Reversal of stress-induced anhedonia by the dopamine receptor agonist,pramipexole

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of a palatable (1%) sucrose solution, and to attenuate food-induced place preference conditioning. In this study the effects of pramipexole (SND-919), a dopamine D₂ agonist, were studied during 7–9 weeks of chronic treatment. Pramipexole (1.0 mg/kg per day) reversed the suppression of sucrose intake in stressed animals, increasing sucrose intakes above the levels seen in untreated nonstressed controls. Pramipexole also increased sucrose intake in nonstressed animals; these effects were accompanied by increases in water intake and tended to correlate with weight loss. Drug-treated stressed animals also lost weight, but in this case water intake was unaffected. A second group of animals received a higher dose of pramipexole (2.0 mg/kg per day). The effects of the two doses were very similar. After three weeks of treatment, these animals were switched to a lower dose of pramipexole (0.1 mg/kg per day). Increases in sucrose intake were maintained over three weeks of treatment at the lower dose, with significant recovery of body weight. Two further groups received the same doses of pramipexole (1.0 mg/kg for 6 weeks or 2.0 mg/kg for 3 weeks followed by 0.1 mg/kg thereafter), but received intermittent (twice-weekly) drug treatment. Intermittent pramipexole treatments also tended to increase sucrose intakes, but the results were less consistent from week to week. Following 6–8 weeks of pramipexole treatment, food-induced place preference conditioning was studied in all animals. Untreated stressed animals showed no evidence of place conditioning. Normal conditioning was seen in both groups of stressed animals treated daily with pramipexole (at 1.0 and 0.1 mg/kg) and in the group treated twice weekly at the higher dose (1.0 mg/kg); intermittent treatment at the lower dose (0.1 mg/kg) was ineffective. The results indicate that pramipexole exerts rapid anti-anhedonic effects in the chronic mild stress model. This conclusion is complicated, but not undermined, by drug-induced weight loss and by the presence of significant drug effects in nonstressed control animals.     

Ontogeny of behavioral sensitization to cocaine

The ontogeny of the behavioral effects of acute cocaine administration and behavioral sensitization to cocaine in rat pups was investigated. Acute behavior stimulating effects of cocaine were observed in pups as young as 7 postnatal days (PND) old, although they needed a higher dose of cocaine than adult rats to evoke the same motor effects. An adult dose-response curve pattern of stereotypy and locomotion to acute cocaine treatment was observed at PND 21, and of rearing at PND 28. Rats aged PND 7, 14, 21, 28, and 56 received repeated injections of saline or cocaine (15 mg/kg) twice a day for 5 consecutive days. After a 3-week period of abstinence, sensitization to a challenge dose of cocaine was assessed. Cocaine-induced stereotyped behavior was enhanced significantly only in rats in which cocaine pretreatment was initiated on PND 21, 28, and 56, but not earlier on PND 7 and 14. Adult female rats given repeated cocaine injections on PND 56–60 showed significantly greater sensitization than males, but no such sex difference was observed in pups given cocaine repeatedly on PND 21–25 or 28–32. These results show clearly that cocaine-induced behavioral sensitization in rats occurred only when subchronic cocaine administration was commenced on PND 21 or later.     

Adverse reactions to non-ionic contrast media with special regard to high-risk patients

Non-ionic contrast media (CM) are proven to be significantly safer than the high osmolar ionic contrast media (HOCM). Nevertheless deaths are reported after administration of non-ionic agents. The aim of the study was to investigate the rate of adverse reactions to non-ionic CM with special regard to high-risk patients and the effects of premedication with H1-and H2-receptor antagonists.In a prospective study conducted over about 2 years 12 995 examinations with intravenous or intra-arterial non-ionic CM were evaluated. Premedication with H1-and H2-antagonists was used in 1276 high-risk patients with known adverse reaction to CM, history of allergy or severe cardiac or pulmonary disease. 229 patients received no premedication inspite of known risk factors. In total, there were 143 (1.10%) adverse reactions (mild in 0.58%, moderate in 0.41% and severe in 0.05%). In high-risk patients there were adverse reactions in 4.37% without and in 1.57% with premedication. There were no severe adverse reactions in the high-risk patients after premedication. The age of the patient, CM dosage and CM concentration were not shown to be risk factors in the present study. In conclusion, the additional premedication with H1- and H2-antagonists could be an effective agent to reduce the risk of mild and moderate adverse reactions and to avoid severe adverse reactions in high-risk patients. Correspondence to: U. Fink     

CHANGES IN PREJUNCTIONAL POTENCY OF B-HT 933 DURING AGING IN THE RAT VAS DEFERENS

1. Age-related changes in prejunctional alpha 2-adrenoceptors were examined in the rat vas deferens using pharmacological techniques. 2. B-HT 933 (1 x 10(-8) - 1 x 10(-6) mol/L) caused a concentration-dependent inhibition of isometric contractions (tetrodotoxin-sensitive) induced by stimulation with single field-stimulus pulses, in both the epididymal and prostatic regions of rat vas deferens. The concentration-response curve to B-HT 933 was shifted to the right with age in the prostatic regions of the vas deferens. 3. In high concentrations (10(-6) - 3 x 10(-4) mol/L), B-HT 933 caused concentration-dependent enhancement of the contractile response to stimulation and evoked spontaneous contractile activity. No significant difference in this postjunctional activity occurred with age in either the prostatic or epididymal regions of the vas deferens. 4. Schild analysis revealed no significant differences in pA2 values for the antagonisms of the prejunctional inhibitory effect of B-HT 933 by rauwolscine in either the prostatic or epididymal regions of vas deferens between young and old rats. 5. These results could be interpreted as a decrease in alpha 2-adrenoceptor number with age. The more marked decrease in the prejunctional inhibitor potency of B-HT 933 in prostatic regions of vas deferens with aging may be due to a smaller receptor reserve in this region of the vas deferens.     

Hypercalcemic hyperparathyroidism and hypophosphatemic osteomalacia complicating neurofibromatosis

Summary Neurofibromatosis is sometimes complicated by impaired renal tubular reabsorption of phosphate, hypophosphatemia, and osteomalacia. Hyperparathyroidism has also been reported in patients with neurofibromatosis. When hypercalcemia and elevated levels of parathyroid hormone are found in osteomalacia, however, it may be difficult to determine if the hyperparathyroidism was primary or tertiary. We describe a patient with neurofibromatosis, hypercalcemic hyperparathyroidism, hypophosphatemic osteomalacia, vitamin D deficiency, and clear-cell hyperplasia of all four parathyroid glands. Serial biomechanical, bone biopsy, and densitometric studies confirmed that treatment with ergocalciferol, calcium, and phosphate supplements significantly improved the osteomalacia but caused increased parathyroid overactivity. After subtotal parathyroidectomy, the parathyroid hormone concentration became normal and the bone mineral content increased at the spine and hip, but inappropriate phosphaturia persisted. The findings indicate that hyperparathyroidism, osteomalacia, and vitamin D deficiency adversely affect each other.     

Interleukin-2, its soluble receptor,and soluble T8 antigen in acute ischemic stroke

The treatment of neoplasia with interleukin-2 (IL-2) can be complicated by neurological deficits resembling transient Ischemic attack and stroke. We investigated whether interleukin-2 contributes to the natural course of cerebrovascular ischemia and particularly to the pathogenesis of infection-associated stroke. Plasma levels of interleukin-2 were below the level of detectability in almost all measurements. Patients with and without previous infection (n = 11, 805 ±445 U/ml vs n = 19, 824 ± 501 U/ml) did not have significantly higher levels of soluble interleukin-2 receptors than control subjects with (n = 14, 667 ± 229 U/ml) or without vascular risk factors (n = 17, 567 ± 176 U/ml). Receptor levels increased in patients during the first week after stroke (n = 15, 1157 ± 1013, p < 0.02). Levels of soluble T8 antigen (sT8) were higher in patients (n – 26, 320 ± 112 U/ml) than in healthy control subjects (n = 15, 246 ± 92 U/ml; p < 0.05) and sT8 levels increased during the first week after stroke (p < 0.05). These results reflect an immunological response to the cerebral infarct; they do not indicate a general role of the IL-2 system in the pathogenesis of ischemic stroke with or without previous infection.     

Cyclin D1 in astrocytic tumours: an immunohistochemical study

Forty-eight astrocytic tumours were stained immunohistochemically with antibodies to the cell cycle-regulating protein, cyclin D1, and to the proliferation marker MIB1 (Ki-67) using formalin fixed paraffin embedded tissue and a microwave antigen retrieval system. Cases were classified by the WHO system (1993). The labelling indices (LI) for both antibodies were compared with each other and with the tumour type. The mean labelling indices for both antibodies increased with the degree of malignancy, and a significant difference was seen between the pilocytic astrocytoma and diffuse astrocytoma together vs anaplastic astrocytoma and glioblastoma together. However, within each tumour type there was considerable variation in the labelling indices and a clear cut off value could not be demonstrated. There was a strong positive correlation between labelling indices for cyclin D1 and MIB1 in diffuse astrocytoma, but this correlation broke down increasingly in anaplastic astrocytoma and glioblastoma. There was poor correlation between cyclin D1 and MIB1 in pilocytic astrocytoma, a feature which appeared to separate them from the diffuse astrocytoma. Average labelling indices for cyclin D1 were higher than those of MIB1, which suggests that cyclin D1 positive cells represent a pool of cells from which proliferation and hence MIB1 expression can take place. In conclusion, cyclin D1 is overexpressed in astrocytic tumours, more so with increasing grade of malignancy and in a way which approximately correlates with MIB1 expression.     

Gingival crevicular fluid IL-8: correlation with local IL-1β levels and patient estrogen status

Gingival crevicular fluid (GCF) IL-8 and IL-1,1β levels were determined by sandwich enzyme-linked immunosorbent assays. Associations between IL-8 and IL-1β GCF levels, and between these cytokines and patient estrogen status were evaluated. IL-8 and IL-1β were detected more frequently and in higher amounts/30 s GCF sample in estrogen-deficient patients than in estrogensufficient patients. IL-8 and IL-1β GCF levels were significantly correlated. These lindings suggest that GCF IL-8 levels are associated with patient estrogen status and local IL-1β concentrations.     

Structured treatment and teaching of patients with Type 2 diabetes mellitus and impaired cognitive function--the DICOF trial.

BACKGROUND: Patient education is integral part of any diabetes therapy in Germany, but elderly patients are not able to follow the variety of topics comprising standard treatment and teaching programmes (TTP), primarily due to impaired neuropsychological function. This leads to deficits in diabetes knowledge and hindered ability for diabetes self-management. AIM: To evaluate structured TTP for geriatric patients with impaired cognitive function. PATIENTS AND METHODS: A neuropsychological examination was performed on all patients over 54 years [n=102, age 68.6 +/- 8.7 years, diabetes duration 10.3 (0.03-35.4) years, HbA1c 10.3 +/- 1.7% (HPLC, Diamat, NR 4.5-6.3%), cognitive function 87.7 +/- 12.3 IQ points] who took part in TTP for insulin therapy. Patients with impaired cognitive function participated either in the standard TTP of Berger [n = 35, age 67.6 +/- 8.9 years, diabetes duration 9.9 (0.04-35.4) years, HbA1c 10.3 +/- 2.0%] or in the specialized structured geriatric DICOF-TTP [n=33, age 70.4 +/- 8.2 years, diabetes duration 10.4 (0.03-24.9) years, HbA1c 10.7 +/- 1.8%]. RESULTS: After TTP there were no differences in knowledge and ability for diabetes self-management (standard/DICOF: knowledge 11.0 +/- 2.6 vs. 12.2 +/- 2.7 points, P = 0.11; handling 14.9 +/- 3.3 vs. 15.9 +/- 2.5 points, P = 0.18). However, patients who took part in the DICOF programme showed better scores in satisfaction with the education programme [standard/DICOF 44.7 (31-57) vs. 52.5 (45-59) points, P < 0.001]. Six months later the DICOF participants showed better results regarding diabetes self-management (standard/DICOF: handling 12.5 +/- 4.1 vs. 15.9 +/- 3.1 points, P = 0.001). Both groups showed HbA1c decrease (8.3 +/- 1.4 vs. 8.5 +/- 1.3%, P=0.62) and similar incidence of acute complications. CONCLUSIONS: Elderly patients with impaired cognitive function should take part in specialized structured TTP. This leads to both better satisfaction with the education programme and an improved ability for diabetes self-management.     

Evidence for a Type 1 diabetes‐specific mechanism for the insulin gene‐associated IDDM2 locus rather than a general influence on autoimmunity

Aims The Type 1 diabetes susceptibility locus, IDDM2, has been mapped to a variable number of tandem repeats (VNTR) region 5′ upstream of the insulin (INS) and insulin‐like growth factor (IGF2) genes on chromosome 11p15. The function of the VNTR is uncertain; however, it may influence the thymic expression of the insulin gene and affect the development of immune self‐tolerance. The aim of this study was to investigate whether the INS VNTR region is a Type 1 diabetes‐specific locus or acting as a general autoimmunity gene. Methods We genotyped the INS‐IGF2 VNTR [using the surrogate INS?23 HphI single nucleotide polymorphism (SNP)] in 823 Graves’ disease (GD)/multiple sclerosis (MS) families, 1433 GD/MS patients and 837 healthy control subjects. Results We found no evidence of excess transmission of the allele associated with Type 1 diabetes to individuals affected by GD or MS within the families. Analysis of the case–control dataset showed no genotypic or allelic difference between the two populations. Conclusions These data suggest that the INS‐IGF2 VNTR is acting as a Type 1 diabetes‐specific susceptibility gene rather than as an influence on general autoimmunity.