Aggrecan and chondroitin-6-sulfate abnormalities in schizophrenia and bipolar disorder: a postmortem study on the amygdala.

Perineuronal nets (PNNs) are specialized extracellular matrix aggregates surrounding distinct neuronal populations and regulating synaptic functions and plasticity. Previous findings showed robust PNN decreases in amygdala, entorhinal cortex and prefrontal cortex of subjects with schizophrenia (SZ), but not bipolar disorder (BD). These studies were carried out using a chondroitin sulfate proteoglycan (CSPG) lectin marker. Here, we tested the hypothesis that the CSPG aggrecan, and 6-sulfated chondroitin sulfate (CS-6) chains highly represented in aggrecan, may contribute to these abnormalities. Antibodies against aggrecan and CS-6 (3B3 and CS56) were used in the amygdala of healthy control, SZ and BD subjects. In controls, aggrecan immunoreactivity (IR) was observed in PNNs and glial cells. Antibody 3B3, but not CS56, also labeled PNNs in the amygdala. In addition, dense clusters of CS56 and 3B3 IR encompassed CS56- and 3B3-IR glia, respectively. In SZ, numbers of aggrecan- and 3B3-IR PNNs were decreased, together with marked reductions of aggrecan-IR glial cells and CS-6 (3B3 and CS56)-IR 'clusters'. In BD, numbers of 3B3-IR PNNs and CS56-IR clusters were reduced. Our findings show disruption of multiple PNN populations in the amygdala of SZ and, more modestly, BD. Decreases of aggrecan-IR glia and CS-6-IR glial 'clusters', in sharp contrast to increases of CSPG/lectin-positive glia previously observed, indicate that CSPG abnormalities may affect distinct glial cell populations and suggest a potential mechanism for PNN decreases. Together, these abnormalities may contribute to a destabilization of synaptic connectivity and regulation of neuronal functions in the amygdala of subjects with major psychoses.

Positron emission tomographic analysis of dose-dependent MDL 100,907 binding to 5-hydroxytryptamine-2A receptors in the human brain.

Selective 5-hydroxytryptamine-2A (5-HT2A) antagonism has been proposed as a mechanism of atypical antipsychotic drug action. MDL 100,907, a new selective 5-HT2A receptor antagonist, has high affinity in vitro for 5-HT2A receptors and is being developed as a potential antipsychotic drug. In this study, neocortical 5-HT2A receptor occupancy was measured in six healthy male volunteers after placebo and escalating single doses (1-72 mg) of MDL 100,907 using positron emission tomography and the nonspecific radioligand [11C]N-methylspiperone ([11C]NMSP). Receptor occupancy was calculated using a ratio-equilibrium analysis, assuming that maximal radioligand binding inhibition represents 100% 5-HT2A receptor occupancy. Plasma concentrations of MDL 100,907 were measured with high-pressure liquid chromatography. The pharmacokinetic parameters area under the curve and peak plasma concentration increased linearly with dose, with rapid absorption and a 6- to 9-hour elimination half-life. The neocortical binding of [11C]NMSP was inhibited dose-dependently. After administration of 6 mg of MDL 100,907 the inhibition was 70%, corresponding to a 5-HT2A receptor occupancy of 90%. The calculated maximal inhibition was 77%. These observations indicate that MDL 100,907 passes the blood-brain barrier and binds to 5-HT2A receptors in a saturable manner in the living human brain. Repeated doses of MDL 100,907, 10 mg/day or more, should induce a sustained 5-HT2A receptor occupancy in most patients. Thus, MDL 100,907 provides a suitable tool to evaluate the potential of selective 5-HT2A receptor antagonism in the treatment of schizophrenia.

Effects of age and gender on ambulatory blood pressure and heart rate.

In a large group of young (n = 194) and elderly (n = 148) healthy subjects, we explored the relationship between ambulatory blood pressure (BP) levels, within-subject BP variability, and age in men and women. The questions asked were: Do elderly subjects display higher BP levels and variability compared to a young group? Are there gender differences in BP level and variability? Are these gender differences similar in the young and the elderly subjects? Do age or gender influence BP in a similar way during waking and during sleep? Subjects wore an ambulatory BP monitor (Accutracker II) for 24 h. Individual levels and variability (standard deviations) were calculated for periods when subjects were awake and during sleep. Systolic BP was higher in the elderly women than in the young group. In comparison to the young subjects, both elderly men and women had higher diastolic BP. BP variability while subjects were awake was higher in the elderly, in women in particular. The higher levels of BP variability found in the elderly women may indicate relatively higher risk for end-organ damage, such as silent cerebrovascular damage.

Whole-blood pharmacokinetics and metabolic effects of the topical carbonic anhydrase inhibitor dorzolamide.

Following a single-dose, open-label, pilot pharmacokinetic study in six subjects, the systemic pharmacokinetics and metabolic effects of dorzolamide after topical ocular administration were investigated in a double-blind, randomised, placebo-controlled study in 12 healthy volunteers. The subjects received a controlled diet on the 5 days before treatment initiation and throughout the study. For 14 days, a bilateral q.i.d. regimen of 3% dorzolamide, consisting of approximately 7.7 micrograms per day (21.3 mumol) dorzolamide hydrochloride, or placebo was given. Blood and urine electrolytes and acid-base profiles were measured 1 day prior to treatment and on days 1, 7 and 14 of treatment, and 24-h urine samples were collected daily. Topically applied dorzolamide was slowly taken up in erythrocytes and eliminated with a half life of approximately 120 days. Compared to the pre-study values, no significant treatment effect was observed in either the daily profiles or the 14-day cumulative sodium, potassium and citrate excretions. Two other volunteers given acetazolamide (125 mg q.i.d.) and assessed with the identical set of observations demonstrated marked metabolic changes. In spite of the prolonged and marked inhibition of carbonic anhydrase in red blood cells by dorzolamide, clinically significant metabolic and renal effects were not observed. The ocular tolerability profile was acceptable to all subjects.

Effects of carbohydrate and protein meals on cardiovascular levels and reactivity.

This study examined the effects of standard laboratory stressors on cardiovascular measures before and after the consumption of a modest meal. A mental arithmetic task and a reaction time task were administered before and 2 h after a carbohydrate or a protein meal. A noncaloric placebo meal and a fasting condition were included as control treatments. The caloric meals, in particular the carbohydrate meal, induced an increase in cardiac output, ventricular contractility, and systolic blood pressure. Total peripheral resistance and diastolic blood pressure dropped. Although postprandial adjustments were substantial, stress reactivity patterns generally were not perturbed by the meals. Only heart rate reactivity was stronger after eating the carbohydrate meal. It is concluded that subjects' meal consumption prior to their participation in a psychophysiological experiment needs to be taken into account.

Specificity of Bacillus thuringiensis Delta-Endotoxin.

The insecticidal activity of the delta-endotoxins of 14 Bacillus thuringiensis strains belonging to 12 subspecies was determined against Pieris brassicae, Heliothis virescens, and Spodoptera littoralis. Larvae of P. brassicae were highly susceptible to purified crystals of strains of B. thuringiensis subsp. thuringiensis and B. thuringiensis subsp. morrisoni, whereas H. virescens responded best to B. thuringiensis subsp. kenyae and B. thuringiensis subsp. kurstaki. The crystals of the B. thuringiensis subsp. entomocidus strain were the most potent against S. littoralis. It was shown that the solubility of the crystals within the gut of the three insect species is a first important step in the mode of action. Predissolution of the crystals especially enhanced the insecticidal activity against H. virescens. When in vitro-activated toxins were applied, the relative potency range varied greatly from one insect species to another. It can be concluded that at least three factors influence the potency of B. thuringiensis delta-endotoxins: the strain-related origin of the toxin, the degree of solubility of the crystals in the gut juice, and the intrinsic susceptibility of the insect to the toxin.

Characterization of monoclonal antibodies to a crystal protein of Bacillus thuringiensis subsp. kurstaki.

Ten monoclonal antibodies were produced against a k-1-type crystal protein of Bacillus thuringiensis subsp. kurstaki. Eight of the antibodies belong to the immunoglobulin G1 (IgG1) subclass, with pI values ranging from 5.5 to 8.6, one could be assigned to the IgG2b subclass, and one could be assigned to the IgM class. Competitive antibody-binding assays and analysis of antibody specificity indicated that the 10 antibodies recognized at least nine distinct antigenic determinants. Eight antibodies bound to both protoxin and toxin, whereas the other two interacted with protoxin only. One antibody completely inhibited the biological activity of the delta-endotoxin, five antibodies reduced it by 15 to 82%, and four antibodies did not affect it at all. Based on cross-reaction studies, homologies and differences in the crystal protein structures of different B. thuringiensis subspecies were revealed. All of the monoclonal antibodies strongly cross-reacted with crystal proteins from strains of B. thuringiensis subsp. tolworthi, B. thuringiensis subsp. galleriae, B. thuringiensis subsp. dendrolimus, B. thuringiensis subsp. sotto, and B. thuringiensis subsp. subtoxicus. Some antibodies interacted only weakly with crystal proteins from strains of B. thuringiensis subsp. morrisoni and B. thuringiensis subsp. entomocidus, and some of these did not interact with B. thuringiensis subsp. kenyae and B. thuringiensis subsp. darmstadiensis. No cross-reaction was found with the parasporal inclusion protein of B. thuringiensis subsp. israelensis. Studies with the monoclonal antibodies also disclosed that crystal proteins from strains of the same subspecies can exhibit substantial differences in antigenic structure. In particular, striking strain-specific differences in the protoxins of B. thuringiensis subsp. kurstaki and B. thuringiensis subsp. thuringiensis were observed.