 patients with varicocele showed significant seminal abnormalities (i.e., oligoasthenospermia): all patients showed a normal karyotype and no microdeletions were detected on the Yq chromosome. The authors underline the importance of presurgical GnRH testing in patients with low grade varicocele, given the close correlation between gonadotropin-stimulated peaks and varicocele grade found in the study. The presence of significant seminal abnormalities, even in patients with low grade varicocele, suggests the use of molecular genetic techniques to detect possible microdeletions on the Yq chromosome, which may be responsible for the infertility.

Summary: The effect of long-term nontoxic treatment with phenytoin on the cerebellar Purkinje cell activity as determined by simultaneous monitoring of plasma and cerebellar levels of the drug has been studied in rats for the first time. The electrophysiological observations allowed the analysis of the spontaneous firing rate of the Purkinje cells and of the cerebellar field potentials generated by electrical stimulation of the ipsilateral radial nerve. The responses of single Purkinje cells to radial nerve stimulation were studied by constructing poststimulus time histograms and cumulative frequency distributions. The chronic treatment with phenytoin, which did not induce motor impairment or cerebellar symptoms, modified the firing rate of the Purkinje cells and the two modalities of Purkinje cell activation. In fact, phenytoin decreased significantly the spontaneous activity of the Purkinje cells and modified the strength of the mossy and climbing afferents. RESUMEN Por primera vez se ha estudiado en ratas el efecto del tratamiento cronico, pero no toxico, con fenitoina sobre la actividad de las cealulas de Purkinje durante la monitorizacion simultanea de niveles plasmaticos y cerebelosos de la droga. Las observaciones electrofisiologicas permitieron el analisis de la frecuencia de la actividad espontanea de las celulas de Purkinje y de los potenciales cerebelosos de campo, generados mediante estimulacion electrica del nervio radial homolateral. Las respuestas de celulas de Purkinje aisladas a la estimulacion del nervio radial han sido estudiadas mediante la construccion de histogramas de tiempo post-estimulo y las distribuciones de frecuencias acumuladas. El tratamiento cronico COR fenitoina, que no habia inducido alteraciones motoras o sintomas cerebelosos, modifico la frecuencia de la actividad de las celulas de Purkinje y las dos modalidades de activacion de estas celulas. En realidad la fenitoina redujo significativamente la actividad espontanea de las celulas de Purkinje y modifico la fuerza de las aferentes musgosas y ascendentes. ZUSAMMENFASSUNG Erstmalige Untersuchung der Wirkung einer chronischen, nicht toxischen Behandlung mit Phenytoin auf die Aktivitat der cerebellaren Purkinjezellen der Ratte bei gleichzeitiger Unter-suchung der Medikamentenspiegel im Plasma und Cerebellum. Die elektrophysiologischen Beobachtungen erlauben eine Analyse der spontanen Entladungsrate der Purkinjezellen und der cerebellaren Feldpotential, die durch Elektrostimulation des ipsilateralen Radialisnewen gebildet werden. Die Antwort einzelner Purkinjezellen auf die Stimulation des Nervus radialis wurden durch Konstruktion von Zeit-Histogrammen und kummulativen Frequenzverteilungen im Gefolge des Stimulus untersucht. Die chronische Behandlung mit Phenytoin, die keine motorische Beeintrachtigung Oder cerebellare Symptome verursachte, modifizierte die Entladungsrate der Purkinjezellen und die zwei Modalitaten der Aktivierung von Purkinjezellen. Tatsachlich verminderte Phenytoin signifikant die spontane Aktivitat der derkinjezellen und modifizierte die Starke der afferenten Moos- und Kletterfasern.

Ethosuximide (ESM) was determined by the EMIT technique in tears, saliva, cerebrospinal fluid (CSF), and plasma of epileptic subjects. CSF/plasma, saliva/plasma and saliva/CSF ratios were in good agreement with gas-liquid chromatography (GLC). The tears/plasma ratio was not significantly different from the saliva/plasma ratio, although the standard deviation was higher in the latter. These data indicate that ESM can be determined in a quantitatively similar manner in both saliva and tears by EMIT.

Summary: The penetration of phenobarbital (PB) into cerebral tissue was determined in cats rendered epileptic by parenteral penicillin and in cats with focal penicillin-induced epilepsy. The results were compared with those from normal controls. In both kinds of experimental models of epilepsy, PB penetration was impaired, although a gradual and progressive accumulation of the drug in the brain tissue was observed in all three groups of cats (binding occurring from time 30 min on). Similar to the events with other substances, such as carbamazepine, the prolonged epileptic activity may have contributed to the impaired penetration of PB, because of severe metabolic alterations secondary to seizures. The present data confirm previous reports indicating that epileptic seizures alter the pharmacokinetics of drugs. RESUMEN Se determineo la penetracion de fenobarbital (FB) en el tejido cerebral en gatos con epilepsyia inducida por penicilina parenteral y en gatos con epilipsia por penicilina focal. Los resultados fueron comparados a controles normales. En ambos tipos de modelos experimentales de epilepsyia la penetracion de FB estuvo afectada, aunque se observo una acumulacion gradual y progresiva de la droga en el tejido cerebral en los tres grupos de gatos (desde los 30 minutos del inicio). De manera similar a otras sustancias, tal como la carbamazepina, la actividad epileptica prolongada puede haber contribuido a causar la pobre penetracion de FB, debido a las severas alteraciones metabolicas secundarias a las crisis. Los datos actuales confirman informes previos que senalaban que las crisis epilepticas alteran la farmacocinetica de las drogas. ZUSAMMENFASSUNG Bei Katzen mit Epilepsie durch parenteral oder fokal appliziertes Penizilhn wurde die Eindringfahig-keit von Phenobarbital (PB) in das Hirngewebe unter-sucht. Die Ergebnisse wurden mit normalen Kon-trollen verglichen. Bei beiden Epilepsiemodellen war die PB-Durchlassigkeit gestort, obwohl bei alien drei Gruppen von Katzen eine graduelle und zunehmende Anreicherung der Substanz im Hirngewebe beobachtet wurde (in gebundener Form nach mindestens 30 Minuten). Ahnlich wie fur andere Substanzen Z. B. Carbamazepin konnte die langerbestehende epileptische Aktivitat zur Stoning der Penetration von PB aufgrund der schweren metabolischen Veranderungen infolge der Anfalle beigetragen haben. Die Daten bestatigen fruhere Berichte, die darauf hinweisen, das epileptische Anfalle die Pharmakokinetik verandern.

We studied the effect of varying potassium (K+) concentrations on spontaneous and pentylenetetrazol (PTZ)-induced population burst discharges in mouse hippocampal slices. Standard techniques were used to obtain extracellular recordings in the CA3 region of hippocampal slices from Swiss-Webster mice (21-28 days old). No spontaneous burst discharges occurred at 3.25 mM K+, but population bursts were observed in 20 and 90% of the slices at 6.25 and 9.25 mM K+, respectively. In the presence of 3.25 mM K+, PTZ produced bursts in 12% of the slices at a concentration of 200 micrograms/ml, in 36% at 300 micrograms/ml, and in 40% at 400 micrograms/ml. Slices exhibiting no burst discharges in the presence of 6.25 mM K+ could be induced to do so with the addition of PTZ; bursts were produced in 11% of these slices at a PTZ concentration of 100 micrograms/ml, in 65% at 150 micrograms/ml, and in 87% at 200 micrograms/ml. The PTZ-induced bursting activity was reversible. Clonazepam abolished the bursting elicited with 200 micrograms/ml PTZ at 6.25 mM K+, and phenytoin reduced, but did not stop, bursting activity. Ethosuximide (ETH) was ineffective in stopping or reducing the burst discharges at a concentration of 125 micrograms/ml ETH was there a consistent reduction in the frequency of population bursts. The induction of PTZ discharges in the hippocampal in vitro preparation offers the advantage of a simplified model for studying the pharmacology of antiepileptic drugs.

The repeated administration of subconvulsant doses of pentylenetetrazole (24 mg/kg, i.p.) produced chemically kindled seizures in 16 of 20 mice. Hippocampal slices prepared from the mice with kindled seizures were tested for input-output characteristics in the denate gyrus, and for spontaneous burst discharge frequency in area CA3. The kindled slices displayed no change in the magnitude of the evoked granule cell excitatory postsynaptic potential (pEPSP) to a given stimulus intensity applied to the perforant path, nor in magnitude of the granule cell population spike for a given pEPSP. Although long-term potentiation of synaptic transmission has been proposed as the cellular mechanism of kindling, these results indicate either that long-term potentiation may not underlie kindling or that systemic pentylenetetrazole kindling and focal electrical kindling may be accomplished by different mechanisms. Hippocampal slices from kindled animals did, however, show an increased incidence of spontaneous burst discharges in area CA3 pyramidal neurons in both the absence and the presence of pentylenetetrazole in the bathing medium.

In nine patients affected with dystrophia myotonica the effect of taurine parenteral treatment has been studied. Taurine administration remarkably reduced the hyperexcitability of myotonic muscles. The greater effectiveness of intravenousversus intra-arterial therapy can probably be ascribed to the higher plasma concentration of the amino acid brought about by the former route of administration. A dose-dependent antimyotonic effect of taurine is therefore suggested.

SUMMARY Carbamazepine-10,11-epoxide (CBZ-OX) was determined in physiological solutions by means of EMIT carbamazepine reagent. It was recognized as 12 to 20% of the total amount, the cross-reaction being higher at lower CBZ-OX concentrations. A correction for CBZ-OX is necessary when one wants to correlate EMIT carbamazepine values with gas-liquid chromatography values. However, this correction is relevant only for body fluids other than plasma, since the unbound fraction of CBZ-OX would greatly influence the ultrafiltrate serum ratios. ZUSAMMENFASSUNG Carbamazepin-10,11-Epoxyd (CBZ-OX) wurde in physiologischen Losungen mit Hilfe eines EMIT Carbamazepin-Reagens bestimmt. Es wurde aus 12–20% der Gesamtmenge erkannt. Die Kreuzreaktion ist hoher bei niednger CBZ-OX-Konzentration. Eine Korrektur fur CBZ-OX ist notwendig, wenn man die durch EMIT bestimmten Carbamazepin-Werte mit den durch GLC bestimmten Werten vergleichen will. Diese Korrektur ist jedoch nur fur andere Korperflus-sigkeiten als das Plasma relevant, da der ungebundene Anteil des CBZ-OX in hohem Mase das Ultrafiltrat/Serumverhaltnis beeinflussen wurde.

Summary: We studied the effects of four antiepileptic drugs on pentylenetetrazole-induced burst discharges in the CA3 region of the in vitro hippocampus. Diazepam and carbamazepine abolished the bursting activity in a gradual and dose-dependent manner. Phenobarbital only decreased the burst frequency. Valproic acid was either ineffective or actually caused an increase in both burst frequency and amplitude. The findings in this model were compared with results obtained by other investigators in a penicillin-induced model of epileptiform activity in the hippocampal slice. Diazepam had a similar effect on both pentylenetetrazole- and penicillin-induced burst discharges, but phenobarbital was ineffective in the pentylenetetrazole model, indicating that these chemically induced hippocampal epileptiform activities may be differentially sensitive to antiepileptic drugs. RESUME L'effet de quatre antiepileptiques a eteetudie sur les decharges induites par le pentylenetetrazol, in vitro, sur des tranches de la region CA3 de l'hippocampe. Le diazepam et la carbamazepine suppriment les decharges d'une maniere graduelle et dose-dependante. Le Phenobarbital diminue seulement la frequence des decharges. L'acide valproique est inefficace ou měme augmente la frequence et l'amplitude des decharges. Les constatations faites sur ce modele ont ete comparees a celles d'autres chercheurs sur un modele d'activiteepileptiforme induite par la penicilline dans des tranches d'hippocampe. Le diazepam a un effet similaire a la fois sur les decharges induites sur le pentylenetetrazol et sur celles induites par la penicilline, mais le phenobarbital est inefficace sur le modele au pentylenetetrazol, ce qui indique que diverses modalites d'induction des decharges epileptiques de l'hippocampe peuvent ětre sensibles d'une ma-niere differente aux medicaments antiepileptiques. RESUMEN Hemos estudiado el efecto de cuatro drogas anticomiciales sobre los brotes de descarga inducida por pentilentetrazol en la region CA3 del hipocampo in vitro. Diazepam y carbamazepina suprimen la actividad en brotes de una forma graduai y dosis-dependiente. El fenobarbital solo disminuye la frecuencia de los brotes. El acido valproico fue ineficaz o incluso causo un incremento de la frecuencia y amplitud de los brotes. Los hallazgos con este modelo fueron comparados con los resultados obtenidos por otros investigadores en un modelo de actividad epileptiforme inducido por penicilina en cortes de hipocampo. El diazepam tenia un efecto similar en las descargas de brotes inducidas por pentilentetrazol y penicilina, pero el fenobarbital fue inefectivo en el modelo pentilentetrazol, indicando que estas actividades epileptiformes hipocampales inducidas quimicamente pueden tener diferente sensibilidad a las drogas anticomiciales. ZUSAMMENFASSUNG Wir untersuchten die Wirkung von 4 Antiepileptika auf die Pentylentetrazol-induzierten bursts in der CA3-Region von Hippocampus-Schnitten. Diazepam und Carbamazepin brachten die burst-Aktivitat allmahlich und dosisabhangig zum Verschwinden. Phenobarbital verminderte nur die burst-Frequenz. Valproinsaure war entweder unwirksam oder zeigte im Gegensatz eine Vermehrung sowohl der burst-Frequenz als ihrer Amplitude. Die Befunde an diesem Modell wurden mit Ergebnissen verglichen die andere Untersucher am Penicillin-induzierten Modell der epileptiformen Aktivitat in Hippocampus-Schnitten erhoben. Diazepam hatte eine ahnliche Wirkung sowohl auf die durch Pentylentetrazol als durch Penicillin induzierten burst-Entladungen, wahrend Phenobarbital im Pentylentetrazol-Modell unwirksam war. Das deutet darauf hin, das diese chemisch induzierte hippocampale epileptiforme Aktivitat Antiepileptika gegenuber unterschiedlich sensibel sein konnte.

Summary: Valproic acid (VPA) was determined by EMIT® assay in plasma, tears, saliva, and cerebrospinal fluid (CSF) of patients with epilepsy. Closer correlation was shown between tear/plasma and tear/CSF ratios than between saliva/plasma and saliva/CSF ratios. The VPA CSF/serum ratio was in good agreement with data in the literature. Salivary levels were extremely erratic, while those for tears were much more reliable. Determination of VPA in tears is therefore the best method of studying the VPA free fraction in those cases in which investigations of protein binding of the drug are necessary. RESUMEN Con el procedimiento EMIT se ha determinado el acido valproico (VPA) en plasma, lagrimas, saliva y liquido cefaloraquideo (LCR) en pacientes con epilepsia. Se encontro una correlation mas estrecha entre lagrima/plasma y lagrima/LCR que entre saliva/plasma y saliva/LCR. La relacion LCR/suero de VPA estaba de acuerdo con la information aparecida en la literature. Los niveles salivares fueron extremadamente er-raticos mientras que los de las lagrimas eran mas fiables. La determination del VPA en las lagrimas constituye el mejor metodo para el estudio de la fraction libre de VPA en los casos en los que, investigaciones sobre el acoplamiento de la droga (binding) a las proteinas, resultan necesarias. ZUSAMMENFASSUNG Valproinsaure wurde mit der Emit-Methode im Plasma, in der Tranenflussigkeit, im Speichel und im Liquor cerebrospinalis (CSF) von Patienten mit Epilepsie bestimmt. Eine engere Korrelation zeigte sich zwischen Tranenflussigkeit und Plasma sowie Tranenflussigkeit und CSF als zwischen Speichel und Plasma bzw. Speichel und CSF. Das Verhaltnis des VPA im CSF und im Serum entsprach den Daten der Literatur. Die Speichelwerte waren auserst regellos, wahrend solche der Tranenflussigkeit sich als viel verlasslicher erwiesen. Die Bestimmung des VPA in der Tranenflussigkeit ist deshalb die beste Methode fur die Untersuchung der freien Fraktion des VPA in den Fallen, in denen Untersuchungen der Eiweisbindung des Medikaments notwendig sind.

Carbamazepine (CBZ) brain distribution was studied in cats rendered epileptic by penicillin topically applied on neocortex. CBZ penetration into the focus did not differ significantly from penetration into the other areas of the brain, with the drug rapidly entering the cerebral tissue (peak at 30 min). As no difference was found between CBZ brain concentrations at 15 and 90 min, substantial early binding of the drug was confirmed in this experimental model of epilepsy. As CBZ was able to decrease rapidly the spike frequency of the penicillin focus, it may be speculated that it was also able to prevent the metabolic alterations associated with severe epileptogenesis that would have caused an impaired CBZ brain distribution.

Carbamazepine (CBZ) brain uptake was determined in cats rendered epileptic by administration of 250,000 IU penicillin/kg intramuscularly, and the results were compared with those in a control group. CBZ penetration in the brain was significantly different in the epileptic cats, the uptake of the drug in the generalized epileptic brain being decreased and delayed, although substantial binding occurred also in this case. Plasma and CSF levels behaved similarly in normal and epileptic cats. Arguably the impaired CBZ brain uptake was due to the epileptic activity itself, which per se can be responsible for marked inhibition of protein synthesis, thus modifying the proven ability of CBZ to bind to phospholipid and protein components of neuronal cells.

Diphenylhydantoin (PHT) and primidone (PRM) were determined by the EMIT technique in the plasma, tears, saliva, and CSF of epileptic patients. Results indicate for PHT that tear values are more strictly correlated than are the saliva values to plasma and CSF concentrations. As for PRM, the data obtained show great interindividual variability of concentration in the different body fluids--in agreement with the wide range of both protein binding and half-life of this drug.

Carbamazepine (CBZ) was determined by EMIT assay in plasma, cerebrospinal fluid (CSF), and brain samples of cats after administration of the drug (40 mg/kg, i.p.). Plasma and CSF levels increase in a parallel manner from time 0 to 90 min after completion of injection, indicating a passive transport from one body fluid to the other. Brain levels reach a steady state at 15 min, with no significant difference being found between the concentrations at 15, 30, 60, and 90 min postinjection; this indicates that substantial early binding occurs in the brain. Since peak CSF concentrations occur at 90 min, concomitant with those for plasma, while brain levels are already high at 15 min, it is likely that CBZ enters the two compartments by independent mechanisms.

In awake paralyzed Wistar rats, the following effects of an acute nontoxic dose of phenytoin (PHT) on different parameters of cerebellar electrical activity were evaluated: spontaneous discharge rate of single Purkinje cells (P-cells), field potentials, and responses of P-cells generated by electrical stimulation of a forelimb nerve. Variations of the response of single neurons located in the inferior olive were also studied, in order to assess the effects of PHT on this precerebellar relay station. The drug was administered orally and plasma and cerebellar levels regularly estimated. The results indicate that an acute, nontoxic dose of PHT is associated with an increase of P-cell firing rate. This finding is supported by the analysis of the frequency distribution of interspike intervals, and by the field potentials, P-cell, and olivary responses induced by stimulation of a radial nerve. In addition, it was observed that the increase in P-cell firing was mainly depending upon a higher activity of the climbing fibers. The increase in the response of P-cells and olivary cells was correlated with plasma and cerebellar drug levels. The conclusion was reached that PHT increases the cerebellar cortical activity through two mechanisms: (a) by acting directly on the cerebellar P-cell; and (b) indirectly by acting on the origin of climbing fibers at the inferior olive nucleus.

A case is reported of a woman in whom acute manic attacks were followed later in life by neurological signs of multiple sclerosis, thus suggesting a possible correlation between the two clinical entities.