Cytochrome P450 Enzymes and Drug Metabolism in Humans

Human cytochrome P450 (CYP) enzymes, as membrane-bound hemoproteins, play important roles in the detoxification of drugs, cellular metabolism, and homeostasis. In humans, almost 80% of oxidative metabolism and approximately 50% of the overall elimination of common clinical drugs can be attributed to one or more of the various CYPs, from the CYP families 1–3. In addition to the basic metabolic effects for elimination, CYPs are also capable of affecting drug responses by influencing drug action, safety, bioavailability, and drug resistance through metabolism, in both metabolic organs and local sites of action. Structures of CYPs have recently provided new insights into both understanding the mechanisms of drug metabolism and exploiting CYPs as drug targets. Genetic polymorphisms and epigenetic changes in CYP genes and environmental factors may be responsible for interethnic and interindividual variations in the therapeutic efficacy of drugs. In this review, we summarize and highlight the structural knowledge about CYPs and the major CYPs in drug metabolism. Additionally, genetic and epigenetic factors, as well as several intrinsic and extrinsic factors that contribute to interindividual variation in drug response are also reviewed, to reveal the multifarious and important roles of CYP-mediated metabolism and elimination in drug therapy.

Transcranial brain stimulation and structural MRI

Non-invasive transcranial brain stimulation (NTBS) benefits in multiple ways from structural magnetic resonance imaging (sMRI). Individual structural brain scans can be used to guide spatial targeting with frameless stereotaxy. For instance, sMRI informed transcranial magnetic stimulation (TMS) enables personalized cortical mapping aligned to the individual gyral anatomy. Segmented sMRI scans increase the accuracy and robustness of computational dosimetry approaches which are key to standardize the individual dose across individuals, mapping the NTBS induced electrical fields onto the individual brain. Several sMRI modalities can be used to identify macro and microstructural features that are related to the physiological and behavioral effects of NTBS. Structural MRI before NTBS can identify interindividual variations in brain structure that influence NTBS outcomes, including disease or age related anatomical changes. Repeated structural MRI measurements can trace NTBS induced changes in regional macro and microstructure. NTBS based functional markers can be combined with MRI based structural markers to predict disease progression or recovery in individual patients.

Acute Effects of a Combined Strength and Endurance Training Rehabilitation Protocol for Patients in Different Professions with Back Pain

Objective The purpose of this study was to investigate the effects of a combined strength and endurance training rehabilitation protocol for patients in different professions with back pain. Material and Methods 162 patients (craftsman n=56, preschool teachers n=45 and nurses n=61) were included into a prospective observational study. Peak force of trunk muscles (isometric testing), endurance (PWC130) and back pain dysfunction (ODI) were assessed before (t1) and after (t2) a 3-week-period of individually tailored but not professionally clustered rehabilitation training. Results The ODI (%) disability as well as all trunk muscle peak forces and aerobic endurence improved significantly in all subsamples (p<0.01), with the exception of the preschool teachers. They showed unaltered PWC130 values (p=0.255), which was in turn accompanied by a significant weight gain (+1%, p<0.001), while craftsmen and nurses demonstrated no changes in weight or waist circumference (p>0.05). But all analyses revealed great interindividual variations. Pre-post changes did not differ significantly among the profession groups (p>0.05). Conclusions Interindividual response variations should be considered as a typical finding well known in back pain rehabilitation studies. We did not reveal benefit differences between occupational subsamples after the present combined strength and endurance training protocol. Future research should apply a randomized study design to compare the regular rehabilitation program and enriched programs including specific occupational demands.

Resting-state functional connectivity relates to interindividual variations in positive memory

Individual differences in positive memory recollection are of interest in mental health, as positive memories can help protect people against stress and depression. However, it is unclear how individual differences in positive memory recollection are reflected in brain activity in the resting state. Here, we investigate the resting-state functional connectivity (FC) associated with interindividual variations in positive memory by employing cluster-level inferences based on randomization/permutation region of interest (ROI)-to-ROI analyses. We identified a cluster of FCs that was positively associated with positive memory performance, including the frontal operculum, central operculum, parietal operculum, Heschl's gyrus, and planum temporale. The current results suggest that positive memory is innervated by frontotemporal network connectivity, which may have implications for future investigations of vulnerability to stress and depression.

Conductive Hearing Loss with Age—A Histologic and Audiometric Evaluation

A retrospective analysis to quantify age-related changes of the incudo-malleolar joint (IMJ) and incudo-stapedial joint (ISJ), and to analyse changes in the air-bone gap (ABG) with age, was performed. Defined histologic parameters of 153 IMJ and 106 ISJ from subjects aged from birth to 70 years were correlated to age. Additionally, audiograms of 1760 ears of 974 other subjects aged 20 to 80 years were retrospectively analysed and the ABG was correlated to age. The joint space (age group from 0 to 10 compared to 61 to 70 years) became significantly wider with age (IMJ: from a mean of 44 µm to 100 µm, p < 0.001; ISJ: from a mean of 28 µm to 69 µm, p < 0.009. The thickness of cartilage of the incus decreased in the first 20 years of life (IMJ, from a mean of 88 µm to 65 µm, p < 0.01; ISJ: from a mean of 44 µm to 35 µm, p < 0.01). The ABGs of younger ears (20–40 years) was significantly larger at 500 Hz compared to older ears (60–80 years) by 2–4 dB, while it was significantly smaller by 3–5 dB at 4000 Hz (p < 0.0017). Interindividual variations in all age groups were large for both analyses. The increased joint spaces could potentially reduce the stiffness in the joints and explain the increase in ABG at 4000 Hz and the drop at 500 Hz. While the average change is small and of minimal clinical relevance, a larger increase of ABG with age is seen in some subjects.

Combining Electrostimulation With Fiber Tracking to Stratify the Inferior Fronto-Occipital Fasciculus

The inferior fronto-occipital fasciculus (IFOF) is one of the longest association fiber tracts of the brain. According to the most recent anatomical studies, it may be formed by several layers, suggesting a role in multiple cognitive functions. However, to date, no attempt has been made to dissociate the functional contribution of the IFOF subpathways. In this study, real-time, cortico-subcortical mapping with direct electrostimulation was performed in 111 patients operated on in wide-awake surgery for a right low-grade glioma. Patients performed two behavioral tasks during stimulation, tapping, respectively, mentalizing and visual semantic cognition—two functions supposed to be partly mediated by the IFOF. Responsive white matter sites were first subjected to a clustering analysis to assess potential topological differences in network organization. Then they were used as seeds to generate streamline tractograms based on the HC1021 diffusion dataset (template-based approach). The tractograms obtained for each function were overlapped and contrasted to determine whether some fiber pathways were more frequently involved in one or the other function. The obtained results not only provided strong evidence for a role of the right IFOF in both functions, but also revealed that the tract is dissociable into two functional strata according to a ventral (semantic) and dorsal (mentalizing) compartmentalization. Besides, they showed a high degree of anatomo-functionnal variability across patients in the functional implication of the IFOF, possibly related to symmetrical/hemispheric differences in network organization. Collectively, these findings support the view that the right IFOF is a functionally multi-layered structure, with nevertheless interindividual variations.

Olfactory Perception in Relation to the Physicochemical Odor Space

A growing body of research aims at solving what is often referred to as the stimulus-percept problem in olfactory perception. Although computational efforts have made it possible to predict perceptual impressions from the physicochemical space of odors, studies with large psychophysical datasets from non-experts remain scarce. Following previous approaches, we developed a physicochemical odor space using 4094 molecular descriptors of 1389 odor molecules. For 20 of these odors, we examined associations with perceived pleasantness, intensity, odor quality and detection threshold, obtained from a dataset of 2000 naïve participants. Our results show significant differences in perceptual ratings, and we were able to replicate previous findings on the association between perceptual ratings and the first dimensions of the physicochemical odor space. However, the present analyses also revealed striking interindividual variations in perceived pleasantness and intensity. Additionally, interactions between pleasantness, intensity, and olfactory and trigeminal qualitative dimensions were found. To conclude, our results support previous findings on the relation between structure and perception on the group level in our sample of non-expert raters. In the challenging task to relate olfactory stimulus and percept, the physicochemical odor space can serve as a reliable and helpful tool to structure the high-dimensional space of olfactory stimuli. Nevertheless, human olfactory perception in the individual is not an analytic process of molecule detection alone, but is part of a holistic integration of multisensory inputs, context and experience.

The efficacy of calcitriol treatment in non-alcoholic fatty liver patients with different genotypes of vitamin D receptor FokI polymorphism

Background Vitamin D deficiency is prevalent in patients with non-alcoholic fatty liver disease (NAFLD), but there are debates on the usefulness of vitamin D treatment. The interindividual variations in response may be due to different genetic backgrounds. The present study evaluated the efficacy of calcitriol treatment in NAFLD patients with regard to the vitamin D receptor (VDR) genotypes of FokI polymorphism. Methods The study was conducted on 128 NAFLD patients randomly divided into two groups and were subjected to intervention with 0.25 mcg calcitriol/day or placebo for 4 months, while anthropometric parameters, glycemic status, lipid profiles, inflammatory markers, liver enzymes, and fatty liver indices were measured. The ARMS-PCR method was used to genotype the VDR FokI polymorphism. Results Calcitriol treatments along with weight loss and diet recommendations decreased the liver enzymes (AST, ALT, and ALP, p < 0.001 for all) and fatty liver indices (HSI, p < 0.01 and APRI, p < 0.001), compared to the baseline. But when the calcitriol effects were compared to the placebo group, only ALP decrease remained significant (17.5 IU. P = 0.02). The prevalent FokI variants in our population were FF (53.1%) and Ff genotype (45.3%). No significant interaction of FokI variants to the calcitriol effects was found except for ALP. The decrease in the ALP activity was higher in calcitriol-received patients with the Ff genotype (p = 0.05). Conclusions The FF and Ff variants of VDR FokI polymorphism did not interact with the effects of calcitriol on fatty liver, but the ALP was more responsive in subjects with the Ff variant. IRCT registration number IRCT2017053034222N1 Registration date: 2017-06-28 - Retrospectively registered, https://en.irct.ir/trial/26203

The influence of dietary compounds on gut microbiota

The gut microbiota is a complex community composed of trillions of microbes that adapts to its host over the lifetime. Recently, the advances of the methods of high-throughput sequencing have allowed the identification of microbial species in a stool sample, and mass spectrometry identification of their metabolites, both of which together have enabled much of the relevant research in the field. It has became evident that gut microbiota plays an important role in human health and influences the risk of developing many chronic diseases, including obesity, inflammatory bowel disease, type 2 diabetes, cardiovascular disease, and cancer. The diverse ecosystem of the gut includes bacteria, viruses, phages, yeasts, archaea, fungi and protozoa. They are responsible for the production of bioactive metabolites, regulation of immune function, energy homeostasis and protection against pathogens. The mentioned functions are dependent on the diversity and abundance of the microbiota which is the reflection of the dietary habits and genetics of the host among other factors. As such, gut microbiota has significant interindividual variations. Diet and lifestyle changes present important determinants in microbiota shaping. The use of antibiotics, different sanitation measures, consumption of processed food and different diets are also reflected in the shifts of gut microbiota composition. Some of the dramatic dietary alterations can cause changes in gut microbiota composition already within 24 h and some of these changes may be difficult to reverse. Through modulation of gut microbiota composition, diet could offer a potential to manage the risk of developing disease and at the same time improving the quality of life and longevity. In this review we look at the role of diet, and specific dietary components, namely carbohydrates, proteins, fats and polyphenols on gut microbiota composition.