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1. Voltage‐activated currents through calcium channels in primary cultures of murine dorsal root ganglion cells (DRG) were studied with the whole‐cell and cell‐attached patch recording techniques. 2. The chemical phosphatase 2,3‐butanedione monoxime (BDM) reversibly reduced the amplitude of L‐type calcium current (ICa) in a dose‐dependent manner; at a concentration of 20 mM, BDM caused a 47% suppression of ICa. 3. Application of 10 mM‐8‐bromo‐cyclic AMP or 50 microM‐isoprenaline onto DRG treated with BDM completely restored ICa to the pre‐BDM level. 4. In striking contrast, bath application of Bay K 8644 (0.5‐5 microM) had no effect on the BDM‐suppressed ICa. As expected, Bay K 8644 alone caused a two‐ to threefold increase of the maximal ICa and shifted its I‐V relationship to the left. Interestingly, if a cell was first exposed to Bay K 8644 further treatment with 20 mM‐BDM resulted in 100% suppression of ICa. This suggests that Bay K 8644 changes the conformation of the calcium channel to one which is more sensitive or more accessible to the action of the phosphatase. 5. Pre‐treatment of DRG with an activator of protein kinase C, 12‐O‐tetradecanoyl‐phorbol‐13‐acetate, did not antagonize BDM's effect on ICa. 6. The depressant action of BDM on ICa was distinct from that of nifedipine in that it did not exhibit use dependence. 7. When single calcium channel currents were recorded in cell‐attached patches (barium as the charge carrier), bath application of BDM reduced the percentage of time that the channel spent in the open state. 8. Superfusion with 8‐bromo‐cyclic AMP restored the ensemble macroscopic ‘ICa’ to the pre‐BDM amplitude. This was due to a dramatic enhancement of the frequency of channel openings. 9. We suggest that BDM acts through the cytoplasm to alter cyclic AMP‐dependent protein kinase modulation of neuronal L‐type calcium channels. The brief, high‐frequency openings which 8‐bromo‐cyclic AMP activates in the presence of BDM may reflect a rapid phosphorylation‐dephosphorylation sequence which controls channel gating.

Combined cross-sectional and longitudinal data often present complex patterns of change. Growth functions representing the change in some measure as a function of chronological age can be a function of initial values of the measurement. Individual differences in developmental age with respect to chronological age tend to distort attempts to fit a single growth curve through combined cross-sectional and longitudinal data. We present a method by which these data can be visualized along with several examples from a data set comprising measurements of intellectual abilities with respect to aging. We call this new method a statistical vector field (svf) plot. An svf plot simultaneously allows the visualization of cross-sectional information summarizing sampling densities and longitudinal information summarizing how individuals at each particular age and ability are likely to change over time. The C source code for the svf software described in this paper may be obtained free from the University of Virginia anonymous ftp archive server (ftp. Virginia.EDU), or from the authors.

We describe mathematical and statistical models for factor invariance. We demonstrate that factor invariance is a condition of measurement invariance. In any study of change (as over age) measurement invariance is necessary for valid inference and interpretation. Two important forms of factorial invariance are distinguished: "configural" and "metric." Tests for factorial invariance and the range of tests from strong to weak are illustrated with multiple group factor and structural equation modeling analyses (with programs such as LISREL, COSAN, and RAM). The tests are for models of the organization and age changes of intellectual abilities. The models are derived from current theory of fluid (Gf) and crystallized (Gc) abilities. The models are made manifest with measurements of the WAIS-R in the standardization sample. Although this is a methodological paper, the key issues and major principles and conclusions are presented in basic English, devoid of technical details and obscure notation. Conceptual principles of multivariate methods of data analysis are presented in terms of substantive issues of importance for the science of the psychology of aging.

In this paper we describe some mathematical and statistical models for identifying and dealing with changes over age. We concentrate specifically on the use of a latent growth structural equation model approach to deal with issues of: (1) latent growth models of change, (2) differences in longitudinal and cross-sectional results, and (3) differences due to longitudinal attrition. This is a methodological paper using simulated data, but we base our models on practical and conceptual principles of modeling change in developmental psychology. Our results illustrate both benefits and limitations using structural models to analyze incomplete longitudinal data.

In this paper we describe some mathematical and statistical models based on structural equation modeling (SEM) using computer programs like LISREL. We focus on SEM methodology for the simultaneous examination of the internal validity of psychological constructs and the external validity represented by age relations. To illustrate these ideas we use a latent variable path model to examine the organization of intellectual abilities measured by the WAIS-R in the standardization sample. We also examine different ways in which age can be used to structure this organization. This is primarily a methodological paper, but we try to integrate conceptual principles of modeling with some substantive issues of research on the psychology of aging.

In this paper we describe some mathematical and statistical models for dealing with changes over age. We concentrate specifically on the use of a structural equation modeling (SEM) approach (using computer programs like LISREL) to deal with issues of: (1) group differences in regression parameters, (2) differences in longitudinal and cross-sectional results, (3) differences due to longitudinal attrition, and (4) mixtures of these problems. To illustrate these ideas we use data from a previous study of hypertension and intellectual abilities (from Schultz, Elias, Robbins, Streeten, and Blakeman, 1986).

1. The frequency of miniature end‐plate potentials (m.e.p.p.s) was significantly greater in the fast twitch extensor digitorum longus muscle (extensor) than in the slow twitch soleus, even though end‐plate surface area was greater for fibres in the latter muscle. 2. Crush of the sciatic nerve at birth did not prevent the appearance of this difference in m.e.p.p. frequency. However, the frequency of the potentials in the re‐innervated muscles was less than normal, even though the regenerated neuromuscular junction was qualitatively normal in morphology. 3. Though the re‐innevated muscles were differentiated with respect to twitch time course, the extensor muscle was more responsive than normal to the contracture‐inducing action of caffeine. 4. The Z line of the re‐innervated extensor muscle was similar to that of the normal soleus in thickness. 5. Resting potential, passive electrical properties and action potential generating mechanism of the sarcolemma were normal. 6. Since the re‐innervated muscles lacked muscle spindles, a role of sensory feed‐back in the function of the neuromuscular junction as well as the neutrotrophic regulation of muscle is discussed.

In prior research we have shown how linear structural equation models and computer programs (e.g., LISREL) may be simply and directly used to provide alternatives for the traditional biometric twin design. We use structural equations and path models to define biometric group differences, we write traditional common-factor models in the same way, and then we take a detailed look at some alternative multivariate and biometric models. We contrast the biometricfactors covariance structure approach used by Loehlin and Vandenberg (1968), Martin and Eaves (1977), and others with the psychometric-factors approach used by McArdle et al. (1980) and others. We use the multivariate primary mental abilities data on monozygotic (MZ) and dizygotic (DZ) twins from Loehlin and Vandenberg (1968) to detail fundamental differences in model specification and results. We extend both multivariate biometric approaches using exploratory and confirmatory multiple-factor models. These comparisons show that each alternative multivariate methodology has useful features for empirical applications.

The purpose of this paper is to introduce one kind of latent-variable structural-equation model for multivariate longitudinal data which includes behavioral genetic components. A generic structural-equation model termedRAM (McArdle, J. J. and McDonald, R. P. (1984).Br. J. Math. Stat. Psychol.,37:239–251.) is used to define the univariate twin design, including both covariances and means. This model is extended to multivariate form using a latent-variable growth-curve model recently presented by W. Meredith and J. Tisak [(1984). “Tuckerizing” curves. Psychometric Society Annual Meetings]. The model presented herein further permits hypothesis testing of various biometric models of the sources of these individual differences in latent growth. Aspects of this model are illustrated using the LISREL algorithm [Jöreskog, K. G. and Sörbom, D. (1979).Advances in Factor Analysis and Structural Equation Models, Abt Books, Cambridge, Mass.] and longitudinal twin data on early childhood abilities [Wilson, R. S. (1983).Child Dev.54:298–316].

Abstract:  Hippocampal neurones were freshly isolated from the brain of adult mice and voltage-dependent K+ currents were recorded with the whole-cell patch-clamp technique. Three components of transient K+ current (IA) were isolated when analyzing data with exponential functions or treating neurones with a variety of voltage protocols and pharmacologic agents. Subtraction of the delayed rectifier current (I K) from the K+ currents elicited after prepulses to –120 mV of varying duration revealed fast (IAf) and slow (IAs) components with decay time constants of 45 ± 8 and 612 ± 140 ms, respectively; the corresponding time constants for the removal of inactivation were 12.3 and 189.6 ms. Both tetraethylammonium and dendrotoxin selectively inhibited IAs. 4-Aminopyridine (4-AP) specifically blocked IAf and 40% of IAs with different affinities. Therefore, the properties of a 4-AP-resistant (IAsR) and a 4-AP-sensitive (IAsS) component of IAs were compared. These data suggest that three distinct subtypes of K+ currents contribute to the IA of mature murine hippocampal neurones.

The whole cell recording technique was used to explore the depressant effect of the tricyclic antidepressant imipramine (IP) on calcium currents of neurons in cultures of murine dorsal root ganglia. The maximal whole cell current (ICa) mediated by the L-type calcium channel declined to 54% of control within 3 min of superfusing neurons with a solution containing 30 microM IP. In contrast, the T-type calcium current was unchanged. The IP-induced reduction of ICa was not associated with a change of the current-voltage relations of ICa. The depressant effect of IP on ICa was greatly reduced if neurons were pretreated with pertussis toxin or dialyzed with an intracellular solution containing guanosine 5'-O-2-thiodiphosphate. In contrast, superfusion of neurons with 5 mM 8-bromo-cyclic-AMP did not alter the effect of IP upon ICa. These data suggest that the selective suppressant effect of IP on the L-type calcium channel involves either an interaction with that region of the channel complex coupled to guanosine nucleotide-binding proteins or with guanosine nucleotide-binding proteins themselves.

2,3-Butanedione monoxime (BDM) has a negative inotropic effect on smooth muscles as well as the myocardium. Therefore, in the present study we compared the sensitivity to BDM of the cardiovascular system of the spontaneously hypertensive (SHR) and the normotensive Wistar-Kyoto (WKY) rat. While BDM significantly decreased the blood pressure (BP) for both strains, the SHR was significantly more responsive. Specifically, 5, 30, 100, and 200 mg/kg BDM (intravenously) reduced BP of the SHR by 9 +/- 3, 20 +/- 3, 49 +/- 5, and 63 +/- 7 mm Hg, respectively. The same doses of BDM reduced BP of the WKY by 0, 2 +/- 0.4, 18 +/- 3, and 26 +/- 3 mm Hg. The duration of the hypotensive effect of BDM was also greater for the SHR. In vitro, BDM had a greater suppressant effect on the L-type Ca2+ current (ICa(L)) of SHR ventricular myocytes; the IC50 for the suppression of ICa(L) was 17 and 29 mM for SHR and WKY ventricular myocytes, respectively. The beta-adrenergic receptor agonist isoproterenol antagonized the suppressant effect of BDM on ICa(L). Furthermore, BDM significantly reduced the duration of both spontaneous and electrically stimulated action potentials of cultured neonatal rat cardiomyocytes. Intracellular dialysis with the catalytic unit of protein kinase A antagonized BDM's effect on the action potential. These data suggest that suppression of myocardial activity contributes to the hypotensive effect of BDM. In addition, the elevated response to BDM of SHR cardiac myocytes may indicate that the conformation and/or modulation of the L-type Ca2+ channel differ for the SHR and WKY lines of rat.

Action potentials (APs) were recorded from the extrajunctional membrane of surface fibers of the fast-twitch extensor digitorum longus (extensor) and the slow-twitch soleus muscles of adult rats. APs of the extensor muscle had a significantly faster rate of rise and fall, as well as a shorter duration, than those of the soleus. In addition, the overshoot of APs and the resting membrane potential was greater for the extensor. Whereas the soleus produced only one AP regardless of the stimulus duration, the number of extensor responses was directly proportional to the stimulus duration. This repetitive activity was greatly reduced by a concentration of tetrodotoxin (TTX) as low as 5 X 10(11) g/ml. Within 8 d after crush of the nerves to these two muscles, all differences in AP properties disappeared and both muscles became partially resistant to TTX. Reinnervation brought about a redifferentiation so that differences in AP were again significant at 22 d after nerve crush. However, the rate of rise of extensor APs did not attain normal values even as late as 60 d after nerve crush. APs were found to be the same for extensor and soleus muscles from 12-d-old rats. At 18 d after birth, rate of rise was equivalent to that of adult muscle for the soleus although 50--60 d were required before this parameter was fully mature for the extensor. Nevertheless, APs of the extensor and soleus were clearly differentiated within 25 d after birth. Differences in fast and slow muscle APs are discussed with regard to differences in ion gradients and sarcolemmal conductance.

The effects of cibenzoline on transmembrane action potentials were examined in guinea pig papillary muscle. Cibenzoline (1-128 microM) did not alter the action potential durations at 50 and 90% of repolarization, the effective refractory period or the ratio of effective refractory period to action potential duration at 90% of repolarization. Likewise, the maximum diastolic potential was virtually unaffected. Cibenzoline depressed the maximum rate of rise of phase 0 (dV/dtmax). This effect was dependent on the rate of stimulation and occurred at a relatively low concentration (2 microM). The onset of use-dependent depression was monoexponential and dependent on the drug concentration, as well as the rate of stimulation. The rate of recovery from use-dependent depression also followed a single exponential time course but was independent of drug concentration and stimulation rate. When cibenzoline and lidocaine were combined in the tissue bath, dV/dtmax recovered with a double exponential time course. The first and second components of this recovery corresponded to the time course observed with lidocaine (first) and cibenzoline (second) alone. Also, the magnitude of the second component was less with the combination than with cibenzoline alone, indicating an interaction between the two drugs. In addition, cibenzoline shifted the curve relating normalized dV/dtmax to membrane potential in the hyperpolarizing direction. Finally, cibenzoline did not alter slow-response action potentials induced by elevated [K]o and isoproterenol. The authors conclude that cibenzoline acts as a class la antiarrhythmic agent in guinea pig papillary muscle.

Abstract: The spate of medicolegal inquiries following the disqualification of Parlodel (bromocriptine mesylate) by the Food and Drug Administration for postpartum ablactation, uncovered previously unreported side effects associated with its postpartum administration. In 1994, bromocriptine mesylate was withdrawn from the market as a milk suppressant. Since this time, over a dozen cases of postpartum intracranial hemorrhages associated with its use have been reported. We describe three additional cases of postpartum intracranial hemorrhage related to bromocriptine usage. One patient, previously normotensive, developed hypertension and a headache; initial CT was normal, but CT 24 h later demonstrated intracranial hemorrhage. This suggests that the blood-pressure elevation was drug-induced and was the cause, rather than the consequence, of bromocriptine-related intracranial hemorrhage.

The origins of the present series of articles on quantitative topics in aging research are presented. Specific articles are described, the purposes and goals of the quantitative series are set forth, and the relationship of this body of knowledge to the scientific status of the area of aging research is discussed.