The effect of mGlu8 deficiency in animal models of psychiatric diseases.

The metabotropic glutamate receptor subtype 8 (mGlu(8)) is presynaptically located and regulates the release of the transmitter. Dysfunctions of this mechanism are involved in the pathophysiology of different psychiatric disorders. mGlu(8) deficient mice have been previously investigated in a range of studies, but the results are contradictory and there are still many open questions. Therefore, we tested mGlu(8)-deficient animals in different behavioral tasks that are commonly used in neuropsychiatric research. Our results show a robust contextual fear deficit in mGlu(8)-deficient mice. Furthermore, novel object recognition, chlordiazepoxide-facilitated extinction of operant conditioning and the acoustic startle response were attenuated by mGlu(8) deficiency. We found no changes in sensory processing, locomotor activity, prepulse inhibition, phencyclidine-induced changes in locomotion or prepulse inhibition, operant conditioning, conditioned fear to a discrete cue or in animal models of innate fear and post-traumatic stress disorder. We conclude that mGlu(8) might be a potential target for disorders with pathophysiological changes in brain areas where mGlu(8) modulates glutamate and gamma-amino butyric acid (GABA) transmission. Our data especially point to anxiety disorders involving exaggerated contextual fear, such as generalized anxiety disorders, and to conditions with disturbed declarative memory.

[Effects of hip arthroplasty followed by by inpatient rehabilitation on physical function and quality of life]. / Effekte der Hüftarthroplastik und der nachfolgenden stationären postoperativen Rehabilitation auf körperliche Funktion und Lebensqualität.

The aim of the present study was to investigate the effects of hip arthroplasty followed by an inpatient rehabilitation. Moreover, the relationships among functional status, quality of life and satisfaction with life or health status were examined. Patients were assessed before hip arthroplasty, at the start and at the end of the inpatient rehabilitation. Functional status was measured by using the WOMAC questionnaire and quality of life with the Medical Outcome Survey Short Form 36 (SF-36). Satisfaction was determined with a specific questionnaire (FLZ). Hip arthroplasty followed by an inpatient rehabilitation resulted in significant and clinically highly important improvements of functional status, quality of life and satisfaction with health and life.

Lateral approach with osteotomy of the tibial tubercle in primary total knee arthroplasty.

In a prospective study of 51 patients (61 cases) with primary total knee arthroplasty (valgus knees and/or knees that had undergone previous nonarthroplasty surgery), a lateral approach with osteotomy of the tibial tubercle was performed. In a lateral approach, lateral release techniques form part of the approach. In addition, the medial blood supply to the patella is preserved. An additional tibial osteotomy grants wide exposure with little tension on the extensor mechanism during eversion of the patella. The patients were followed up clinically (51 patients, 61 cases) and radiologically (44 patients, 52 cases) for 1 year. No postoperative tibial fractures, no delayed unions, and no nonunions at the site of the osteotomy were seen. No patellar necrosis occurred. The results after 1 year were good or excellent in 45 (88%) patients, fair in four (8%), and poor in two (4%). Complications related to technique were hematoma (four patients) and compartment syndrome (one patient). These complications occurred early in the series and were eliminated by technical modifications.

[Late results following surgical repair of aneurysm of the descending thoracic aorta]. / Spätresultate nach chirurgischer Sanierung von Aneurysmen der deszendierenden thorakalen Aorta.

A consecutive series of 74 patients was analyzed after repair of descending thoracic and thoracoabdominal aortic aneurysms. After hospital discharge there were 13/71 deaths (18%) during a mean follow-up of 60 +/- 20 months (range: 28-107). Actuarial analysis showed a mean survival rate of 89% after 1 year, 78% after 5 years and 71% after 9 years. During the same time period there were reoperations of the aorta in 10/71 patients (14%). Actuarial analysis showed freedom of reoperation in 97% after 1 year and in 80% after 5 years. Elective repair of these aneurysmal lesions can be recommended.

Outcome and risk factors in surgery of descending thoracic aneurysms.

In a series of 100 consecutive patients operated upon for aneurysmatic lesions of the descending thoracic aorta, the mean age was 52 +/- 16 years (male = 81, female = 19). There were 31 dissections (acute 10, chronic 21); 28 post-traumatic aneurysms (ruptured 5, acute 7, chronic 16); 22 arteriosclerotic aneurysms (ruptured 1, chronic 21); 11 thoracoabdominal aneurysms, 5 anastomotic aneurysms and 3 mycotic aneurysms. No symptomatic patient was refused. Preoperative risk factors were graded on a scale of 6 by counting 1 point for each of the following elements: central nervous system disease; heart, pulmonary, and renal disease; arterial hypertension, age greater than 60. In-hospital mortality and paraplegia for the whole series were 25% and 7% respectively. In acute dissection, the mortality was 6/10 patients versus 2/21 in chronic events. In post-traumatic aneurysms, mortality was 2/5 in ruptured, 2/7 in acute and 0/16 in chronic events. In arteriosclerotic aneurysms, mortality was 1/2 in ruptured and 6/20 in chronic events. In thoracoabdominal aneurysms, mortality was 5/11, in anastomotic 1/5 and in mycotic 0/3 patients. The mean number of risk factors in non-survivors versus survivors was significantly higher in acute dissection, chronic dissection, chronic arteriosclerotic aneurysms and thoracoabdominal aneurysms. Rupture and acute events are related to a high surgical mortality. Non-survivors appear to have significantly more preoperative risk factors.

Effects of the selective 5-hydroxytryptamine uptake inhibitors paroxetine and zimeldine on EEG sleep and waking stages in the rat.

The effects of oral paroxetine and zimeldine on EEG sleep-waking phases in the rat were investigated over a wide dose range. To ascertain that at the doses used for the EEG studies paroxetine and zimeldine selectively affect the serotoninergic system, their effects on brain 5-hydroxytryptamine (5-HT), dopamine and noradrenaline were determined. It was found that paroxetine and zimeldine at doses of 1-18 mg/kg dose-dependently prolonged waking and shortened slow-wave sleep and paradoxical sleep. In the same dose range cortical 5-HT turnover was significantly reduced, whereas the other aminergic systems were not influenced. These results suggest that 5-HT uptake inhibitors increase vigilance in rats at oral doses which selectively stimulate the serotoninergic system.

Binding of psychoactive drugs to rat brain amine receptors, measured ex vivo, and their effects on the metabolism of biogenic amines.

Ex vivo receptor binding experiments and measurements of the concentrations of the amine metabolites HVA, MOPEG-SO4 and 5-HIAA were carried out on rat brain tissues to analyse the effects of several neuroleptics (haloperidol, chlorpromazine, thioridazine, clozapine, fluperlapine), antidepressants (amitriptyline, mianserin, zimelidine) and other drugs (pizotifen, ketanserin, prazosin) on brain aminergic systems. It was found that in all cases where drugs reduced 3H-haloperidol binding to striatal D2-receptors ex vivo (haloperidol, chlorpromazine, thioridazine, clozapine, fluperlapine, pizotifen, zimelidine), the same drugs caused a pronounced increase, in vivo, in the striatal HVA-concentration, i.e. an increase in DA-turnover. The HVA-increase was directly proportional to the extent of the reduction of 3H-haloperidol binding. These findings suggested that in the 3H-haloperidol assay binding of drugs is to functional D2-receptors regulating the release of DA. In contrast, reduction of binding of 3H-prazosin to brain stem alpha 1-receptors ex vivo (all drugs except zimelidine) was only associated with an in vivo increase in the MOPEG-SO4 concentration in some cases (haloperidol, chlorpromazine, thioridazine, clozapine, fluperlapine, ketanserine). Similarly, reduction of 3H-spiperone binding to 5-HT2-receptors in the frontal cortex (all agents except prazosin and zimelidine) was only associated with an increase in the 5-HIAA concentration in certain cases (thioridazine, clozapine, fluperlapine, pizotifen, ketanserin). The present data indicate that in the brain alpha 1- and 5-HT2-receptors do not seem to be linked directly to the processes which govern the turnover of the neurotransmitters DA, NA or 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of fluperlapine on dopaminergic systems in rat brain.

Fluperlapine has been reported to possess antischizophrenic and antidepressant properties, with low incidence of extrapyramidal side-effects. In order to get more information about the interactions of fluperlapine with rat brain dopaminergic systems, its binding to striatal D2 receptors, measured ex vivo, and its effects on DA metabolism in different brain areas were investigated. Clozapine and haloperidol served as reference compounds in these investigations. It was found that all three agents blocked D2 receptors and increased DA metabolism. Clozapine and fluperlapine differed from haloperidol in that their potency was much lower. Although occupation of striatal D2 receptors by the two dibenzo-epines developed rapidly, the duration was considerably shorter than that of haloperidol. There was no indication that the two dibenzo-epines had a stronger or longer-lasting effect on limbic or cortical DA metabolism compared to that on the striatum. Both drugs caused a weak increase in striatal DA, whereas haloperidol decreased it. It was concluded that the low incidence of extrapyramidal side-effects of fluperlapine, and also of clozapine, is probably due to their weak and relatively brief action on brain DA systems and not due to a selective action on A10 neurotransmission. The anticholinergic properties of the dibenzo-epines might even further reduce the consequences of their already weak effects on DA systems.

Measurement of cholecystokinin octapeptide-induced motility of rat antrum, pylorus, and duodenum in vitro.

Motor effects of cholecystokinin octapeptide (CCK-OP) on rat antrum, pylorus, and duodenum have been studied in vitro under standard conditions. Intraluminal pressure changes were simultaneously measured at the three locations using a perfusion manometric system with a novel intraluminal pressure-sensor device. This device comprised an acrylic cast of the rat gastroduodenal tract containing the perfusion catheters that reached the surface of the cast with their outlets in the antrum, pylorus, and duodenum. A selective and sensitive intraluminal local pressure measurement was achieved with this pressure sensor due to its shape. CCK-OP increased base-line pressure in the antrum, pylorus, and duodenum; frequencies of phasic contractions in the antrum and pylorus; and amplitudes in the duodenum. The peptide also decreased contraction amplitudes in the antrum and pylorus and frequency of phasic contractions in the duodenum. It is concluded that the novel intraluminal pressure sensor is a useful tool for measuring local pressure changes in the gastroduodenal tract of the rat. In this experimental model, effects of CCK-OP on antral, pyloric, and duodenal base-line pressure are comparable with those observed in isolated muscle strips and in the intact organ of humans, dogs, and opossums. A different behavior, however, was observed in the force of antral and frequency of duodenal phasic contractions.

Mechanism of action of cholecystokinin octapeptide on rat antrum, pylorus, and duodenum.

The mechanism of action of cholecystokinin octapeptide (CCK-OP) on tonic and phasic contraction of antral, pyloric, and duodenal smooth muscles was studied with a novel perfusion manometric system in isolated esophagogastroduodenal preparations of the rat. CCK-OP increased baseline pressure at each site, frequencies of phasic contractions in the antrum and pylorus, and amplitudes in the duodenum. It decreased antral and pyloric amplitudes and frequency of duodenal phasic contractions. CCK-OP action on tonic contraction was tetradotoxin (TTX) susceptible and its action on phasic contractions was TTX resistant. Phentolamine, phenoxybenzamine, propranolol, catecholamine depletion of preparations by reserpine-tetrabenazine, and the block of catecholamine synthesis at different levels significantly inhibited CCK-OP-induced tonic contraction, whereas atropine had no influence. Adrenergic and cholinergic neural actions on phasic contractions altered the level of amplitudes and frequencies on which CCK-OP action occurred. It is concluded that CCK-OP action on tonic contraction of the rat gastroduodenal junction is mediated by a neural noncholinergic pathway, whereas its effect on muscles responsible for phasic contractions is a direct one.

Radiation-induced lethality and mutation in a repair-deficient CHO cell line.

A U.V.-sensitive, DNA repair-deficient mutant of Chinese hamster ovary cells was tested for its response to the lethal effects of X-irradiation and simulated solar light, and to the mutagenic actions of X-rays. A slight sensitivity to killing by X-rays and a greater sensitivity to solar light was observed relative to the wild-type CHO cells. More mutations were induced at a given dose of X-rays in the sensitive cell line than in the wild-type. These results are interpreted in terms of overlap in the repair processes which take place after U.V. damage in mammalian cells with those that take place after other types of radiation damage.

Early changes in lymphocyte traffic between distant lymph nodes following regional antigenic stimulation.

Regional labeling of mice by injection of cytidine-3H ([3H]CR) into the footpad of the left hind leg was used to evaluate lymphocyte traffic from the left regional nodes to the right popliteal lymph node (PLN) within a 24-h period, with or without concomitant primary or secondary stimulation of the right PLN with fluid tetanus toxoid. Results indicate that 1) in the case of primary antigen injection the relative contribution of lymphocytes from the left regional nodes to the small lymphocyte population present in the stimulated right PLN 24 h after labeling was slightly, but not significantly, greater than in non-stimulated controls; 2) a booster injection of antigen into the right hind leg footpad resulted in a significantly smaller relative contribution of lymphocytes from the previously primed left regional nodes to the small lymphocyte population in the right PLN, 24 h after injection of [3H]CR and secondary stimulation, as compared with controls or animals given a primary stimulation to the receiver node; and 3) in contrast to controls and mice subjected to primary stimulation only, the right PLN 24 h after booster contained a significant number of large lymphoid cells which, or whose precursors, had migrated to this site from contralateral nodes within a day, possibly also in the form of small lymphocytes. These findings are discussed in relation to the problem of lymphocyte recruitment and divergent behavior of non-committed lymphocytes as compared with memory cells in the initial phase after primary or secondary antigenic stimulation.

Repair capability and the cellular age response for killing and mutation induction after UV.

The cell-cycle response for killing and mutation induction by ultraviolet irradiation was measured in synchronous Chinese hamster ovary cells (CHO wild-type) and in a UV-hypersensitive mutant (43-3B) derived from this line. The CHO 43-3B line shows a greatly enhanced sensitivity to killing (D0 of 0.3 as compared to 3.2 J/m2 for the wild-type), is hypermutable, and deficient in DNA repair. For the wild-type, a characteristic age response is seen for killing by UV, with maximum sensitivity in early-S and resistance increasing through the S-phase. There is also a life-cycle specificity for induction of diphtheria-toxin resistance in late-G1 and early-S. Relatively little variation is seen through the cell cycle for induced 6-thioguanine and ouabain resistance. In contrast, the 43-3B cell line shows a relatively 'flat' response to UV throughout the cell cycle, for both killing and mutation induction. Therefore it appears that the characteristic age responses seen in the wild-type CHO are associated with the function of an essentially error-free repair process. A variation in the ability of this repair process to act in eliminating potentially lethal and mutagenic lesions (either due to a variation in repair enzyme activities through the cell cycle, or in the time available for repair) would account for most of the age response which is seen in the wild-type for killing and mutation induction by ultraviolet light.

Survival of tumor-bearing mice exposed to heavy water or heavy water plus methotrexate.

Moderate body deuteration combined with a cytostatic drug [methotrexate (MTX)] significantly increases the survival time of young adult DBA/2 mice bearing transplantable P815. L5178Y, or L1210 tumors. Neoplastic cells were grown in vitro from tumor stock and injected i.p. into mice from two groups, one drinking tap water, and other drinking 30% heavy water in tap water. One-half of the animals in each of these two groups was given a single injection of MTX (4 mg/kg body weight) on 3 consecutive days per week. At death, extension of primary and metastatic tumors was examined and was found to be macro- and microscopically comparable in the corresponding groups. The mean survival time of untreated mice drinking tap water was about 2 weeks following injection of the fast-growing P815, L5178Y, or L1210 (V) tumors and approximately 5 weeks after injection of cells from a slower-growing L1210 subline. Body deuteration alone roughly doubled the survival time solely of mice bearing this L1210 subline. Treatment with MTX approximately doubled the mean survival time of hosts bearing one of the fast-growing tumors. Combined treatment with heavy water and MTX increased the mean survival time of the mice in all groups by 15 to 125% as compared to control values. The reasons for this effect are unknown. However, heavy water has been shown to exert antimitotic activity and to depress the incorporation of radioactive precursors into DNA of proliferating mammalian cells. The depression of antibody formation following antigenic stimulation and the reduction in numbers of nonneoplastic lymphoid cells of mice following moderate body deuteration may have contributed to the enhancement of MTX activity in addition to other effects of deuterium.

Receptor dynamics: effect of repeated administration of desmethylimipramine on the noradrenergic systems in rat brain.

The effects of a single and of repeated administration of desmethylimipramine (DMI) on the densities of various receptors and on the metabolism of noradrenaline (NA) were determined in rat brain. Inhibition of the uptake of NA into cortex slices, measured in vitro, was not diminished after repeated administration of DMI. The turnover of NA was inhibited only after the single administration of the drug. After repeated administration the turnover of NA was again within the normal range, but now the density of beta-receptors was significantly reduced. Repeated administration of DMI had no significant effect on the densities of alpha-adrenergic, dopaminergic, cholinergic, histaminergic, opiate and serotoninergic receptors. These results indicate that the continued blockade of NA-reuptake caused a selective desensitization of beta-receptor-regulated systems in the brain.

UV-light-induced mutations in synchronous CHO cells.

Asynchronous and synchronous CHO cells were irradiated with germicidal UV light to determine the fluence response curve for cell killing, and the induction of resistance to 6-thioguanine, ouabain, and diphtheria toxin. For asynchronous populations the data show a sigmoidal response for induced reproductive death, as has been seen by others, with a D0 of 6 J/m2 and an extrapolation number of 2.5. The induction of mutations appears to be a linear function for all three mutagenic markers up to a dose of 17 J/m2. Reproductive death induced in the synchronous populations is a function of the time at which exposure occurs in the cell cycle, with late G1 and early S being the sensitive stages. The induction of resistance to 6TG, ouabain, and diphtheria toxin (DT) all seem to depend on the time of exposure in the cell cycle. As in the case of UV-induced reproductive death, the more sensitive periods for mutation induction appear also to be the G1 and early S period of the cell cycle, with the largest cyclic variation occurring for induced DT resistance. A comparison of the results reported here for the UV exposure with exposures of synchronous CHO cells to X-rays and ethylnitrosourea suggests that there are different age-specific responses to mutation induction for each agent, and that there are often different age responses for different mutagenic endpoints with the same mutagen.