Measurement of lithium transport in RBC from psychiatric patients receiving lithium carbonate and normal individuals by 7Li NMR spectroscopy.

A reproducible 7Li nuclear magnetic resonance (NMR) method, based on a modified inversion recovery (MIR) pulse sequence, was used to discriminate between intra- and extracellular lithium concentrations in red blood cell (RBC) suspensions. The rates of Na(+)-Li+ countertransport determined by the 7Li NMR method were significantly correlated with the measurements made by atomic absorption (AA) for 14 psychiatric patients receiving lithium carbonate (r = 0.937) and 14 normal individuals (r = 0.931). As expected, the rates of Na(+)-Li+ countertransport measured by MIR were significantly lower for the psychiatric patients receiving lithium carbonate than for normal individuals. The 7Li NMR method provides RBC Li+ countertransport information comparable to AA for psychiatric patients and normal individuals. A description of the advantages of the 7Li NMR method in contrast to the AA method, including the study of Li+ interactions with RBC components such as membrane proteins and anionic phospholipids, is included.

Nuclear magnetic resonance studies of lithium transport in erythrocyte suspensions of hypertensives.

We have applied a nuclear magnetic resonance (NMR) method, based on the 7Li nucleus, to discriminate between intracellular and extracellular lithium ions (Li+) in red blood cell (RBC) suspensions. The NMR method was compared with atomic absorption, a technique that requires physical separation of intra- and extracellular Li+ prior to chemical analysis. The rates and rate constants of RBC Na(+)-Li+ countertransport measured by the 7Li NMR method correlated significantly with the measurements made by atomic absorption for both the hypertensive (r = 0.964) and control (r = 0.961) groups. The rates of RBC Na(+)-Li+ countertransport measured by NMR were significantly higher for hypertensive patients than for normotensive controls. The fact that the NMR method does not require cell membrane lysis, and its potential to reveal structural and mechanistic information on Li+ binding and transport in cellular systems, makes it promising for understanding the basis of Li+ transport variations in RBCs, and possibly other tissues, from hypertensive patients.

The bacterial Kdp K(+)-ATPase and its relation to other transport ATPases, such as the Na+/K(+)- and Ca2(+)-ATPases in higher organisms.

The Kdp system is a three-subunit member of the E1-E2 family of transport ATPases. There is sequence homology of the 72 kDa KdpB protein, the largest subunit of Kdp, with the other members of this family. The predicted structure of the 21 kDa KdpC subunit resembles that of the beta subunit of the Na+,K(+)-ATPase, suggesting that these subunits may have a similar function. The 59 kDa KdpA subunit has no known homologue; it is very hydrophobic and is predicted to cross the membrane 10-12 times. Genetic studies implicate this subunit in the binding of K+. As the binding site must be close to the beginning of the transmembrane channel, we suggest that KdpA also forms most or all of the latter. KdpA may have evolved from a K+/H+ antiporter that was recruited by the KdpB precursor to achieve the high affinity and specificity for K+, and the activation of transport by low turgor pressure characteristic of Kdp. Turgor pressure controls the expression of Kdp. This action is dependent on the 70 kDa KdpD and 23 kDa KdpE proteins. We are in the process of sequencing these genes. KdpE is homologous to the smaller protein of other members of a family of pairs of regulatory proteins implicated in control of a variety of bacterial processes such as porin synthesis, phosphate regulon expression, nitrogen metabolism, chemotaxis and nodule formation.

Pharmacologic evidence for specificity of pursuit dysfunction to schizophrenia. Lithium carbonate associated with abnormal pursuit.

Conflicting findings regarding the prevalence of abnormal smooth-pursuit eye movements in patients with major affective disorders call into question the specificity of impaired smooth-pursuit eye movements to schizophrenia. We report that pursuit is impaired in 88% of lithium carbonate-treated affective disorder patients whose pursuit was normal prior to receiving this drug. Over half of lithium carbonate-treated affective disorder patients in remission also showed impairment of smooth-pursuit eye movements. In conjunction with recent prevalence data on family members of psychiatric patients, the findings support the specificity of abnormal pursuit as a biological trait associated with schizophrenia, but not with the major affective disorders. The mechanisms by which lithium carbonate impairs pursuit are discussed.

Sequence homology between two membrane transport ATPases, the Kdp-ATPase of Escherichia coli and the Ca2+-ATPase of sarcoplasmic reticulum.

We have determined the DNA sequences of the genes encoding the three structural proteins of the Kdp-ATPase, an ATP-driven potassium transport system of Escherichia coli. Regions of the predicted amino acid sequence of KdpB, the phosphorylated protein of the system, are homologous to regions of the Ca2+-ATPase of rabbit sarcoplasmic reticulum. The phosphorylated aspartate residue of the latter is within a region of homology.

Mixture distributions in psychiatric research.

This paper describes the application of Gaussian mixture distributions to biological marker research in psychiatry. Mixtures of univariate and multivariate normal distributions can be used to determine if diagnostically similar psychiatric patients belong to biologically distinct subpopulations. The resulting biological subtypes may be important in understanding the etiology of psychiatric disorders. The general model and estimation procedure are described (EM algorithm; Dempster, Laird and Rubin 1977). The method is illustrated using two examples of biological data: (1) red cell membranes and monoamine oxidase activity data in normal individuals having no family history of psychiatric illness, the first-degree relatives of bipolar depressed patients and a heterogeneous patient population; and (2) smooth pursuit eye movements that classify relatives of schizophrenics, nonschizophrenics and normal controls into biologically distinct populations.

Lithium transport in red cells of patients with affective disorders.

Variation in red cell Li+ transport as mediated by the Li+-Na+ exchange pathway (Li+-Na+ counterflow) appears to cause wide variation between psychiatric patients in the Li+ ratio (erythrocyte/plasma) in vivo during Li+ treatment. We obtained significant correlations between Li+ ratios determined in vivo and several measures of Li+ transport as mediated by Li+-Na+ exchange. Patients with bipolar illness had significantly lower rates of Li+ transport as mediated by this pathway than did normal subjects.

Relatives of unipolar and bipolar patients have normal pursuit.

Impaired smooth pursuit eye movements are significantly less prevalent among the first-degree relatives of patients who have major affective disorders than among the first-degree relatives of schizophrenics. The distribution of normal and abnormal smooth pursuit among the relatives of unipolar and bipolar patients does not differ from that of normal individuals having no family history of major psychosis. Smooth pursuit impairment is thus specific to relatives of schizophrenic patients and is not characteristic of relatives of patients with major affective disorders.

Lithium ion transport and affective disorders within families of bipolar patients. Identification of a major gene locus.

We have identified a genetic polymorphism in which one allele results in elevated RBC lithium ion ratios and also contributes to vulnerability to some forms of affective disorders. Interindividual variability in the lithium ion ratio (the ratio of the RBC to the plasma lithium ion concentration) is determined by variability in a lithium ion ratio (the ratio of the RBC to the plasma lithium ion concentration) is determined by variability in a lithium-sodium ion counterflow mechanism. Segregation analyses were conducted on lithium ion ratios in vitro in members of 120 normal families and on both the lithium ion ratio and the history of affective disorder in first-degree relatives of 31 bipolar patients. These analyses provided evidence for an autosomal major gene locus that influences the lithium ion ratio both in members of normal families and in relatives of bipolar patients. The allele at the major locus resulting in elevated lithium ion ratios was associated with an increased likelihood of psychiatric hospitalization among relatives of bipolar patients.

Reduced platelet MAO activity and vulnerability to psychiatric disorders.

Platelet monoamine oxidase (MAO) is a genetically controlled mitochondrial enzyme that metabolizes amines in the brain by deamination. We investigated the relationship between MAO activity and the presence or absence of psychopathology by determining MAO activity and the psychiatric diagnosis in 61 first-degree relatives of 31 patients with bipolar (manic-depressive) illness. Relatives who themselves were diagnosed as having bipolar I illness or alcoholism had a significantly lower mean MAO activity level than did other relatives or 255 normal individuals. These findings indicate that a relationship exists within pedigrees between MAO activity and psychiatric disorders. Reduced MAO activity may play a role in vulnerability to some types of psychopathology.

Variability in the Y chromosome and variability of human behavior.

Two kinds of variability in the Y chromosome have been assessed in relation to variability of human behavior. The first is the presence of a supernumerary Y chromosome, which is found in two karyotypic variants, 47,XYY and 48,XXYY. The second is inherited variability in the length of the Y chromosome, which results from variability in the length of the quinacrine-binding fluorescent segment. In this article, I review the evidence that these two kinds of variability in the Y chromosome are related to variability of human behavior, and I indicate the methodological and statistical difficulties that are encountered in assessments of such a relationship. My final purpose is to underscore the need for mapping of the Y chromosome and to elucidate the function of the constitutive heterochromatin that constitutes its fluorescent segment so that progress can be made in the study of the Y chromosome and the possible effect of its variability on behavior.

Personality correlates of platelet monoamine oxidase activity anbd red cell lithium transport.

Platelet monoamine oxidase (MAO) activity and the ratio of red cell to plasma lithium concentrations (Li ratio) may be important in the pathophysiology of, and genetic vulnerability to, some psychiatric disorders. By using the Clinical Analysis Questionnaire, we assessed personality correlates of MAO activity and the Li ratio in vitro in a sample of psychiatrically normal adult women. We found that there were correlates of each variable, and a unique constellation of personality traits when the two variables were considered simultaneously.

A ring 14 chromosome with deleted short arm.

We report a 46,XX,r(14) karyotype in a female infant having craniofacial dysmorphology, a seizure disorder, and developmental retardation.

Lithium transport across the RBC membrane. A study of genetic factors.

The measurement of the ratio of RBC to plasma lithium ion levels in vitro in 291 members of 120 families indicated that genetic factors contribute substantially to interindividual variability in the lithium ion distribution across the RBC membrane. These factors affect the lithium-sodium ion exchange system that determines the lithium ion distribution.