Prostaglandin G/H synthase-2 is required for maximal formation of osteoclast-like cells in culture.

We examined the effect on osteoclast formation of disrupting the prostaglandin G/H synthase genes PGHS-1 and-2. Prostaglandin E(2) (PGE(2)) production was significantly reduced in marrow cultures from mice lacking PGHS-2 (PGHS-2(-/-)) compared with wild-type (PGHS-2(+/+)) cultures. Osteoclast formation, whether stimulated by 1,25-dihydroxyvitamin D(3) (1,25-D) or by parathyroid hormone (PTH), was reduced by 60-70% in PGHS-2(-/-) cultures relative to wild-type cultures, an effect that could be reversed by providing exogenous PGE(2). Cultures from heterozygous mice showed an intermediate response. PGHS inhibitors caused a similar drop in osteoclast formation in wild-type cultures. Co-culture experiments showed that supporting osteoblasts, rather than osteoclast precursors, accounted for the blunted response to 1,25-D and PTH. This lack of response appeared to result from reduced expression of RANK ligand (RANKL) in osteoblasts. We cultured spleen cells with exogenous RANKL and found that osteoclast formation was 50% lower in PGHS-2(-/-) than in wild-type cultures, apparently because the former cells expressed high levels of GM-CSF. Injection of PTH above the calvaria caused hypercalcemia in wild-type but not PGHS-2(-/-) mice. Histological examination of bone from 5-week-old PGHS-2(-/-) mice revealed no abnormalities. Mice lacking PGHS-1 were similar to wild-type mice in all of these parameters. These data suggest that PGHS-2 is not necessary for wild-type bone development but plays a critical role in bone resorption stimulated by 1,25-D and PTH.

The interaction of soluble human complement receptor type 1 (sCR1, BRL55730) with human complement component C4.

Human CR1 is a membrane-bound protein which plays an important role in the control of the human complement system. In addition to its involvement in the processing and clearance of immune complexes with C3b or C4b on their surface, CR1 acts as a cofactor for the proteolysis of C3b and C4b by Factor I. sCR1 is a recombinant, soluble form of CR1 which retains the cofactor activities of CR1, and is of potential therapeutic value for the suppression of complement-mediated tissue damage in vivo. An assay has been established using microtitre plates to explore the binding of sCR1 to the two isotypes of C4, C4A and C4B, and to C4 fragments. Specific binding of 125I-sCR1 to C4b and ammonia-treated C4 has been demonstrated. The binding of 125I-sCR1 to ammonia-treated C4 is dependent on pH and ionic strength, decreasing with an increase in pH and with an increase in ionic strength. At physiological ionic strength, up to twice as much 125I-sCR1 bound to ammonia-treated C4A as bound to ammonia-treated C4B. This preference of sCR1 for binding to the C4A isotype has implications for the clinical association of immune complex disease with C4A null alleles.

Persecutory delusions: a cybernetic model.

The authors propose a cybernetic model for the formation and maintenance of persecutory delusions. During the formation of persecutory ideation, the threat of loss of control over the self or others interacts with predictions of control from others. This interaction may result in feelings of alien control followed by persecutory explanations. Since the persecutory explanations provide the individual with a new goal of resisting others' influence in order to prevent being controlled, they reduce the threat of loss of self-control. This is how persecutory delusions are maintained.

Temporal disorganization and inner-outer confusion in acute mental illness.

The authors found that changes in temporal disorganization covaried substantially and significantly with changes in Schneider's first-rank symptoms in 58 acutely ill psychiatric patients. Schneiderian symptoms reflect a confusion of inner and outer events; therefore, the findings suggest that difficulties in indexing events in time are closely related to problems in distinguishing experiences that arise within the self from outer experiences.

Depersonalization and temporal disintegration in acute mental illness.

The authors assessed the relationship between depersonalization (defined by self-estrangement and body image diffusion) and temporal disintegration (impaired goal-directedness and temporal indistinction) in 37 acutely ill hospitalized psychiatric patients. Substantial correlations were found between these two phenomena, confirming previous work. The finding that body image diffusion is positively correlated with temporal disintegration suggests that distortions of personal space accompany distortions of personal time.

Cognitive function after coronary bypass surgery: effect of decreased cerebral blood flow.

The effect of regional cerebral blood flow during coronary bypass surgery on performance on the Mini-Mental State Examination was studied in 14 patients. No association between lowered regional cerebral blood flow and cognitive scores was found.

Factors and their influence on regional cerebral blood flow during nonpulsatile cardiopulmonary bypass.

In this study we examined the relationship of regional cerebral blood flow (CBF) to mean arterial pressure, systemic blood flow, partial pressure of arterial carbon dioxide (PaCO2), nasopharyngeal temperature, and hemoglobin during hypothermic nonpulsatile cardiopulmonary bypass (CPB). Regional CBF was determined by clearance of xenon 133 in 67 patients undergoing coronary bypass grafting procedures. There was a significant decrease in regional CBF (55% decrease) during CPB, with nasopharyngeal temperature and PaCO2 being the only two significant factors (p less than 0.05). In a subgroup of 10 patients, variation of pump flow between 1.0 and 2.0 L/min/m2 did not significantly affect regional CBF. We conclude that cerebral autoregulation is retained during hypothermic CPB. Under the usual conditions of CPB, variations in flow and pressure are not associated with important physiological or detrimental clinical affects.

Inhibition of glucose transport in PC12 cells by the atypical antipsychotic drugs risperidone and clozapine, and structural analogs of clozapine.

Treatment of schizophrenics with some antipsychotic drugs has been associated with an increased incidence of hyperglycemia and new-onset type 2 diabetes. Some of these drugs also inhibit glucose transport in rat pheochromocytoma (PC12) cells. The current study was designed to examine the effects of the atypical antipsychotic drugs--risperidone, clozapine and analogs of clozapine on glucose uptake in PC12 cells. Glucose transport was measured in cells incubated with vehicle or drug over a range of concentrations (0.2-100 microM). Uptake of 3H-2-deoxyglucose was measured over 5 min and the data were normalized on the basis of total cell protein. Risperidone and clozapine inhibited glucose transport in a dose-dependent fashion with IC(50)'s estimated to be 35 and 20 microM, respectively. The clozapine metabolite, desmethylclozapine, was considerably more potent than the parent drug, whereas clozapine N-oxide was essentially inactive. The structural analogs of clozapine, loxapine and amoxapine, both inhibited glucose transport with amoxapine being the least potent. The ability of the drugs to inhibit glucose transport was significantly decreased by including 2-deoxyglucose (5 mM) in the uptake medium. Schild analysis of the glucose sensitivity of clozapine, loxapine and risperidone indicated that 2-deoxyglucose non-competitively antagonized the inhibitory effects of these drugs. Moreover, clozapine and fluphenazine inhibited glucose transport in the rat muscle cell line, L6. These studies suggest that the drugs may block glucose accumulation directly at the level of the glucose transporter (GLUT) protein in cells derived from both peripheral and brain tissue. Furthermore, this work may provide clues about how the antipsychotic drugs produce hyperglycemia in vivo.

Münchausen's syndrome and other factitious illness.

Current perspectives on Münchausen's syndrome and other factitious illnesses are presented in this article. Self-destructive behavior manifested by the artificial production of illness remains a puzzling but fascinating clinical entity. A distinction between the clinical features of those cases that are more treatable suggests an optimistic rationale for approaching these difficult patients.

Psychopathology of chronic haemodialysis: is it a behavioural cognitive continuum?

Neuropsychiatric complications of chronic renal haemodialysis cover a wide gamut of clinical syndromes. These pictures can be diagnostically classified as non-psychotic and psychotic-like syndromes. On the basis of a review of the literature, some nosological precisions are formulated, and a hypothesized cognitive-behavioural psychopathological continuum is presented. The hypothesis postulates that a central cognitive disturbance, due to multiple organic aetiopathogenic factors, results in a step-wise decline, initially disguised as an affective, neurotic or personality disorder, and further deteriorating into the well-known "dialysis dementia", with a variety of other clinical presentations in between. Additional research in the biological and psychosocial areas is needed to verify different aspects of these conditions, their validity in the context of the authors' hypothesis, and their relevance to the overall "quality of life" of chronic haemodialysis patients.

Time distortion in acute phencyclidine (PCP) psychosis. A correlation between 30 seconds estimation and urine drugs levels.

In fifteen patients hospitalized with phencyclidine (PCP) psychosis, several measures of psychopathology, including those of time distorsion, were examined in relationship to urine PCP levels and duration of hsopitalization. Impaired ability to estimate thirty seconds duration was found to correlate significantly with a higher urine PCP level and a longer hospitalization, the test for ability to estimate thirty seconds may be useful in clinical management of patients with PCP psychosis particularly when there is no urine PCP level available.

Planning community treatment for sex offenders.

In California and in Great Britain plans are being made to move the treatment setting for many sex offenders from large state hospitals to community sites. The most useful aspects of the state hospital programs can be adapted to the community setting. In the proposed treatment centers, graded levels of security may include inpatient, half-way house, and outpatient facilities. The therapist will coordinate social and educational programs as well as psychiatric care. Optimally, the community treatment center will have university support so as to facilitate training in forensic psychiatry and research into the etiology and management of sexually aggressive behavior.

Psychiatric consultation to a rehabilitation program for amputees.

Staff on the rehabilitation unit for amputees at the Navy Regional Medical Center in Oakland, California, requested psychiatric consultation after a group of young patients had shown destructive behavior and resistance to the rehabilitation program. After two unsuccessful attempts at consultation, an approach was adopted in which a psychiatrist functions as a training consultant in group therapy to the orthopedic staff. The primary therapists are two orthopedic nurses, who conduct two weekly therapy sessions for the amputees under the consultant's supervision. The sessions have given amputees a chance to ventilate their feelings of alienation, powerlessness, and boredom, and have been effective in halting destructive behavior and increasing self-esteem.