The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within ...

The Microbiota-Gut-Brain Axis

This book is one of our contemporary medical bibles. It needs no introduction; those who have frequent need of it know it very well, and those who use it less often seek it out on the library shelf when problems arise. The book is truly encyclopedic. Everything relevant discovered during the six-year intervals between publication finds its way into these pages. By today's standards, its 1,778 closely packed small-print pages are a bargain. The mutant gene is both hero and villain in this book. It is reponsible for the biochemical abnormality that results in disease, no matter how rare a given abnormality may be. By the same token, however, it is truly an experiment of nature, shedding light on fundamental metabolic sequences and biologic mechanisms. This volume, more than most, explains the contributions of the laboratory to clinical medicine. Each chapter seems to have been rewritten, so that the exciting

The Metabolic Basis Of Inherited Disease.

Clinics in Developmental Medicine

The etiology of alcoholism in women is no longer a question of nature or nurture. Most observers would agree that alcoholism, both male and female, is mediated by genetic factors. The question is how much of the variance is explained by genetic factors and to what degree is this genetically mediated disorder moderated by personal characteristics of the woman. Among the most salient personal characteristics moderating the genetic vulnerability may be factors such as age, ethnicity, and presence of psychiatric comorbidity. Cultural factors and familial environmental factors are most likely predictors as well. Therefore, the chapter will discuss the genetic epidemiology of alcoholism in women. Genetic heterogeneity will be discussed and evidence presented that suggests the existence of two forms of alcoholism in women: one more environmentally determined and one more influenced by genetic mediation. Evidence for the existence of a genetic diathesis in women will be presented, noting extant literature involving twin and adoption designs. Suggestions for what might be transmitted from generation to generation (e.g., neurobiological factors, temperament) with special reference to preadolescent and adolescent girls will also be discussed.

Recent Developments in Alcoholism

Objective: To evaluate the empirical associations between alcohol use and risky sex at two levels of analysis. Global associations test whether individuals who engage in one behavior are more likely to engage in the other, whereas event-specific associations test whether the likelihood of engaging in one behavior on a given occasion varies as a function of engaging in the other on that same occasion. Methods: Studies examining the association between drinking and risky sex in samples of college students and youth were reviewed. Those published in the past 10 years and using event-level methodology or random sampling were emphasized. Results: Findings were generally consistent across levels of analysis, but differed across types of risky behaviors. Drinking was strongly related to the decision to have sex and to indiscriminate forms of risky sex (e.g., having multiple or casual sex partners), but was inconsistently related to protective behaviors (e.g., condom use). Moreover, the links among alcohol use, t...

/pdf/alcohol-use-and-risky-sexual-behavior-among-college-students-2w3de1ao3h.pdf

Alcohol use and risky sexual behavior among college students and youth: Evaluating the evidence

Regulatory and functional aspects of the kynurenine (K) pathway (KP) of tryptophan (Trp) degradation are reviewed. The KP accounts for ~95% of dietary Trp degradation, of which 90% is attributed to the hepatic KP. During immune activation, the minor extrahepatic KP plays a more active role. The KP is rate-limited by its first enzyme, Trp 2,3-dioxygenase (TDO), in liver and indoleamine 2,3-dioxygenase (IDO) elsewhere. TDO is regulated by glucocorticoid induction, substrate activation and stabilization by Trp, cofactor activation by heme, and end-product inhibition by reduced nicotinamide adenine dinucleotide (phosphate). IDO is regulated by IFN-γ and other cytokines and by nitric oxide. The KP disposes of excess Trp, controls hepatic heme synthesis and Trp availability for cerebral serotonin synthesis, and produces immunoregulatory and neuroactive metabolites, the B3 "vitamin" nicotinic acid, and oxidized nicotinamide adenine dinucleotide. Various KP enzymes are undermined in disease and are targeted for therapy of conditions ranging from immunological, neurological, and neurodegenerative conditions to cancer.

https://journals.sagepub.com/doi/pdf/10.1177/1178646917691938

Kynurenine Pathway of Tryptophan Metabolism: Regulatory and Functional Aspects

Tryptophan availability for kynurenine pathway metabolism across the life span: Control mechanisms and focus on aging, exercise, diet and nutritional supplements

Tryptophan (Trp) requirements in pregnancy are several-fold: (1) the need for increased protein synthesis by mother and for fetal growth and development; (2) serotonin (5-HT) for signalling pathways; (3) kynurenic acid (KA) for neuronal protection; (4) quinolinic acid (QA) for NAD+ synthesis (5) other kynurenines (Ks) for suppressing fetal rejection. These goals could not be achieved if maternal plasma [Trp] is depleted. Although plasma total (free + albumin-bound) Trp is decreased in pregnancy, free Trp is elevated. The above requirements are best expressed in terms of a Trp utilization concept. Briefly, Trp is utilized as follows: (1) In early and mid-pregnancy, emphasis is on increased maternal Trp availability to meet the demand for protein synthesis and fetal development, most probably mediated by maternal liver Trp 2,3-dioxygenase (TDO) inhibition by progesterone and oestrogens. (2) In mid- and late pregnancy, Trp availability is maintained and enhanced by the release of albumin-bound Trp by albumin depletion and non-esterified fatty acid (NEFA) elevation, leading to increased flux of Trp down the K pathway to elevate immunosuppressive Ks. An excessive release of free Trp could undermine pregnancy by abolishing T-cell suppression by Ks. Detailed assessment of parameters of Trp metabolism and disposition and related measures (free and total Trp, albumin, NEFA, K and its metabolites and pro- and anti-inflammatory cytokines in maternal blood and, where appropriate, placental and fetal material) in normal and abnormal pregnancies may establish missing gaps in our knowledge of the Trp status in pregnancy and help identify appropriate intervention strategies.

Tryptophan metabolism, disposition and utilization in pregnancy.

The plasma kynurenine to tryptophan ([Kyn]/[Trp]) ratio is frequently used to express or reflect the activity of the extrahepatic Trp-degrading enzyme indoleamine 2,3-dioxygenase (IDO). This ratio is increasingly used instead of measurement of IDO activity, which is often low or undetectable in immune and other cells under basal conditions, but is greatly enhanced after immune activation. The use of this ratio is valid in in vitro studies, eg, in cell cultures or isolated organs, but its 'blanket' use in in vivo situations is not, because of modulating factors, such as supply of nutrients; the presence of multiple cell types; complex structural and functional tissue arrangements; the extracellular matrix; and hormonal, cytokine, and paracrine interactions. Determinants other than IDO may therefore be involved in vivo. These are hepatic tryptophan 2,3-dioxygenase (TDO) activity and the flux of plasma-free Trp down the Kyn pathway. In addition, conditions leading to accumulation of Kyn, eg, inhibition of activities of Kyn monooxygenase and kynureninase, could lead to elevation of the aforementioned ratio. In this review, the origin of use of this ratio will be discussed, variations in extent of its elevation will be described, evidence against its indiscriminate use will be presented, and examining determinants other than IDO activity and their correlates will be proposed for future studies.

https://journals.sagepub.com/doi/pdf/10.1177/1178646919868978

The Plasma [Kynurenine]/[Tryptophan] Ratio and Indoleamine 2,3-Dioxygenase: Time for Appraisal.

The Phenomenex EZ:faast™ amino acid analysis kit is available for gas (GC) or liquid (LC) chromatographic analysis of amino acids (AA) using mass spectrometry (MS) and other GC detectors. We used it for rapid GC determination of plasma tryptophan, its brain uptake competitors (Val, Leu, Ile, Phe and Tyr) and many other amino acids. Based on solid-phase extraction, this fast method enables one person to process two plasma samples in 8–10 min and six samples in ∼15 min up to GC injection and a 7-min GC run per plasma sample. Using a Perkin-Elmer Clarus 500 GC, a Total Chrome software, a flame-ionisation detector (FID) and norvaline as internal standard, we used this method to analyse ∼1,000 plasma samples from normal subjects undergoing acute tryptophan depletion and loading tests. The limit of detection for most amino acids is 1 nmol/ml (1 μM) and in many cases less. With manual injection, coefficients of variation for the above six amino acids were 1.5–6.2% (intra-assay) and 3.8–9.7% (inter-assay). This simple, rapid and elegant method will be valuable to the amino acid analyst and researcher, as it can save much manpower time and meet urgent emergency requests and the demands of a high-throughput laboratory.

https://link.springer.com/content/pdf/10.1007%2Fs00726-007-0012-7.pdf

Application of the Phenomenex EZ:faast™ amino acid analysis kit for rapid gas-chromatographic determination of concentrations of plasma tryptophan and its brain uptake competitors

Abdulla A.-B. Badawy

Papers

Kynurenine Pathway of Tryptophan Metabolism: Regulatory and Functional Aspects

Tryptophan availability for kynurenine pathway metabolism across the life span: Control mechanisms and focus on aging, exercise, diet and nutritional supplements

Tryptophan metabolism, disposition and utilization in pregnancy.

The Plasma [Kynurenine]/[Tryptophan] Ratio and Indoleamine 2,3-Dioxygenase: Time for Appraisal.

Application of the Phenomenex EZ:faast™ amino acid analysis kit for rapid gas-chromatographic determination of concentrations of plasma tryptophan and its brain uptake competitors