Effect of dopamine denervation and dopamine agonist administration on serine phosphorylation of striatal NMDA receptor subunits

Sensitization of striatal N-methyl-d-aspartate (NMDA) receptors has been implicated in the pathogenesis of the response alterations associated with dopaminomimetic treatment of parkinsonian animals and patients. To determine whether serine phosphorylation of NMDA receptor subunits by activation of Ca2+/calmodulin-dependent protein-kinase II (CaMKII) contributes to this process, we examined the effects of unilateral nigrostriatal ablation with 6-hydroxydopamine and subsequent treatment with levodopa, SKF 38393 (D1-preferring dopamine agonist), or quinpirole (D2-preferring agonist) on motor responses and phosphorylation states. Three weeks of twice-daily levodopa administration to rats shortened the duration of their rotational response to levodopa or SKF 38393 challenge, but prolonged the duration of quinpirole-induced rotation. At the same time, levodopa treatment elevated serine phosphorylation of striatal NR2A (p<0.02), but not that of NR2B subunits, without associated changes in subunit protein levels. Chronic treatment with SKF 38393 increased NR2A (p<0.0001) but decreased NR2B (p<0.004) serine phosphorylation. In contrast, chronic quinpirole treatment had no effect on NR2A but increased NR2B phosphorylation (p<0.0001). The acute intrastriatal injection of the CaMKII inhibitor KN93 (1.0 micrograms) not only normalized the levodopa-induced motor response alterations but also attenuated the D1 and D2 receptor-mediated serine phosphorylation of NR2A and NR2B subunits, respectively (p<0.02). These results suggest that a CaMKII-mediated rise in serine phosphorylation of NMDA receptor subunits induced by intermittent stimulation of D1 or D2 dopaminergic receptors contributes to the apparent enhancement in striatal NMDA receptor sensitivity and thus to the dopaminergic response plasticity in levodopa-treated parkinsonian rats.     

Altered bladder function in transgenic mice expressing rat elastin

The elasticity of tissues subjected to repeated deformation is provided by the presence of elastic fibers in the extracellular matrix (ECM). The most abundant component of elastic fibers is elastin, whose soluble precursor is tropoelastin. To establish the role elastin plays in the bladder, this study describes the biosynthetic, histologic, and physiologic consequences of expression of an isoform of rat tropoelastin in transgenic mouse bladder. The polymerase chain reaction (PCR) was used to determine expression of a rat tropoelastin minigene in transgenic mice. Histochemical methods were used to demonstrate changes in elastic fibers in frozen sections of bladder. Cystometric analysis was carried out in transgenic and non-transgenic mice, prior to and after 3 weeks of partial outlet obstruction. The PCR assay demonstrated that bladder tissue of transgenic mice expressed rat tropoelastin mRNA, whereas non-transgenes did not. Increased deposition of elastic fibers was demonstrated with the Verhoeff-van Gieson stain. Bladders of transgenic animals were more compliant than bladders of their non-transgenic littermates. Partial outlet obstruction resulted in increased bladder volume and more compliant bladders in non-transgenic mice. In contrast, the bladder volume and compliance in transgenes was almost unchanged by obstruction. This study demonstrates that normal elastic fiber assembly is prerequisite for the compliant properties of the bladder wall. Moreover, the response of the bladder to obstruction is critically influenced by elastin synthesis.     

Financing the World Health Organisation: global importance of extrabudgetary funds

From 1948, when WHO was established, the Organisation has relied on the assessed contributions of its member states for its regular budget. However, since the early 1980s the WHO World Health Assembly has had a policy of zero real growth for the regular budget and has had to rely increasingly, therefore, on attracting additional voluntary contributions, called extrabudgetary funds (EBFs). Between 1984-85 and 1992-93 the real value of the EBFs apparently increased by more than 60% and in the 1990-91 biennium expenditure of extrabudgetary funds exceeded the regular budget for the first time. All WHO programmes, except the Assembly and the Executive Board, receive some EBFs. However, three cosponsored and six large regular programmes account for about 70% of these EBFs, mainly for vertically managed programmes in the areas of disease control, health promotion and human reproduction. Eighty percent of all EBFs received by WHO for assisted activities have been contributed by donor governments, with the top 10 countries (in Europe, North America and Japan) contributing about 90% of this total, whereas the UN funds and the World Bank have donated only about 6% of the total to date. By contrast, about 70% of the regular budget expenditure has been for organisational expenses and for the support of programmes in the area of health systems. Despite the fact that the more successful programmes are heavily reliant on EBFs, there are strong indications that donors, particularly donor governments, are reluctant to maintain the current level of funding without major reforms in the leadership and management of the Organisation. This has major implications for WHO's international role as the leading UN specialised agency for health.     

Creutzfeldt-Jakob disease latest unknown in struggle to restore faith in blood supply.

There was considerable medical interest in a recent Toronto conference on prion disease--and in Creutzfeldt-Jakob disease (CJD) in particular--because of the recent tainted-beef controversy in Britain. Although there is no proven link between a newly recognized variant form of CJD and "mad cow disease," and no evidence that CJD can be spread through the blood supply, the theoretical risk has scientists scrambling to understand how the disease is spread and policymakers struggling with the thorny issue of whether to notify persons who have received blood or blood products that may place them at risk. Until the mysteries of prion diseases and their transmission are unravelled, Dr. Peter Vaughan reports, physicians and their patients will have to live with uncertainty.     

Effective chemotherapy of acute myelocytic leukemia occurring after alkylating agent or radiation therapy for prior malignancy

Eleven consecutive patients with acute myelocytic leukemia occurring as a second malignancy were treated with high-dose, timed, sequential chemotherapy. Eight of the patients were felt to have "secondary" acute leukemia because they had received an alkylating agent or radiation therapy. The other three patients were considered controls. Despite a median age of 65, four of the eight secondary leukemia patients achieved complete remission with this regimen. One of the three control patients also achieved complete remission. This remission rate and duration are comparable to what was achieved with this treatment of "primary" acute myelocytic leukemia during the same period of time. These results suggest that patients with leukemia occurring after an alkylating agent or radiation therapy are not at especially high risk if treated aggressively.     

Kinetic analysis of chloride conductance in frog skeletal muscle at pH 5

At pH 5 the steady-state chloride chord conductance in frog skeletal muscle rises to an asymptotic maximum at very negative voltages and approaches an asymptotic minimum at positive voltages. When a two-pulse test paradigm is used, the conductance computed from steady-state currents during the first (conditioning) voltage step are not duplicated by the conductance at the onset of a second (test) step. If the test step is to a more negative voltage than the conditioning step the steady-state conductance is overestimated; if it is to a less negative voltage the conductance is underestimated. In some fibres the initial currents accompanying steps from the resting potential are inwardly rectified. From this it was inferred that chloride channel conductance is voltage dependent: in those fibres in which no such initial inward rectification was observed it was inferred that at rest the voltage-dependent chloride channels are all closed. Time-dependent (gated) changes of conductance could be reasonably described by a first-order process, but the relaxations were not simple exponentials. Simulation of the experimental set-up predicted the type of deviation from exponentiality seen experimentally, although the observed deviations were often more pronounced than those predicted.     

Community treatment orders: relationship to clinical care, medication compliance, behavioural disturbance and readmission

OBJECTIVE: The objective of this study was to investigate the readmission rate, and the level of patient disturbance and community care associated with readmission following Community Treatment Orders (CTOs) in New South Wales, Australia. METHOD: The readmission rates of all patients given CTOs within a 4-year period and a matched comparison group were investigated. The following factors were compared before, during and following a CTO: medication non-compliance, number of clinical services and duration of disturbed behaviour preceding hospitalisations. RESULTS: Of 123 patients on CTOs (mean length, 288 days; SD, 210 days), 38 were readmitted during the CTO, the majority in the first 3 months and a further 21 patients were readmitted following termination of the CTO. Evidence of lower severity of illness in the comparison patients prevented meaningful evaluation of the readmission rates of the two groups. While on CTOs, patients receiving depot medications showed high compliance and a significantly reduced readmission rate compared with that of patients receiving oral medications. In the 2 months prior to hospitalisations during CTOs, compared with those before or after CTOs, patients received more frequent consultations and showed a shorter duration of medication non-compliance and disturbed behaviour. The level of services in the 3 months following discharge were comparable for patients on CTOs and the comparison group. CONCLUSIONS: CTOs may reduce rehospitalisations by use of depot medication. Earlier and possibly more frequent readmissions in the CTO group shortened the disturbance associated with illness recurrence. It would appear that to establish a control group with equivalent severity of disorder necessary to evaluate the impact of CTOs requires a random allocation design.     

Effect of aging on bladder function and the response to outlet obstruction in female rats

Bladder dysfunction in the aging population is a significant problem. However the concomitant presence of other diseases in many patients can make it difficult to distinguish between changes in bladder function and other influences. The present study was designed to study, in aging rats, bladder function and the effect of partial bladder outlet obstruction (BOO) on bladder function. Cystometrics were performed in awake, female Fischer 344 rats of four age groups (6, 12, 18 and 24 months) following subcutaneous implantation of a mediport catheter. Cystometric evaluations were carried out in control rats or those subject to three weeks of BOO. Bladder compliance significantly decreased with aging, which reflected an increase in threshold pressure without changes in bladder capacity. Partial BOO caused development of severe bladder instability. Following BOO, bladder capacity and compliance were significantly increased in all age groups. Threshold pressure was lower in obstructed animals, except for 6-month rats. Younger animals were able to generate a higher contraction pressure to compensate for the BOO, whereas older animals did not. Using an awake model of cystometric measurement, we have demonstrated that aging, by itself can affect bladder function. Furthermore, aged animals respond differently to BOO than younger animals. These results demonstrate that both aging and disease can contribute to bladder dysfunction, and suggest that treatment of bladder dysfunction may require a combination of therapies targeted to multiple etiologies. Received: 18 August 1998 / Accepted: 6 July 1999