Intact Prototype Formation but Impaired Generalization in Autism.

Cognitive processing in autism has been characterized by a difficulty with the abstraction of information across multiple stimuli or situations and subsequent generalization to new stimuli or situations. This apparent difficulty leads to the suggestion that prototype formation, a process of creating a mental summary representation of multiple experienced stimuli that go together in a category, may be impaired in autism. Adults with high functioning autism and a typically developing comparison group matched on age and IQ completed a random dot pattern categorization task. Participants with autism demonstrated intact prototype formation in all four ways it was operationally defined, and this performance was not significantly different from that of control participants. However, participants with autism categorized dot patterns that were more highly distorted from the category prototypes less accurately than did control participants. These findings suggest, at least within the constraints of the random dot pattern task, that although prototype formation may not be impaired in autism, difficulties may exist with the generalization of what has been learned about a category to novel stimuli, particularly as they become less similar to the category's prototype.

Alterations in neuronal gene expression profiles in response to experimental demyelination and axonal transection.

The main pathological features of multiple sclerosis, demyelination and axonal transection, are considered to cause reversible and irreversible neurological deficits, respectively. This study aimed to separately analyze the effects of these pathological hallmarks on neuronal gene expression in experimental paradigms. The pontocerebellar pathway was targeted with either lysolecithin-induced chemical demyelination or a complete pathway transection (axonal transection) in rats. Transcriptional changes in the pontocerebellar neurons were investigated with microarrays at days 4, 10 and 37 post-intervention, which was confirmed by immunohistochemistry on protein level. A common as well as unique set of injury-response genes was identified. The increased expression of activating transcription factor 3 (Atf3) and thyrotropin-releasing hormone (Trh) in both injury paradigms was validated by immunohistochemistry. The expression of Atf3 in a patient with Marburg's variant of multiple sclerosis was also detected, also confirming the activation of the Atf3 pathway in a human disease sample. It was concluded that this experimental approach may be useful for the identification of pathways that could be targeted for remyelinative or neuroprotective drug development.

Modelling of hypoxaemia after gynaecological laparotomy.

BACKGROUND: Late postoperative arterial hypoxaemia is common after major surgery, and may contribute to cardiovascular, cerebral or wound complications. This study investigates the time course of hypoxaemia following gynaecological laparotomy, and estimates parameters of mathematical models of pulmonary gas exchange to describe hypoxaemia. METHODS: Twelve patients were studied on four occasions; preoperatively, 2, 8 and 48 h after surgery. On each occasion inspired oxygen fraction (FIO2) was varied, changing end-expired oxygen fraction (FEO2) to achieve arterial oxygen saturations (SaO2) ranging from 90% to 100%. Measurements of ventilation and blood gases were taken. Oxygenation was characterized plotting FEO2 against SaO2. The shape and position of the FEO2/SaO2 curve was described using two mathematical models including parameters describing gas exchange: either shunt and resistance to oxygen diffusion (Rdiff); or shunt and asymmetry of ventilation-perfusion (fA2). RESULTS: Two hours after surgery SaO2 was reduced from 97.5%+/-1.2% (mean+/-SD) to 93.8%+/-2.7% (mean+/-SD) (P<0.001). Values of shunt, Rdiff and fA2 were significantly changed at 2 and 8 h postoperatively. Forty-eight hours postoperatively Rdiff and fA2 were still significantly changed. CONCLUSION: Oxygenation in 12 patients preoperatively, 2, 8 and 48 h after gynaecological laparotomy is described. Two patients were hypoxaemic (SaO2 <92%) 48 h postoperatively. When two different models of oxygen transport are fitted to patient data, high values of Rdiff or low values of fA2 describe the right shift in the FEO2/SaO2 curve seen in patients with oxygenation problems. These models fit patient data identically, and may be useful in quantifying postoperative hypoxaemia.

[Complications after spinal analgesia using three different spinal needles: Sprotee, Spinocan and Atraucan]. / Komplikationer efter spinal analgesi ved anvendelse af tre forskellige spinalkanyler: Sprotte, Spinocan og Atraucan.

In this prospective, randomised study 197 patients aged below 40 years received spinal analgesia using one of the following needles: Sprotte G24, Spinocan G27 or Atraucan G26. The incidence of insufficient or failed analgesia and difficulties handling the needles were noted. Patients were interviewed within three weeks after anaesthesia so as to establish the incidence of postoperative complications including post-dural puncture headache (PDPH). Headache was noted in 63 patients of which 33 (16.8%) were of PDPH type. The Sprotte needle caused significantly fewer cases of PDPH (Sprotte: 8.1%; Spinocan: 19.7; Atraucan: 21.7%. p < 0.05). Furthermore a significantly lower incidence of insufficient analgesia was observed with the Sprotte needle (0% versus 12.1% with the Spinocan and 11.6% with the Atraucan, p < 0.05). In conclusion, the Sprotte needle had the best profile with respect to PDPH and successful analgesia. This confirms the importance of the needle tip design.

[Relationship between distal systolic blood pressure and wound healing. A retrospective study of patients with crural ulcers]. / Relationen mellem distale systoliske blodtryk og sårheling. En retrospektiv undersøgelse af patienter med krurale ulcera.

To anticipate the need for ensuring quality in treatment of patients with ulceration of the lower leg and complicating arterial occlusive disease, three authors examined the files of 56 patients with systolic digital blood pressure (SDBP) below 60 mmHg, all admitted to the geriatric in-patient department over a 11-year period in a retrospective study. In 40 patients (71%) the ulcer healed. Eight patients (14%) required amputation, six patients (11%) died and two patients (4%) were unsolved. We found a significant correlation between SDBP and ulcer healing (p = 0.006). In patients with SDBP < or = 35 mmHg, healing on conservative pharmacotherapy was demonstrated even with critical ischaemia.

[The post-thrombotic syndrome. A review]. / Det posttrombotiske syndrom. En oversigt.

The post-thrombotic syndrome which is caused by deep venous thrombosis and characterized by pain, oedema, pigmentation, eczema, lipodermatosis, varices and ulceration, is due to deficient function of the venous valves and/or obstruction of the deep veins with venous hypertension. The diagnosis may be established by investigation of the investigation of the muscular-venous pump by pletysmography or dynamic phlebography and invasive measurement of the venous pressure is not employed to any great extent. The results of valvuloplasty have, by and large, been negative. The main form of treatment is, therefore, conservative compressive bandaging which can reduce the symptoms, facilitate healing of venous ulcers and prevent recurrence of ulcers. It is emphasized, however, that this treatment must be continued consequently during the remainder of the patient's life, regardless of other treatment.

Sertraline, a serotonin-uptake inhibitor, reduces food intake and body weight in lean rats and genetically obese mice.

Sertraline was found to inhibit weight gain and decrease food intake without affecting locomotion in rats and genetically obese (ob/ob) mice. Doses of 10, 17.8, and 32 mg/kg, administered intraperitoneally, (bid) significantly reduced the time rats spent in contact with their feeders and body weight in a dose-related manner. During a 5-d bid treatment regimen, vehicle-treated rats gained 37 +/- 3 g (mean +/- SEM), whereas animals treated with 32 mg sertraline/kg lost 34 +/- 4 g. The effects of sertraline on feeding and body weight in rats appeared to be specific because locomotor activity was not altered. In ob/ob mice, sertraline (44 mg/kg, ip, bid) lowered body weight relative to vehicle-treated controls for the duration of a 12-d study. There was no evidence for tolerance to the hypophagic and weight-loss effects of sertraline during either of the chronic dosing studies. These results suggest a potential role for sertraline in the treatment of human obesity.

Structure-activity relationship of quinazolinedione inhibitors of calcium-independent phosphodiesterase.

A series of quinazolinediones and azaquinazolinediones is described which possess potent inhibitory activity toward the calcium-independent phosphodiesterase enzyme (CaIPDE). In vivo testing showed that this in vitro activity translates to animal models predictive of chronic diseases such as depression and inflammation. These results support the hypothesis that inhibition of CaIPDE may lead to useful activity in such chronic diseases.

Calcium-independent phosphodiesterase inhibitors as putative antidepressants: [3-(bicycloalkyloxy)-4-methoxyphenyl]-2-imidazolidinones.

The synthesis and biological properties of a novel series of selective calcium-independent phosphodiesterase inhibitors are described. These compounds also inhibit the specific binding of [3H]rolipram to rat brain membranes and exhibit efficacy in preclinical models of antidepressant activity in mice, such as reducing immobility in the forced-swim test and reversing reserpine-induced hypothermia. Imidazolidinones 4 and 16 were found to be the most potent compounds studied.

Nicotinamide ethers: novel inhibitors of calcium-independent phosphodiesterase and [3H]rolipram binding.

The synthesis and biological properties of a series of nicotinamide ethers are described. These compounds, structurally novel calcium-independent phosphodiesterase inhibitors, also inhibit the binding of [3H]rolipram to rat brain membranes and reverse reserpine-induced hypothermia in the mouse. Several compounds exhibited potent in vivo activity comparable to the standard agent, rolipram.

[Epicrisis. A report from the county of Copenhagen]. / Udskrivningsbreve. En opgørelse fra Københavns amt.

During a random week in 1987, 35% of the general practitioners from all of the municipalities in the County of Copenhagen participated in a questionnaire survey whose objective was to illuminate the quality, expedition time, and possible problems associated with the letter of discharge (LD), an important link between the primary and secondary medical services. It can be concluded that the expedition time for a large number of LD's from the hospitals of Copenhagen County is unacceptably lengthy. A surprisingly large number of patients visited their own general practitioner during the week following discharge with questions about the information which had been given them during their hospital stay, regardless of agreements for ambulatory monitoring at the department from which they had been discharged. A preliminary LD can, to a certain extent, alleviate the problems brought about by the lack af an LD but ought not to replace or delay the issuance of the actual LD, and is a more expensive solution. The quality and content of the LD can be evaluated generally as good, but could be improved if the recommended follow-up treatment and information to the patients and relatives is routinely carried out.

3-(1,2,5,6-Tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one: a potent and selective serotonin (5-HT1B) agonist and rotationally restricted phenolic analogue of 5-methoxy-3-(1,2,5,6-tetrahydropyrid-4-yl)indole.

The synthesis and in vitro and in vivo characteristics of 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (1, CP-93,129) are described. This rotationally restricted phenolic analogue of RU-24,969 is a potent (15 nM) and selective (200x vs the 5-HT1A receptor, 150x vs the 5HT1D receptor) functional agonist for the 5-HT1B receptor. Direct infusion of 1 into the paraventricular nucleus of the hypothalamus of rats significantly inhibits food intake, implicating the role of 5-HT1B receptors in regulating feeding behavior in rodents. 3-(1,2,5,6-Tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (1) has also been shown to be biochemically discriminatory in its ability to selectively inhibit forskolin-stimulated adenylate cyclase activity only at the 5-HT1B receptor. The source of the selectivity of 1 appears to lie in the ability of a pyrrolo[3,2-b]pyrid-5-one to act as a rotationally restricted bioisosteric replacement for 5-hydroxyindole.

Correlation of brain levels of 9-amino-1,2,3,4-tetrahydroacridine (THA) with neurochemical and behavioral changes.

9-Amino-1,2,3,4-tetrahydroacridine (THA) has been reported to cause improvement in patients with senile dementia of the Alzheimer's type. We have examined some effects of THA in vitro and in vivo to define its mechanism of action. In vitro, THA inhibits acetylcholinesterase (AChE) (IC50 = 223 nM) and blocks [3H]AFDX-116 (M2) and [3H]telenzepine (M1) binding (IC50 s of 1.5 and 9.1 microM respectively). In vivo levels of THA were 10-fold higher in brain than plasma following 3.2 mg/kg i.p., a dose which was found to be active in reversing amnesia induced by scopolamine assessed in T-maze tests in rats and passive avoidance tests in mice. Additionally, these brain concentrations were above the IC50 of THA for AChE inhibition. THA (5.6-17.8 mg/kg i.p.) also elevated acetylcholine levels in the rat CNS. THA-induced side effects were blocked by the central muscarinic antagonist, scopolamine, but not by the peripheral antagonists methscopolamine and glycopyrrolate, nor by nicotinic antagonists. We conclude that brain AChE inhibition by THA is sufficient to explain its purported therapeutic activity in Alzheimer's disease and that its favorable brain/plasma distribution in vivo may account for its central cholinergic action without inducing the severe peripheral cholinergic effects typically seen with other AChE inhibitors.

Stressful life events preceding the acute onset of schizophrenia: a cross-national study from the World Health Organization.

This study reports on the findings from a WHO sponsored cross-national investigation of life events and schizophrenia. Data are presented from a series of 386 acutely ill schizophrenic patients selected from nine field research centers located in developing and developed countries (Aarhus, Denmark; Agra, India; Cali, Colombia; Chandigarh, India; Honolulu, USA; Ibadan, Nigeria; Nagasaki, Japan; Prague, Czechoslovakia; Rochester, USA). On a methodological level, the study demonstrates that life event methodologies originating in the developed countries can be adapted for international studies and may be used to collect reasonably reliable and comparable cross-cultural data on psychosocial factors affecting the course of schizophrenic disorders. Substantive findings replicate the results of prior studies which conclude that socioenvironmental stressors may precipitate schizophrenic attacks and such events tend to cluster in the two to three week period immediately preceding illness onset.

Comfort care: an alternative treatment programme for seriously burned patients.

Modern intensive care is capable of keeping burned patients alive for substantial periods of time, despite burn severity with an 'unprecedented' or a marginal probability of survival. When the patient is initially judged to be that severely injured, or when, later in the course of the illness, a point is reached when further curative treatment is clearly futile (Civetta, 1981), the patient and/or the close relatives should be presented with the option of changing the treatment regimen from curative to comfort care. We (Frank and Wachtel, 1984) have described a process for reaching such decisions and a protocol for administering comfort care. During a 5-year period we offered this option to 24 patients. This paper reports the outcome in these cases.

Effects of acute and chronic bupropion on locomotor activity and dopaminergic neurons.

Acute administration of bupropion (10 or 30 mg/kg) to rats increased locomotor activity in a dose-related manner. The highest dose increased the dopamine (DA) concentration while both doses reduced the concentration of dihydroxyphenylacetic acid (DOPAC) in the striatum. The enhancement of locomotor activity and the decrease of striatal DOPAC concentrations were increased with chronic administration (up to 40 days) of bupropion. The rate of DA synthesis in the striatum was increased by the acute administration of d-amphetamine but was not altered by acute or chronic administration of bupropion.

Chlorimipramine, fenfluramine and quipazine decrease 5-hydroxytryptamine synthesis in discrete rat brain nuclei.

A procedure for studying 5-hydroxytryptamine synthesis by determining the rate of accumulation of 5-hydroxytryptophan after administering m-hydroxybenzylhydrazine, an inhibitor of aromatic-l-amino acid decarboxylase, and large doses of l-tryptophan was characterized. The utility of this method as an index of 5-hydroxytryptamine neuronal activity was studied by determining the effects on 5-hydroxytryptophan accumulation of direct and indirect 5-hydroxytryptamine agonists; viz, chlorimipramine-a 5-hydroxytryptamine uptake inhibitor, fenfluramine-a 5-hydroxytryptamine releaser, and quipazine-a 5-hydroxytryptamine receptor agonist. In the absence of m-hydroxybenzylhydrazine pretreatment 5-hydroxytryptophan and the dopamine precursor 3,4-dihydroxyphenylalanine were not readily detectable in any brain region studied. They both accumulated after m-hydroxybenzylhydrazine treatment in a time-dependent manner with the 30 min time point being on the linear portion of the curve. Administration of l-tryptophan 60 min before sacrifice increased 5-hydroxytryptophan, but not 3,4-dihydroxyphenylalanine, in a dose-related manner with the peak effect occurring after 100-300 mg/kg. Chlorimipramine, fenfluramine and quipazine all decreased 5-hydroxytryptophan, but not 3,4-dihydroxyphenylalanine, in m-hydroxybenzylhydrazine and l-tryptophan-treated animals. Chlorimipramine produced these effects in a dose-related manner only after l-tryptophan loading and without affecting brain concentrations of l-tryptophan. These results suggest that the measurement of 5-hydroxytryptophan after l-tryptophan administration and aromatic-l-amino acid decarboxylase inhibition might serve as a useful index of 5-hydroxytryptamine synthesis.