Chronic lithium treatment increases the phosphorylation of a 64-kDa protein in rat brains

Despite the wide clinical use of lithium in the treatment of manic depressive illness there is no adequate explanation for its mechanism of action. In the light of lithium's suggestive effects on the second messenger system in the brain, we studied the effects of chronic dietary lithium treatment (achieving blood levels in the therapeutic range) on protein phosphorylation in different areas of rat brain. An increase in the phosphorylation of a 64-kDa membrane-associated protein was evident in the lithium-treated rats compared to controls. This increase was observed only under basal phosphorylating conditions and was abolished when the phosphorylation was performed in the presence of Ca²⁺ or Ca²⁺ and calmodulin. The possibility that this 64-kDa protein affected by lithium is the beta-subunit of the calmodulin-dependent protein kinase or a different protein which co-migrates with it is discussed.     

An epidemiological study of digoxin prescribing in general practice

The epidemiology of prescribing long-term digoxin was studied in 241 patients from six group general practices. Each patient was assessed for the initial reason for prescribing digoxin and present clinical status, and the serum digoxin concentration was measured between six and 12 hours after the previous dose.

The results show that digoxin was most commonly prescribed for elderly patients; 90% of patients were aged 60 years or more. The reasons for prescribing digoxin were considered adequate in only 55% of the total group; 71% of the patients were judged to be clinically well and 75% of the 95 patients with atrial fibrillation had ventricular rates of less than 90 beats per minute. `Therapeutic' serum digoxin concentrations (0.8—2.0 ng ml^-1) were observed in only 48% of patients; the level was sub-therapeutic in 46% and potentially toxic in 6%. No clear-cut relationship was found between clinical well-being and serum digoxin concentration. The type of supervision (whether hospital or general practice) did not affect appropriateness of prescribing, clinical well-being or likelihood of achieving a therapeutic serum digoxin level.

This study would suggest the need for critical review of digoxin therapy in all patients who are taking it long-term. In some patients its continuance would appear unnecessary; in others, efficacy may be improved either by dose adjustment or by ensuring compliance. On occasions, particularly in patients with sinus rhythm, measurement of serum digoxin concentrations may prove helpful in this evaluation.

     

The role of H-2 I region genes in regulation of the immune response

The evidence of the past 10 years indicates that genes mapping in the I region of the mouse major histocompatibility complex (H-2) regulate a bewildering array of immunologic functions. A survey of H-2-linked specific immune response (Ir) genes shows that the phenotypic effect of these genes is to enable a particular inbred strain to discriminate and recognize remarkably precise chemical specificities, such as one or two amino acid interchanges in a polypeptide chain. The only I region gene products which have been identified to date are the Ia antigens. These include five readily detectable polypeptide chains (Aa, Ab, Ae, Ea, and Ii) and several other serologically distinct entities which are selectively expressed on functionally distinct T cell subsets (J1, J2?, J3? and C). The specificity of recognition of Ir genes would seem to require a larger number of I region gene products than can be generated even by combinatorial association of the four readily identifiable peptides (to give eight combinatorial associations) and the other serologically identified gene products. If the Ia antigens are to function as an antigen specific receptor system, separate from immunoglobulin molecules, there must be other, as yet undetected, I region gene products (e.g. Ia antigens). Alternatively, the known I region gene products could function by any one of several postulated mechanisms to generate an antigen specific T cell receptor system. The available evidence for the total number of I region gene products is reviewed, and the alternate possibilities are briefly discussed in this presentation.     

NO LINKAGE OR ASSOCIATION OF TELOMERIC AND CENTROMERIC T-CELL RECEPTOR β-CHAIN MARKERS WITH SUSCEPTIBILITY TO TYPE 1 INSULIN-DEPENDENT DIABETES IN HLA-DR4 MULTIPLEX FAMILIES

The T-cell receptor β locus (TCRB) on chromosome 7q35 was studied as a candidate region for genetic susceptibility to type 1 insulin-dependent diabetes (IDDM). A highly polymorphic microsatellite marker mapping to the TCRBV6.7 gene and a TCRB C-region RFLP were used to genotype the members of a total of 21 multiplex IDDM families from two different geographical areas. There was no evidence to support linkage to either of these markers with IDDM, and conventional two-point analysis excluded linkage to the telomeric end of the TCRB complex, in the region of the highly informative TCRBV6.7 marker. There was significant linkage of IDDM to the class II HLA-D locus with significant lod scores >3.0 obtained for the HLA-DRB1 and HLA-DQB1 genes. Affected sib-pair (ASP) and transmission disequilibrium (TDT) association tests confirmed these findings.