Hector Sabelli

Septic Encephalopathy: Evidence for Altered Phenylalanine Metabolism and Comparison With Hepatic Encephalopathy

We elected to test the hypothesis that the metabolic encephalopathy associated with systemic sepsis may have a pathogenesis that is similar to hepatic encepathology, ie, as the consequence of hepatic dysfunction that induces alterations in synthesis of catecholic and noncatecholic neurotransmitters. Eleven patients with septic encephalopathy were compared with nine patients with septic encephalopathy and nine normal controls with respect to blood and cerebrospinal fluid (CSF) amino acid profile, phenylethylamine and its metabolite phenylacetic acid, and blood ammonia. Blood and CSF levels of phenylacetic acid increased markedly in septic and hepatic encephalopathy while CSF phenylethylamine levels were not increased in either condition, presumably due to rapid turnover. The CSF concentrations of all the aromatic amino acids were increased in hepatic encephalopathy, whereas in the patients with sepsis, only phenylalanine levels were increased. Evidence of stimulated neutral amino acid transport into brain was demonstrated in hepatic not septic encephalopathy and appeared to correlate with the CSF glutamine concentration. Blood ammonia levels were increased in hepatic but not in septic encephalopathy. Our data support the hypothesis that metabolites of phenylethylamine contribute to encephalopathy in systemic sepsis and hepatic failure; however, the entities differ in other respects.

Gas-liquid chromatographic determination of total phenylacetic acid in urine

A gas-liquid chromatographic procedure to measure total phenylacetic acid in urine is described. The method is simple, rapid, and reliable. Normal subjects (N = 48) excreted 141.1 +/- 10.1 mg/24 h. Untreated depressed patients (N = 42) excreted 102.77 +/- 15.9 mg/24 h. The difference in the means is significant and supports the role of phenylacetic acid as a biological marker in certain kinds of mental illnesses.

A high-pressure liquid chromatographic method for plasma phenylacetic acid, a putative marker for depressive disorders.

An HPLC procedure for the determination of total phenylacetic acid (PAA) in human plasma is described. After precipitation of plasma proteins with 0.4 N HClO4, the supernatant was hydrolyzed with 1.5 N HCl at 100 degrees C for 5 h, and PAA was extracted with benzene. From the organic layer PAA was back-extracted into 0.5 ml of 0.1 N NaOH. After neutralization with HCl the sample was directly injected onto the HPLC column (C18). An ultraviolet detector at 210 nm was used to monitor PAA. The plasma PAA values for a control population (536.18 +/- 54.99 ng/ml, N = 10) (X +/- SE) obtained by the described method are in agreement with values reported using GC/MS methods. Depressed subjects showed significantly lower values (327.64 +/- 45.44 ng/ml, N = 10), supporting the view that PAA may be a marker for depressive disorders.

The union of opposites: from Taoism to process theory

This article is an attempt to incorporate Taoist wisdom into contemporary process theory, and clinical and social philosophy. It highlights the coexistence of opposites (harmony and conflict, creation and decay, union and separation) in varying proportions, and the priority of differentiation over synthesis, and of creation over decay. Opposites are complementary, and complementaries are opposite, both synergic and antagonistic. Opposites coexist (dialectics) but separated (logic). Interacting opposites co-create novelty, complexity and diversity. Life and culture emerge from the intercourse of opposites. Creation requires and fosters diversity. The oneness of nature is primary, but opposites separate and differentiate as the universe expands. Bifurcation and differentiation have objective and logical priority over dialectic synthesis and system formation. The current economic and cultural globalization impoverishes life insofar as it suppresses diversity. As corporations replace empires as international powers, the separation of the economy and the state from each other is a desirable and possible choice. While learning from Eastern philosophy to seek personal and social Tao, process theory also features action, ethical commitment, and co-creation.

Urinary phenylacetic acid in panic disorder with and without depression

Phenylacetic acid (PAA) excretion was measured in 39 patients who met criteria for panic disorder; 9 of these also had major depression, and 30 did not. Patients with panic and depression excreted 66 ± 23 mg/day of PAA, an amount significantly lower than in normal controls; patients with panic disorder but without depression excreted 104 ± 23 mg/day of PAA (not significantly lower than controls). The results support previous studies indicating that PAA excretion is a marker for depressive disorder.

Stimulant Challenge Tests

In our chapter on “CNS Amine Metabolites” (chapter 3), we focused on the importance of different monoamine systems in the pathophysiology of psychiatric disorders. Over the past decade stimulants have emerged as useful tools for studying alterations in monoamine function because of their effects on these systems. In addition to biochemical measurements, response to various drugs with selective effects on neurotransmitter processes may serve to elucidate the disorders of central synaptic transmission that underlie psychiatric illnesses. Thus, the mood elevating effects of amphetamines and their ability to induce manic-like and schizophreniclike symptoms has been important in the development of the hypotheses than an excess and a deficit in brain adrenergic amines underlie mania and depression respectively, and that dopaminergic hyperactivity plays a major role in schizophrenia. In addition, the study of such pharmacological responses has practical clinical value. Thus, amphetamines (AMPH) and methylphenidate have been widely used as diagnostic aids for sub classifying depressive disorders as well as predictors of response to treatment [1–7]. More recently, there is some evidence that amphetamines may also be useful in determining the diagnosis and treatment of schizophrenia [8] and attention deficit disorder [9,10]. It seems that patients with different illnesses show a qualitatively different response to AMPH. With the availability of a complex array of therapeutic agents to choose from, it has become more imperative to choose the agent most likely to be therapeutically efficacious. Further, because of the novel effects of some of these drugs, we have become even more inquisitive and curious to know the mechanism of action of this diverse array of drugs [11], and even more so, the underlying pathophysiology of the disorders we treat with these agents. Thus the “Stimulant Challenge Test” has acquired an important place both in terms of fostering basic research into the mechanisms of both drug action and the pathophysiology of psychiatric disorders, as well as enhancing practical clinical psychopharmacotherapeutics. We review the current status of stimulants in challenge studies and propose some hypotheses regarding the biochemical and neuroendocrine mediation accounting for affective response to stimulants.

CNS Amine Metabolites

There is an extensive body of indirect evidence from animal studies which indicates that the “biogenic amines” act as central nervous system (CNS) neurotransmitters, particularly in critical integrative brain pathways. The catecholamines (CA) norepinephrine (NE) and dopamine (DA), the indoleamine (IA) serotonin (5-HT), and the quaternary alkyl-amine acetylcholine (ACh) are the brain amines on which most interest has been focused. In addition, the brain has also been found to contain and form other adrenergic amines, such as phenylethylamine (PEA) and octopamine, and indoleamines such as tryptamine, etc. One or more of these amines may act as co-transmitters, modulators, or regulators of synaptic transmission mediated by chemically related transmitters. Thus, tryptamine may be a modulator of serotonergic synapses [1] and PEA may be a modulator of CA synapses [1,2], as evidenced by studies on the ocular sympathetic system [3]. Octopamine appears to be co-transmitter in sympathetic nerves [4]. Based on the metabolic and functional unity of the neuron [5], Dale [6] proposed that a neuron releases the same transmitter at all its endings. Although Dale’s law has been interpreted to mean that there is only one transmitter, this latter assumption does not appear to hold true. Sabelli and associates [7] have thus proposed to extend Dale’s principle as follows: Each neuron releases at all its endings the same transmitter and metabolically related co-transmitters, and contains the same receptors throughout its surface membrane. In addition, there may be cells which contain the metabolic machinery for producing more than one family of transmitters; for instance, sympathetic neurons contain not only CA and metabolically related amines (octopamine, PEA) but also ACh [7–12] and possibly histamine [7,12,13]. Thus, we may have to allow for complex interactions at the synapse. One biogenic amine may affect the metabolism or levels of another, and there may be complex interactions between monoaminergic systems and other neurotransmitters or neuromodulator systems.