Limited CD4+ T-cell renewal in early HIV-1 infection: effect of highly active antiretroviral therapy.

We show that the fraction of proliferating CD4+ lymphocytes is similar in HIV-infected subjects in the early stage of disease and in HIV-negative subjects, whereas the fraction of proliferating CD8+ lymphocytes is increased 6.8-fold in HIV-infected subjects. After initiation of antiviral therapy, there is a late increase in proliferating CD4+ T cells associated with the restoration of CD4+ T-cell counts. These results provide strong support for the idea of limited CD4+ T-cell renewal in the early stage of HIV infection and indicate that after effective suppression of virus replication, the mechanisms of CD4+ T-cell production are still functional in early HIV infection.

Effects of chronic prenatal MK-801 treatment on object recognition, cognitive flexibility, and drug-induced locomotor activity in juvenile and adult rat offspring.

BACKGROUND: Patients with schizophrenia display impaired cognitive functioning and increased sensitivity to psychomimetic drugs. The neurodevelopmental hypothesis of schizophrenia posits that disruption of the developing brain predisposes neural networks to lasting structural and functional abnormalities resulting in the emergence of such symptoms in adulthood. Given the critical role of the glutamatergic system in early brain development, we investigated whether chronic prenatal exposure to the glutamate NMDA receptor antagonist, MK-801, induces schizophrenia-like behavioural and neurochemical changes in juvenile and adult rats. METHODS: Pregnant Long-Evans rats were administered saline or MK-801 (0.1mg/kg; s.c.) at gestation day 7-19. Object recognition memory and cognitive flexibility were assessed in the male offspring using a novel object preference task and a maze-based set-shifting procedure, respectively. Locomotor-activating effects of acute amphetamine and MK-801 were also assessed. RESULTS: Adult, but not juvenile, prenatally MK-801-treated rats failed to show novel object preference after a 90min delay, suggesting that object recognition memory may have been impaired. In addition, the set-shifting task revealed impaired acquisition of a new rule in adult prenatally MK-801-treated rats compared to controls. This deficit appeared to be driven by regression to the previously learned behaviour. There were no significant differences in drug-induced locomotor activity in juvenile offspring or in adult offspring following acute amphetamine challenges. Unexpectedly, MK-801-induced locomotor activity in adult prenatally MK-801-treated rats was lower compared to controls. CONCLUSIONS: Glutamate transmission dysfunction during early development may modify behavioural parameters in adulthood, though these parameters do not appear to model deficits observed in schizophrenia.

The cholesterol side chain cleavage system of the rat adrenal cortex and its relationship to the circadian rhythm.

The adrenal mitochondrial cytochrome P450 systems were examined at the low and high points of the circadian rhythm in female rats maintained on a light cycle from 0600--1800 h. The rate of association of cholesterol with the cholesterol side chain cleavage form of cytochorme P450 (P450scc) was measured by light absorption spectrometry. Cholesterol binding to P450scc was as high in rats killed at the beginning of the dark period as it was in stressed rats at the beginning of the light period. Stressing rats at the beginning of the dark period did not result in a further increase in the rate of cholesterol association with P450scc despite a further increase in serum corticosterone levels. This suggests that other reactions of cholesterol metabolism in the adrenal cortex are contributing in a significant way to the increased rate of corticosteroidogenesis seen in the stressed animals.

Resistance to mineralocorticoid-induced hypertensive vascular disease.

To support our contention that the Wistar-Furth rat is resistant to mineralocorticoid hypertension, we assessed the effects of deoxycorticosterone (DOC) administration or renal artery stenosis on the development of hypertension in the Sprague-Dawley and Wistar-Furth rat strains. Weekly administration of mineralocorticoid in the form of DOC pivalate resulted in rapid, severe hypertensive cardiovascular disease in Sprague-Dawley rats. Within 5 weeks the mean conscious systolic blood pressures in steroid-treated and control rats were 186 +/- 4 and 118 +/- 5 mm Hg, respectively. In contrast, blood pressures of Wistar-Furth rats were only moderately elevated, even after 10 weeks of DOC pivalate administration (136 +/- 2 vs 116 +/- 2 mm Hg for controls). Furthermore, none of the steroid-treated Wistar-Furth animals exhibited cardiovascular lesions. In parallel studies, littermates of these rat strains were subjected to renal artery stenosis and blood pressures were determined weekly in conscious rats. Silver clip constriction of the left renal artery, in the presence of the contralateral kidney, resulted in a rapid, sustained elevation of blood pressure in both Sprague-Dawley and Wistar-Furth rat strains (177 +/- 4 and 176 +/- 5 mm Hg, respectively). Corticosteroid levels were also determined in DOC-treated Sprague-Dawley and Wistar-Furth rats. The regimen employed resulted in a 10-fold increase in DOC levels as compared with controls, and the levels achieved were comparable in both strains. Thus, the Wistar-Furth rat appears to be selectively resistant to mineralocorticoid hypertensive vascular disease and thus affords a model for studying mechanisms of steroid hypertension.

Peripheral serum corticosteroid concentrations in relation to the rat adrenal cortical circadian rhythm in androgen-induced hypertension.

Adrenal function was assessed in control rats and in rats treated for 2 and 4 weeks with 17 alpha-methylandrostenediol (MAD; 17 alpha-methyl-5-androstene-3 beta-diol), a synthetic androgen known to produce hypertensive cardiovascular disease. In both groups and at both time periods, a circadian rhythm of blood corticosteroid concentrations was observed. The high point for serum corticosterone (B), 18-hydroxy-11-deoxycorticosterone (18-hydroxy-DOC), and 11-deoxycorticosterone (DOC) concentrations occurred at the beginning of the dark period (1800 hours), and the low point occurred at the onset of the light period (0600 hours). Serum concentrations of DOC were always found to be higher in MAD-treated rats as compared with controls. The serum concentrations of B and 18-hydroxy-DOC were lower than control values at 1800 hours but higher than control concentrations at 0600 hours. The in vitro 11 beta- and 18-hydroxylation of DOC was markedly reduced with MAD treatment. In contrast, cholesterol side-chain cleavage activity was higher in animals treated with MAD. These in vitro findings correlated with spectral studies that showed a decreased binding of DOC to cytochrome P450(11) beta and increased binding of cholesterol to cytochrome P450scc. These studies suggest that MAD treatment selectively decreases 11 beta- and 18-hydroxylation in adrenal mitochondria, and this results in an increased serum concentration of DOC, a hypertensinogenic steroid. This effect of MAD on peripheral serum DOC concentration is most readily observed in quiescent animals at the high point of the circadian rhythm.

Expression of adrenal cytochromes P-450 in testosterone-induced hypertension.

Chronic treatment of rats with the naturally occurring androgen, testosterone, leads to hypertension and cardiovascular disease. This effect is believed to be mediated through the adrenal gland and in particular by action on the steroid 11 beta-hydroxylase enzyme system. To study the possible mechanism of this effect, the enzyme system was examined at several time periods up to the time that hypertension develops. Rats were treated with testosterone (10 mg/day) for 3, 7, 21, and 42 days. Levels of cytochrome P-450(11) beta enzyme and messenger RNA (mRNA) were determined as well as 11 beta-hydroxylase enzyme activity. A significant decrease in enzyme activity was observed after 3 days of treatment. This correlates with a profound decrease in the level of cytochrome P-450(11) beta enzyme as determined by Western blot analysis. A large decrease in cytochrome P-450(11) beta mRNA was also observed after 3 days of treatment. All three parameters remained low throughout the treatment period. The decrease in 11 beta-hydroxylase enzyme activity appears to result from a lower enzyme level brought about by decreased concentrations of mRNA transcripts.

Phenylpropanolamine increases plasma caffeine levels.

The effects of the widely consumed drugs caffeine and phenylpropanolamine are mediated through activation of the central and sympathetic nervous systems. Severe, life-threatening, and occasionally fatal hypertensive reactions have been reported after their combined use. This study examined the possible pharmacokinetic interaction of phenylpropanolamine and caffeine. Sixteen normal subjects received combinations of caffeine, phenylpropanolamine, and placebo. In subjects receiving 400 mg caffeine plus 75 mg phenylpropanolamine, the mean (+/- SEM) peak plasma caffeine concentration of 8.0 +/- 2.2 micrograms/ml was significantly greater than after 400 mg caffeine alone (2.1 +/- 0.3 micrograms/ml; t[24] = 2.4; p less than 0.01). Physical side effects were more frequent after the phenylpropanolamine-caffeine combination than after either drug alone or after placebo. Greater increases in both systolic and diastolic blood pressures occurred after the combination than after either drug alone. Because caffeine levels can be increased greatly when certain other drugs are coconsumed, these data indicate that phenylpropanolamine may enhance absorption or inhibit elimination of caffeine and may explain increased side effects reported after their combined use.

Adverse drug effects attributed to phenylpropanolamine: a review of 142 case reports.

Phenylpropanolamine (PPA) is contained in about 106 products, over half of which are available over-the-counter (OTC). Most are cough/cold remedies; nine are OTC diet aids. More than nine million Americans were using OTC diet aids in 1981, making PPA the fifth most used drug in the United States, responsible for over $200 million in revenues. The safety of PPA remains controversial. Although most controlled studies indicate minimal pressor effects with recommended doses, adverse drug reactions (ADRs) continue to be documented. Since 1965, 142 ADRs have been reported in 85 studies, 69% of these in North America. Many such cases may go unrecognized. About two thirds of all ADRs occurred in females and in patients under 30. Of ADRs attributed to legitimately sold PPA products, 85% occurred after consumption of OTC products versus only 15% after prescription drugs. The PPA product often contained combination ingredients, or PPA was consumed along with additional drugs. An overdose of PPA was taken in about a third of the cases. After ingestion of non-overdose amounts, 82% of the ADRs were severe. The most frequent side effects involved symptoms compatible with acute hypertension, with severe headache the most common complaint. Twenty-four intracranial hemorrhages, eight seizures, and eight deaths (most due to stroke) were associated with PPA ingestion. We have summarized these data in an effort to alert clinicians to the prevalence of usage of PPA products and the potential for adverse effects. In patients who present with elevated blood pressure or signs of acute hypertension, especially hypertensive encephalopathy of undetermined origin, we recommend inquiry about recent ingestion of PPA-containing diet aids and cough/cold products and suggest having such patients remain upright rather than supine.

Temporal regulation by adrenergic receptor stimulation of macrophage (M phi)-derived tumor necrosis factor (TNF) production post-LPS challenge.

Macrophage (M phi) responsiveness can be regulated by various mediators, including those which emanate from, and mimic, the sympathetic nervous system. Whereas beta-adrenergic agonists suppress, alpha 2-adrenergic agonists augment lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) production and gene expressed. The susceptibility of M phi s to regulation of LPS-induced TNF production and mRNA accumulation was examined following beta-adrenergic and alpha 2-adrenergic receptor activation at specific time points post-LPS challenge. Complete Freund's adjuvant-elicited murine M phi s were incubated with LPS (30 ng/ml) in the presence or absence of adrenergic agonists or antagonists. We assessed the susceptibility of immunologically-activated M phi s to adrenergic receptor regulation: a) during the 1 h delay in the production of TNF after LPS-stimulation, and b) during the rapid increase in TNF production which follows. Disparate responsiveness of M phi s to adrenergic drugs was observed during this time course of TNF production and TNF mRNA accumulation. In particular, while the concomitant addition of an alpha 2-adrenergic antagonist and LPS resulted in 45% suppression of TNF production, this selective blockade of alpha 2-adrenergic receptors on M phi s was equally effective throughout the first 45 min post-LPS challenge. After this initial period, the alpha 2-adrenergic receptor became progressively less responsive as demonstrated by the delayed addition of yohimbine (10(-5) M) post-LPS challenge. The addition of the selective alpha 2-adrenergic agonist UK-14304 (10(-7) M) to LPS-activated M phi s augmented TNF mRNA accumulation. However, this augmentation was even greater when the addition of the alpha 2-adrenergic agonist was delayed post-LPS challenge. It was also shown that the beta-adrenergic agonist isoproterenol (10(-6) M) produced maximum suppression of TNF production within the first 1.5 h post-LPS challenge. Suppression by isoproterenol (10(-6) M) of TNF mRNA accumulation occurred throughout the 2-h period assessed post-LPS stimulation of M phi s. The decline in isoproterenol-induced regulation was accompanied by an elevation in beta 2-adrenergic receptor mRNA accumulation. Furthermore, suppression of TNF production induced by a maximum concentration of isoproterenol was observed at various LPS concentrations (0.001-1000 ng/ml), although this was not as pronounced a suppression as demonstrated for dibutyrl cAMP. These results demonstrate that the susceptibility of M phi s to adrenergic receptor regulation changes throughout the time period necessary for gene activation and ultimate release of TNF. Thus, the production of TNF during LPS-dependent disease states may be regulated by adrenergic mediators throughout different temporal windows, better explaining the role played by the nervous system.

Cytochromes P-45011 beta, P-450scc and adrenodoxin gene expression during adrenocortical regeneration in the rat.

Circulating levels of 11-deoxycorticosterone are increased during the development of adrenal-regeneration hypertension. The present studies were undertaken to examine the mechanisms involved in this increase. Plasmids containing cDNA inserts coding for cytochrome P-45011 beta, cytochrome P-450scc and adrenodoxin were used to determine, by Northern blot analysis, mRNA levels at 1, 2 and 3 weeks of adrenal regeneration. There was a striking decrease in mRNA transcripts for all three enzymes during the first week of regeneration when compared with intact adrenal tissue. Over the next 2 weeks the mRNA levels increased to 64% for P-45011 beta, to 80% for P-450scc and to 82% for adrenodoxin. Actin mRNA levels were 70% of control levels in the first week but were back to control levels by the second week. The present findings suggest that decreased expression of steroid 11 beta-hydroxylase could contribute to the increased secretion of 11-deoxycorticosterone during the early stages of adrenal regeneration.

Regulation by chronic drug administration of neuronal and cardiac calcium channel, beta-adrenoceptor and muscarinic receptor levels.

Chronic administration of atropine (40-100 mg/kg, 23 days) produced a 29-33% increase in muscarinic receptors, measured by [3H]quinuclidinyl benzilate binding, in rat brain. Diisopropyl phosphorofluoridate (0.9 mg/kg, 14 days) produced a 35% decrease in muscarinic receptors. Propranolol administration (800 micrograms/kg/hr, 10 days) increased beta-adrenoceptors, measured by [3H]dihydroalprenolol binding, by 69 and 50% in brain and heart respectively. Isoproterenol administration (800 micrograms/kg/hr, 10 days) produced a 50% reduction in cardiac beta-adrenoceptors but did not alter brain receptors. These drug treatments were without effect on binding of the Ca2+ channel ligands, [3H]nimodipine and [3H]nitrendipine, to brain or heart respectively. However, chronic administration of nifedipine for 20 days (36 and 360 micrograms/kg/hr) did produce down-regulation of both cardiac and neuronal Ca2+ channels and a similar down-regulation of beta-adrenoceptors. Co-regulation of Ca2+ channels and neurotransmitter receptors may occur but may not be an automatic consequence of either receptor or channel regulation.

Sex differences in cytochromes oxidase and P-45011 beta in the rat adrenal cortex.

A comparative study of cytochrome c oxidase (COX) activity and expression as well as cytochrome P-45011 beta expression has been carried out on the adrenal cortex of male and female rats. COX has also been examined in rat liver. In addition, the effect of testosterone replacement in orchiectomized male rats on adrenal COX has also been investigated. Adult male rats had higher COX activity in adrenal (255%) and liver (144%) mitochondria compared to adult female rats. Male rat adrenals and liver also had increased levels of COX II, a mitochondria-encoded COX subunit, and of COX IV, a nucleus-encoded COX subunit, as measured by Western analysis. In contrast, cytochrome P-45011 beta levels were lower (48%) in adrenal mitochondria from male rats than those of female rats. There was no significant sex difference in the level COX II and COX IV mRNAs in adrenal or liver, whereas the cytochrome P-45011 beta mRNA was 4-fold higher in female adrenals than in males. In male rats, orchiectomy caused a 23% decrease and testosterone replacement a 66% increase in adrenal COX activity. There were no corresponding changes in the levels of mRNAs encoding for COX subunits, suggesting post-transcriptional effects of testosterone on COX. These results are consistent with a regulatory role of testosterone on the expression of components of the respiratory and steroidogenic electron transport chains.

Premenstrual symptom changes and plasma beta-endorphin/beta-lipotropin throughout the menstrual cycle.

The beta-endorphin (BE) hypothesis of premenstrual symptomatology was assessed in 15 healthy, drug-free normally cycling women. Cycle-phase assignment was aided by measurement of basal body temperature and plasma progesterone. For the entire group, peripheral plasma BE concentrations by radioimmunoassay (with substantial beta-lipotropin (BL) cross-reactivity) were generally unvarying across the menstrual cycle. High and low symptom subgroups were defined by retrospective and prospective daily self-reports of premenstrual changes. For the cycle studied, moderate to extreme symptom severity was defined according to premenstrual increases in impaired concentration, water retention and negative affect. No between-groups difference was observed for any cycle-phase for absolute values of beta-endorphin (BE/BL). When difference scores were examined, there was a positive time-lag correlation between follicular-to-periovulatory changes in BE/BL and the subsequent luteal increase in impaired concentration over the periovulatory baseline (rs = 0.82); considering the number of comparisons, however, the correlation fails to reach significance. The salience of various types of stressors on mood was assessed; there was a trend for "task-demands" to account for a greater percentage of negative attributions premenstrually compared to post-menstrually, for the entire group. The relative inconsistency in plasma BE/BL from cycle to cycle may be related in part, to the lack of stability in certain cycle characteristics from month to month. Future studies of BE/BL across the menstrual cycle may benefit from a demanding task in a provocative stress-paradigm.

Dose-dependent response to phenylpropanolamine: inhibition of orthostasis.

Phenylpropanolamine, a widely consumed over-the-counter drug, is known to elevate blood pressure, but the mechanism is unknown; it may be both a direct and indirect sympathomimetic. This study investigated the effects of 75-mg sustained-release phenylpropanolamine, 75-mg phenylpropanolamine plus 400-mg caffeine, and 150-mg phenylpropanolamine on blood pressure, plasma norepinephrine, and epinephrine levels in 16 normotensive subjects in a double-blind, placebo-controlled crossover design. Mean peak phenylpropanolamine levels of 317 +/- 26, 152 +/- 17, and 157 +/- 17 ng/mL for 150-mg phenylpropanolamine, 75-mg phenylpropanolamine, and 75-mg phenylpropanolamine plus 400-mg caffeine, respectively, were reached at about 3.6 hours after dosing. The maximal increases in supine diastolic blood pressures after all three phenylpropanolamine-containing drugs were almost three times that after placebo (P less than .05), but peak blood pressures occurred at about 2.3 hours earlier than peak phenylpropanolamine levels. Blood pressure increases correlated with phenylpropanolamine plasma levels (r = .49 for systolic blood pressure and r = .34 for diastolic blood pressure; P less than .0001 for both). Norepinephrine levels increased after the administration of 150-mg phenylpropanolamine and 75-mg phenylpropanolamine plus 400-mg caffeine; norepinephrine increases correlated with phenylpropanolamine levels (r = .34, P less than .0001). The expected increment in norepinephrine induced by standing was significantly decreased by phenylpropanolamine in a dose-dependent mode. The study supports the idea that phenylpropanolamine as both a direct (at alpha -1 and alpha-2 receptors) and an indirect sympathomimetic agent.

Daily moods and symptoms: effects of awareness of study focus, gender, menstrual-cycle phase, and day of the week.

Evaluated changes in daily ratings of moods and symptoms in 30 normally cycling women and 23 men. Women were randomly assigned to two groups for manipulating awareness of the study focus (aware vs. unaware). Principal-components analysis revealed six factors (Dysphoric Moods, Well-being, Physical Symptoms, Personal Space, Food Cravings, Depression) that accounted for 70% of the variance in daily ratings. Repeated-measures analyses revealed cyclic variation on each factor and no significant differences between aware and unaware women during premenstrual or menstrual phases on any measure. Unaware women reported less well-being than men during the premenstrual phase but did not differ on any other measure. Aware women did not differ from men in premenstrual or menstrual ratings on any measure. The way these findings relate to retrospective symptom reports, menstrual attitudes, and changes in moods and symptoms across the week was examined.

Effect of thyroid status on beta-adrenoceptors and calcium channels in rat cardiac and vascular tissue.

To determine the influence of thyroid hormone on beta-adrenoceptors and Ca2+ channels, rats were treated with thyroxine (75 micrograms/100 g sc daily for 5 days) or propylthiouracil (0.05% in drinking water for 30 days). beta-Adrenoceptor density in ventricular tissue, measured by [125I]iodocyanopindolol binding, was significantly increased and decreased respectively, following thyroxine or propylthiouracil treatment to 124.7 +/- 7.11 fmol/mg protein and 71.98 +/- 5.37 fmol/mg protein from euthyroid (control) levels of 93.7 +/- 4.58 fmol/mg protein. Ca2+ channel density, measured by [3H]nitrendipine binding, was altered in the opposite direction; it was significantly decreased and increased to 324 +/- 24 fmol/mg protein and 691 +/- 31 fmol/mg protein from 562 +/- 35 fmol/mg protein after thyroxine or propylthiouracil treatment, respectively. No changes in affinity of either ligand were observed. Responses of isolated papillary muscles from propylthiouracil-treated animals accorded with changes seen in the binding studies. The geometric mean EC50 of isoproterenol increased from 9.5 x 10(-9) mol/l to 5.5 x 10(-8) mol/l, and the EC50 for calcium decreased from 3.16 x 10(-3) mol/l to 1.36 x 10(-3) mol/l; moreover, the responsiveness to the Ca2+ channel activator Bay K 8644 was increased. The corresponding responses in thyroxine-treated animals could not be examined because of prominent arrhythmic activity. As with papillary muscles the sensitivity of left atria to isoproterenol was decreased after treatment with propylthiouracil, with geometric mean EC50 values increasing from 3.21 x 10(-9) mol/l to 89.4 x 10(-9) mol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum levels of corticosterone and 18-hydroxy-11-deoxycorticosterone in the female rat at the high and low points of the circadian rhythm.

Serum corticosterone (B) and 18-hydroxy-11-deoxycorticosterone (18-hydroxy-DOC) levels were determined in female rats at the high (1800 h) and low (0600 h) points of the circadian rhythm. In order to carry out these studies, a rapid and accurate non-chromatographic radioimmunoassay method was developed for the measurement of 18-hydroxy-DOC in peripheral blood and similar methodology was used for the B assay. In quiescent rats both steroids were dramatically elevated at 1800 h as compared to 0600 h. The serum levels of B and 18-hydroxy-DOC determined at 1800 h fifteen minutes following stress did not differ significantly from the levels determined following a similar stress at 0600 h. There was a good correlation (r = 0.91) between the levels of B and 18-hydroxy-DOC and it appears that both steroids are regulated by ACTH.

Serum 11-deoxycorticosterone levels in adrenal-regeneration hypertension under conditions of quiescence and stress.

A time course study to measure adrenal cortical function was undertaken for the period prior to the development of hypertension until the onset of hypertension in the adrenal-regeneration hypertension (ARH) model. Quiescent rat kills were used so that all adrenal cortical parameters investigated would reflect basal or resting levels for controls. Thus a more accurate determination of the differences between control and experimental animals could be made. A radioimmunoassay procedure for deoxycorticosterone was developed to measure this steroid in individual rat serum samples. Elevated serum deoxycorticosterone levels were observed in rats with regenerating adrenals when they were killed under quiescent conditions. This agreed with our recently reported in vitro finding of restoration of cholesterol side chain cleavage activity while 11beta-hydroxylase activity remained imparied 25 days after adrenal enucleation. When rats were killed after ether stress, deoxycorticosterone levels were elevated in both control rats and in rats with regenerating adrenals but the difference was not significant. In contrast, after ether stress serum corticosterone levels were lower in rats with regenerating adrenals than in controls. These studies, in conjunction with our previous in vitro findings, point to the importance of deoxycorticosterone in the pathogenesis of adrenal regeneration hypertension and help to explain the anomalous corticosteroid secretion rate data found in this experimental hypertension model.

Carnosine, the protective, anti-aging peptide.

Carnosine attenuates the development of senile features when used as a supplement to a standard diet of senescence accelerated mice (SAM). Its effect is apparent on physical and behavioral parameters and on average life span. Carnosine has a similar effect on mice of the control strain, but this is less pronounced due to the non-accelerated character of their senescence processes.

Perceptron-based learning algorithms.

A key task for connectionist research is the development and analysis of learning algorithms. An examination is made of several supervised learning algorithms for single-cell and network models. The heart of these algorithms is the pocket algorithm, a modification of perceptron learning that makes perceptron learning well-behaved with nonseparable training data, even if the data are noisy and contradictory. Features of these algorithms include speed algorithms fast enough to handle large sets of training data; network scaling properties, i.e. network methods scale up almost as well as single-cell models when the number of inputs is increased; analytic tractability, i.e. upper bounds on classification error are derivable; online learning, i.e. some variants can learn continually, without referring to previous data; and winner-take-all groups or choice groups, i.e. algorithms can be adapted to select one out of a number of possible classifications. These learning algorithms are suitable for applications in machine learning, pattern recognition, and connectionist expert systems.