Receptor binding of N-(methyl-11C) clozapine in the brain of rhesus monkey studied by positron emission tomography (PET)

By means of positron emission tomography the uptake and kinetics of N-(methyl-¹¹C)clozapine in different brain regions have been studied in Rhesus monkeys. ¹¹C-clozapine rapidly entered the brain and maximum radioactive uptake was seen 5–12 min after administration. Highest uptake was measured in the striatum. Other regions with an uptake higher than in the cerebellum were thalamus and mesencephalon. The radioactivity from different brain regions decreased with an elimination half-life of about 5 h and parallelled the plasma kinetics of unlabelled clozapine. The striatum/cerebellum ratio of ¹¹C-clozapine-derived radioactivity remained constant during the period studied and did not change after pretreatment with atropine. In contrast, the striatum/cerebellum ratio was somewhat lower after pretreatment with N-methylspiperone (NMSP), indicating competition for the same binding sites in the striatum. After pretreatment with increasing doses of clozapine, a dose-dependent protection of binding sites in the striatum for ¹¹C-NMSP was seen. It is concluded that clozapine is more loosely bound to dopamine receptors in the striatum than N-methylspiperone and that the kinetics of clozapine in the brain parallel that in the plasma. The binding properties of clozapine within the brain may explain some of the clinical properties of the drug.     

Imaging of fluorescent neurons labelled with fluoro-gold and fluorescent axon terminals labelled with AMCA (7-amino-4-methylcoumarine-3-acetic acid) conjugated antiserum using a UV-laser confocal scanning microscope.

This paper describes the implementation of an ultraviolet (UV) laser (Spectra Physics 171-18 with 3 lines: 334, 351 and 364 nm in UV) as light source for fluorescence confocal scanning microscopy. With this instrument it is possible to use fluorophores not previously available for confocal laser microscopical imaging of fluorophores such as fluoro-gold and AMCA. In the study we show confocal laser microscopical imaging of fluorescent motoneurons labelled by retrograde transport of fluoro-gold and AMCA-fluorescent axon terminals labelled with antisera against immunogenes as thyrotropin-releasing hormone (TRH) and calcitonin gene-related peptide (CGRP). These two fluorophores may be recorded simultaneously or separately by using a filter that suppresses the emission of one of the fluorophores. The described instrument should also be useful in applications involving detection of monoamines by the Falck-Hillarp technique, as well as measurements of cytosolic free calcium by indicators such as Fura-2 and Indo-1. Measurements performed in reflected and fluorescence light indicated that the resolution along the optical axis improved by about 25% when UV (351 nm) is used instead of visible light (514 nm). This figure is close to that expected on theoretical basis. There are, however, also serious problems related to the use of UV excitation. Firstly, objectives must be selected based on their UV transmission properties. Secondly, chromatic aberration may cause a substantial focal shift between illuminating and emitted light, calling for a flexible instrumental design in order to allow for compensation. As shown here, this problem can be circumvented by using reflecting objectives but at a price of lower resolution compared with high-aperture refracting objectives.     

Present status of boron neutron capture therapy.

The neutron capture reaction 10B(1n,4He)7Li produces two energetic particles, 4He2+ and 7Li3+ that are strongly cell toxic. Due to the short range of these nuclear fragments (5-9 microns) mainly those cells that have bound or internalized a 10B-containing substance are growth-inactivated. The most critical and difficult step in an efficient boron neutron capture therapy (BNCT) is the tumour targeting. It is today possible to synthesize a large number of boron compounds and conjugate them to tumour-seeking macromolecules, such as monoclonal antibodies or different polypeptides. The boron-containing substances presently considered for therapy are sulfhydryl boron hydride (BSH) and boron-phenylalanine, (BPA) for the treatment of gliomas and malignant melanomas respectively. Other boronated compounds considered are ligands for receptor-amplified tumour cells, antibodies for tumour cells with specific antigens and thioureas for treatment of melanotic melanomas. The required boron concentration is given by the relative dose due to neutron capture in 10B and that of the competing capture reactions in nitrogen and hydrogen. Capture in nitrogen produces protons with a range of about 10-11 microns and this gives a radiation dose to all cells in the neutron activated area. Calculations show that the local concentration of 10B near the critical radiation target, DNA, must be higher than 10 ppm (10 micrograms/g). Increased emphasis will be put on the development of combinations of treatments that fulfil the requirements for attacking the microscopic spread of the tumour.     

A histomorphometric study of unthreaded hydroxyapatite-coated and titanium-coated implants in rabbit bone.

Hydroxyapatite-coated and titanium-coated IMZ dental implants were investigated in an animal study. The implants were placed in the distal femurs of rabbits. Six months after placement, histomorphometric evaluation of the bone-to-implant contact was conducted. The hydroxyapatite-coated specimens demonstrated significantly more direct bone contact compared to the titanium-coated controls.     

Spigelian hernia

The diagnosis of spigelian hernia presents greater difficulties than its treatment. The clinical presentation varies, depending on the contents of the hernial sac and the degree and type of herniation. The pain, which is the most common symptom, varies and there is no typical pain of spigelian hernia. Findings to facilitate diagnosis are palpable hernia and a palpable hernial orifice. Large, easily palpable spigelian hernias are not a diagnostic problem. It is small hernias and hernial orifices that are overlooked because they are masked by the subcutaneous fat and an intact external aponeurosis. In the absence of a palpable orifice or sac, persistent point tenderness in the spigelian aponeurosis with a tensed abdominal wall most strongly suggests the diagnosis. Spigelian hernia can be ruled out in patients without palpable tenderness. Ultrasonic scanning can be recommended for verification of the diagnosis in both palpable and nonpalpable spigelian hernia. The hernial orifice and sac can also be demonstrated by computed tomography, which gives more detailed information on the contents of the sac than does ultrasonic scanning. The treatment of spigelian hernia is surgical, and the risk of recurrence is small. A gridiron incision is excellent for operations for palpable hernias. If the hernia cannot be palpated preoperatively, preperitoneal dissection through a vertical incision is recommended. This gives good exposure, facilitates hernioplasty, and permits preperitoneal exploration and treatment of other abdominal wall hernias. The incision is also suitable for exploratory laparotomy, which should be performed on patients with abnormal ultrasonographic or computed tomographic findings in whom no palpable hernia can be detected preoperatively.

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Resumen El diagnóstico de la hernia spigeliana presenta mayores dificultades que su tratamiento. La presentación clínica varía según el contenido del saco herniario y el grado y tipo de herniación. El dolor, que es el síntoma más común, es variable y no existe un dolor que sea típico de la hernia spigeliana. Los signos físicos que facilitan el diagnóstico son la hernia palpable y un orificio herniano palpable. Las hernias spigelianas grandes y fácilmente palpables no constituyen un problema diagnóstico. Son más bien las hernias pequeñas y los orificios mínimos los que pueden pasar desapercibidos al ser enmascarados por la grasa subcutánea y por una aponeurosis intacta. En ausencia de un orificio o de un saco palpable, el dolor a la presión sobre la aponeurosis spigeliana, manteniendo tensa la pared abdominal, sugiere fuertemente este diagnóstico; la hernia spigeliana puede ser excluída como posibilidad diagnóstica en pacientes que no exhiban tal dolor a la palpación. La ultrasonografía puede ser recomendada para verificación del diagnóstico, tanto en las hernias spigelianas palpables como en las no palpables. El orificio y el saco herniarios también pueden ser demostrados mediante tomografía computadorizada, estudio que provee información más detallada que la ultrasonografía sobre el contenido del saco.El tratamiento es quirúrgico y el riesgo de recurrencia es bajo. Una incisíon oblicua o transversa resulta excelente para la operación en hernias palpables; si la hernia no es palpable en el examen preoperatorio, se recomienda realizar disección preperitoneal a través de una incisión vertical. Esto da buena exposición, facilita la hernioplastia, y permite la exploración preperitoneal y el tratamiento de otras hernias de la pared abdominal. La incisión también es adecuada para la laparotomía exploratoria, la cual debe ser realizada en pacientes con hallazgos anormales en la ultrasonografía o en la tomografía computadorizada y en quienes no haya sido posible detectar una hernia palpable preoperatoriamente.

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Résumé Le diagnostic d'une hernie de Spiegel est plus difficile que son traitement. Les signes de découverte varient, dépendant du contenu du sac herniaire, d l'importance, et du type de la hernie. La douleur, symptôme le plus fréquent, n'est pas typique. Les signes qui aident au diagnostic sont la palpation de la hernie et de l'orifice herniaire. Lorsque l'orifice est large et palpable, le diagnostic de hernie de Spiegel ne pose pas de problème. Ce sont les hernies de petite taille, à orifice réduit, qui sont souvent masquées par la graisse sous-cutanée et l'aponévrose oblique externe. En l'absence d'orifice ou de hernie palpable, la persistance de la douleur à la palpation au niveau de l'aponévrose, alors que la paroi abdominale est sous tension, est significative. En l'absence de cette douleur provoquée, on peut pratiquement éliminer ce diagnostic. On conseille de vérifier le diagnostic par une échographie, que cette douleur existe ou pas. L'orifice et le sac herniaire se voient bien également par la tomodensitométrie plus performante que l'échographie en ce qui concerne le contenu herniaire.Le traitement de la hernie est chirurgical; le risque de récidive est réduit. Une incision centrée sur la hernie, sans section musculaire, est excellente. Si la hernie ne peut être palpée, on conseille une incision verticale avec un abord extrapéritonéal. L'exposition est excellente, la cure est aisée et l'exploration prépéritonéale ainsi facilitée, permet en outre la cure d'autres hernies pariétales associées. La même incision convient également pour une laparotomie exploratrice, au cas où l'échographie ou la tomodensitométrie ne montrent rien de spécifique et où il n'existe pas de hernie détectée préopérativement.

     

Sexually differentiated actions of 3-PPP enantiomers on prolactin secretion

The ability of the enantiomers of the atypical dopamine receptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) to counteract gamma-butyrolactone-induced hyperprolactinemia was compared in male and female rats. Following gamma-butyrolactone (GBL) pretreatment serum prolactin concentrations were higher in female than in male rats. In males (-)-3-PPP tended to be somewhat less effective than (+)-3-PPP in decreasing serum prolactin concentrations (levels after (+)-3-PPP and (-)-3-PPP: 21% and 33%, respectively, of levels in GBL-pretreated control(s). In females the (-)-form induced a much weaker response than did the (+)-form (levels after (+)-3-PPP and (-)-3-PPP: 8% and 74%, respectively, of levels in GBL pretreated controls). Parallel experiments replacing GBL by reserpine yielded similar results. Data are discussed in terms of sex differences in responsiveness of pituitary dopamine receptors.     

In vivo receptor binding,neurochemical and functional studies with the dopamine D-1 receptor antagonist SCH 23390

Summary A series of in vivo experiments were undertaken, relating functional (motor activity, body temperature), dopamine (DA) receptor binding and neurochemical (catecholamine synthesis and utilization, DA release) aspects of the pharmacology of SCH 23390 in the rat.The compound inhibited the locomotor hyperactivity, but not the hypothermia, induced by the potent DA stimulant DP-5,6-ADTN. Interstingly, SCH 23390 simultaneously failed to displace DP-5,6-ADTN from its binding sites in the rat striatum—used as a direct in vivo biochemical index of DA (D-2) receptor interaction. The spontaneous locomotion in non-pretreated rats was likewise inhibited by SCH 23390. The locomotor-suppressive action, but not the DP-5,6-ADTN-displacing capcity of the D-2 blocker haloperidol was significantly enhanced by SCH 23390, suggesting that motility can be suppressed by either enhanced D-1 or D-2 (postsynaptic) receptor blockade, but also that the D-1 and D-2 sites involved may be physically distinct.SCH 23390 only slightly altered in vivo neurochemical of DA synthesis, release and nerve-impulse flow, indicating that, while similar in suppressing dopaminergic behaviour, the D-1 antagonist is less effective than traditional neuroleptics as an activator of DA neuronal feedback mechanisms. The weak increases of DA synthesis and release nonetheless obtained were equal in magnitude (30–40%) in the limbic vs. striatal brain areas; also in this respect, SCH 23390 thus differs from classical neuroleptics, which generally display more marked effects in the striatum than in limbic tissue.No major changes in the in vivo indices of NA synthesis and utilization (or in 5-HT synthesis) were found after SCH 23390 administration, by and large supporting the DA receptor specificity of the compound.In summary, the studies demonstrated that SCH 23390 can offset and accentuate, respectively, behavioural consequences of D-2 receptor stimulation and blockade. Importantly, at the same time no direct interaction at the level of D-2 DA receptor sites in the striatum was detected. Only slight, D-2 antagonist-like, changes in neurochemical indices of dopaminergic activity were observed after D-1 receptor blockade by means of SCH 23390. With regard to DA agonist hypothermia, SCH 23390 was without effect per se, but (at a high dose) attenuated the action of the D-2 antagonist haloperidol. The observations may indicate that the complex interactions between central D-1 and D-2 receptor-controlled mechanisms that influence behaviour, neurochemistry, and possibly autonomic nervous expression, are not identical.     

Evaluation of regret after tubal sterilization.

Many different criteria and profiles have been suggested for the possible cause of regret and requests for reversal after tubal sterilization. Evaluation of data obtained from 2253 women who had undergone tubal sterilization showed a strong correlation between regrets and youthful age and to changes in marital situation. Previously demonstrated risk factors, such as sterilization in connection with abortion or labor were not related to regret in this study material.     

A study of injuries during life in three male populations

In a population study of samples of 60-, 50-, and 30-year-old men, information about injuries suffered during life was obtained by personal interview. Included were head injuries with unconsciousness, and injuries which had caused restricted activity for more than one day or had caused medical attendance. The interview technique was the only way to cover all these injuries. Possible biases are discussed. The results indicated that the young men tended to report a higher incidence of injuries, to suffer their first injury at an earlier age and to attend medical services to a larger extent than the older men. An incidence peak in adolescence was reported in all three cohorts. Accidents with multiple injuries were more common in higher ages in all cohorts. Falls, blows, and impacts, cutting and piercing agents, and traffic accidents were the most common causes of injuries in all cohorts.