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PubMed2001

Antipsychotic drugs classified by their effects on the release of dopamine and noradrenaline in the prefrontal cortex and striatum.

Dose-effect curves were established for the effects of the antipsychotic drugs haloperidol, clozapine, olanzapine, risperidone and ziprasidone on extracellular levels of dopamine and noradrenaline in the medial prefrontal cortex, and of dopamine in the striatum. Haloperidol was more effective in stimulating the release of dopamine in the striatum, whereas clozapine was much more effective in the medial prefrontal cortex. The efficacy of risperidone, olanzapine and ziprasidone did not differ for the two brain areas. The benzamides sulpiride and raclopride increased dopamine release in the striatum but did not affect the release of dopamine and noradrenaline in the medial prefrontal cortex. In the presence of dopamine/noradrenaline reuptake inhibitors, the benzamides strongly increased the release of dopamine-but not of noradrenaline-in the medial prefrontal cortex. The 5-HT(2) receptor antagonist R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (MDL100,907) (800 nmol/kg) and the dopamine D(2) receptor antagonist raclopride (2 micromol/kg) displayed a clear synergism in increasing the release of dopamine in the medial prefrontal cortex. No such synergism was seen in the case of noradrenaline. Co-administration of the 5-HT(2) receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine HCl (DOI) (850 nmol/kg) with clozapine (10 micromol/kg) or haloperidol (800 nmol/kg) blocked the increase in dopamine as well as noradrenaline in the medial prefrontal cortex. It is concluded that typical and non-benzamide atypical antipsychotics increase extracellular dopamine in the medial prefrontal cortex via a synergistic interaction by blocking 5-HT(2) as well as dopamine D(2) receptors. The increase in extracellular noradrenaline in the medial prefrontal cortex that was observed after administration of antipsychotics is explained by inhibition of 5-HT(2) receptors and not dopamine D(2) receptors. Finally, the significance of the classification of antipsychotic drugs based on their selective action on the release of dopamine and noradrenaline in the medial prefrontal cortex is discussed. In particular, the position of the benzamides is discussed.

Animals↗
PubMed2002

Can antipsychotic drugs be classified by their effects on a particular group of dopamine neurons in the brain?

During the four decades that research has been carried out on antipsychotic drugs, a variety of methods have been used to study the effects of these compounds on dopamine neurotransmission. An important issue in this research was to find an explanation for the difference between "typical" and "atypical" antipsychotic drugs. The hypothesis that the beneficial properties and the motor side effects of antipsychotic drugs result from their effects on different groups of dopamine neurons has received considerable attention. Numerous researchers have tried to discover regiospecific actions of antipsychotic drugs in mesolimbic and in mesocortical dopamine neurons. An overview of these research attempts is presented here. Electrophysiological studies showed a selective action of atypical antipsychotic drugs on A10 dopamine neurons. It was found that chronic treatment with these compounds induced a preferential depolarisation block of the A10 neurons that project to the mesolimbic areas. The model represents certain clinical features of antipsychotic drug use and offers a possible explanation for the lack of extrapyramidal side effects of atypical antipsychotic drugs. Dopamine neurons projecting from A10 to the frontal cortex are also considered as a possible site of action of atypical antipsychotic drugs. Microdialysis studies have shown that certain atypical antipsychotic drugs selectively enhance the release of dopamine in the prefrontal cortex when compared with typical antipsychotic drugs. The finding that repeated treatment with antipsychotic drugs increased dopamine D(2) receptor binding in the frontal cortex confirms the significance of this brain area. These properties might indeed explain certain beneficial effects of atypical antipsychotic drugs such as improvement of cognitive dysfunction. However the effects of typical and atypical antipsychotic drugs in the frontal cortex could not be fully differentiated, which illustrates the difficulty of localising clinical effects of antipsychotic drugs in terms of regional dopamine neurons. Recently new insights into the mechanism of action of typical and atypical antipsychotic drugs have been published. Clinical positron emission tomography (PET) studies have indicated that a moderate dopamine D(2) receptor occupancy, probably combined with a high dissociation rate, might provide the optimal clinical conditions for an antipsychotic drug, without inducing extrapyramidal side effects. Moreover the efficacy of benzamides as atypical antipsychotic drugs suggests that low to moderate dopamine D(2) blockade is probably the most important-if not the only-criterion that determines "atypicality". Interestingly these new insights are based on PET studies of the human basal ganglia and not on the comparison of different brain areas. Apparently, according to this concept an ideal antipsychotic drug need not to act on a particular type of dopamine neurons, as it is the moderate dopamine D(2) receptor occupancy that determines the desirable clinical effects. It is concluded that both beneficial actions and side effects, of antipsychotic drugs might be dose dependently localised in A9 as well as A10 dopamine neurons.

Animals↗
PubMed2000

Identification of meiotic and postmeiotic gene expression in testicular tissue of patients histologically classified as Sertoli cell only.

OBJECTIVE: To determine whether meiotic and postmeiotic germ cell gene products could be detected in biopsy specimen from patients with Sertoli cell only (SCO) and maturation arrest. DESIGN: Prospective clinical study. SETTING: University-based departments and laboratories. PATIENT(S): Nine patients, seven with nonobstructive azoospermia (12 biopsies) and two with obstructive azoospermia (controls) (2 biopsies). INTERVENTION(S): Specimens were divided into three parts: IVF laboratory, histology, and molecular analysis. Germ cell-specific messenger RNAs (mRNAs) were detected by extracting total RNA for Northern blotting or reverse transcription-polymerase chain reaction. MAIN OUTCOME MEASURE(S): Detection of meiotic (lactate dehydrogenase C4) and postmeiotic (transition protein 1 and protamine 1 and 2) gene expression and correlation with histologic and IVF laboratory findings. RESULT(S): The IVF laboratory identified spermatozoa in 3 of 14 biopsies (controls and severe hypospermatogenesis). Histologically, 6 of 14 biopsies (43%) were diagnosed as SCO, 4 (29%) maturation arrest, 2 (14%) severe hypospermatogenesis, and 2 normal. Molecular analysis showed mRNA for meiotic and postmeiotic genes in 12 of 14 biopsies (86%) (P =. 006), of which 4 (67%) in SCO and 3 (75%) in maturation arrest. CONCLUSION(S): Differentiated germ cells are present in biopsies of men histologically diagnosed as SCO. Absence of these molecular markers strengthens the histologic diagnosis and helps the physician in counseling the infertile couple.

Adult↗
PubMed1997

New indices to classify location, severity and progression of calcific lesions in the abdominal aorta: a 25-year follow-up study.

The purpose of the present study was to assess the location, severity and progression of radiopaque lumbar aortic calcifications and to evaluate the utility of summary scores of lumbar calcification in a population-based cohort. Lateral lumbar films, obtained in 617 Framingham heart study participants, were analysed for the presence of abdominal aortic wall calcification in the region corresponding to the first through fourth lumbar vertebrae. The severity of the anterior and posterior aortic calcification were graded individually on a 0-3 scale for each lumbar segment and the results were summarized to develop four different composite scores: (1) affected segments score (range 0-4); (2) anterior and posterior affected score (range 0-8); and (3) antero-posterior severity score (range 0-24). The prevalence of aortic calcification was 37% in men and 27% in women at baseline and 86% in both genders at the follow-up exam 25 years later. During the follow-up interval, the mean of the affected segments score increased from 0.7 in men (0.5 in women) to 2.7 (2.8 in women), the mean of the anterior and posterior affected score from 1.2 (0.8 in women) (P = 0.012 for difference between genders) and the mean of the antero-posterior severity score increased from 1.5 (1.3 in women) to 9.3 (10.3 in women). The antero-posterior severity score offered a slight advantage over other composite scores and had the highest inter-rater intra-class correlations. In summary, lumbar aortic calcification can be graded and composite summary scores are reproducible. This technique appears to provide a simple, low cost assessment of subclinical vascular disease.

Aged↗
PubMed2000

Analysis of size-classified ice crystals by capillary electrophoresis.

In order to analyse the main inorganic cations (NH4+, K+, Na+, Ca2+, Mg2+) and anions (Cl-, NO3-, SO4(2-)) as well as carboxylic and dicarboxylic acids in ice crystals by capillary electrophoresis, electrolyte systems were developed and optimised with respect to limits of detection, resolution, reproducibility and analysis time. We applied indirect UV detection, which enables the simultaneous detection of multiple components. Salicylic acid and 4-methylaminophenolsulfate were used as UV-active co-ions for analysis of anions and cations, respectively. The special features of these systems were low limits of detection in the range 0.3-0.9 micromol L(-1), i.e. absolute limits of detection were in the fmol range, and short analyses times. Separations of cations as well as anions including carboxylic and dicarboxylic acids were completed within 4 min allowing a high sample throughput. Furthermore, the applicability of the newly developed electrolyte systems was demonstrated by comparative analyses with ion chromatography and by first field experimental studies.

Cations↗
PubMed1998

Morphometric analysis of bovine lymphomas classified according to the National Cancer Institute Working Formulation.

The National Cancer Institute Working Formulation (NCI-WF) for the subjective classification of human non-Hodgkin's lymphoma is readily applicable to the classification of bovine lymphomas. Forty-nine cases of bovine lymphoma were analysed morphometrically to see if nuclear size and cleavage were distributed continuously or discretely between different NCI-WF tumour cell types. The mean nuclear area (+/- standard error of the mean, SE) was significantly greater (P < 10(-6)) in cells from the different types of diffuse large-cell lymphoma than in cells from the different types of small-cell lymphoma (42.91 +/- 1.21 micron 2 vs 19.33 +/- 1.08 micron 2, respectively); there was no overlap between the two groups. The mean nuclear are (+/- SE) of cells from diffuse large-cell lymphomas was significantly greater (P < 10(-4)) than that of cells from small non-cleaved lymphomas (42.74 +/- 1.72 micron 2 vs 27.54 +/- 1.08 micron 2, respectively), and there was again no overlap between the two groups; these two cell types are difficult to distinguish by any criteria other than size. Additionally, the cell-to-cell variability in nuclear area within a given tumour was significantly greater (P < 0.001) for the diffuse large-cell type than for the small non-cleaved cell type. The mean nuclear form factor (+/- SE) and mean nuclear contour indices (+/- SE) of the diffuse large cleaved cell type (0.53 +/- 0.02 and 5.08 +/- 0.11, respectively) were significantly different (P < 0.01 to 10(-6)) from the same parameters in the diffuse large-cell type (0.82 +/- 0.01 and 3.94 +/- 0.04, respectively). Some of the major criteria of the NCI-WF used subjectively to discriminate between bovine lymphoma cell types were supported by morphometric measurements. The magnitude of the differences in nuclear morphological characteristics between bovine lymphoma cell types was such that there was no overlap.

Animals↗
PubMed1997

Mutagens and carcinogens in size-classified air particulates of a northern Italian town.

This research was designed to examine the presence of mutagenic/carcinogenic compounds in urban airborne particulate matter in relation to particles aerodynamic size. Inhalable (< 10 microns) airborne particulate (PM-10) was collected at a low traffic site in an industrialized Northern Italian town, using a high volume sampler equipped with a cascade impactor for particles fractionation. The organic extracts of different fractions were examined for mutagenicity in Salmonella typhimurium strains TA98 and TA98/1,8-DNP6 using the microsuspension procedure, and for polycyclic aromatic hydrocarbons (PAHs) content by gas chromatography. Size fractionated particles were also analysed for heavy metals (Fe, Mn, Zn, Pb, Cu, Cd, Cr, Ni, V) using plasma spectrophotometry. The results of mutagenicity and chemical analyses indicate that, at the site investigated, inhalable particulate was largely made of fine (< 0.5 micron) particles, which accounted for most of PAHs and mutagenicity. A similar pattern of distribution was found for heavy metals, which were relatively more abundant in small (< 1.5 microns) particles compared to coarser ones.

Air Pollution↗
PubMed2000

Accuracy of diagnosis by guided biopsy of renal mass lesions classified indeterminate by imaging studies.

OBJECTIVES: To define the accuracy, safety, and impact of percutaneous biopsies of indeterminate mass lesions as an additional diagnostic tool. The vast majority of renal mass lesions are routinely diagnosed by radiographic features alone. However, with the increased use of computed tomography scanning and ultrasound, many smaller renal masses, which are "indeterminate" (refractory to categorization on the basis of imaging alone), are now being discovered. METHODS: We retrospectively reviewed 583 patients (364 male and 219 female) with indeterminate renal mass lesions diagnosed by imaging studies that were further investigated by percutaneous biopsy. Patients were followed up for at least 5 years if the biopsy result demonstrated a benign lesion, or they underwent surgical exploration if the biopsy result demonstrated a malignancy. Biopsy or aspiration material was assessed by histopathologic and cytologic evaluation and, when appropriate, with biochemistry, Gram stain, culture, and sensitivity. The biopsy site was localized by computed tomography, ultrasound, or fluoroscopy. RESULTS: Five hundred eighty-three patients with indeterminate renal mass lesions (representing 7.2% of all renal masses diagnosed from 1967 through 1996) were diagnosed by imaging studies complemented by guided biopsy. Sixty-six patients were lost to follow-up, leaving 517 patients who were analyzed. In 393 cases (76%), the imaging-guided biopsy provided a definitive diagnosis. The incidence of false diagnoses was 1.2% (7 biopsies). In 124 of the cases (21%), imaging-guided biopsy was unable to determine the etiology of the lesion with acceptable confidence; of these, 21 biopsies did not provide enough material to establish the diagnosis (16.9%). CONCLUSIONS: Overall, percutaneous biopsy of the kidney has proved to be a safe and accurate diagnostic procedure, with impact on the management of cystic or solid renal lesions.

Adolescent↗