Non-pharmacological treatment-related changes of molecular biomarkers in major depressive disorder: A systematic review and meta-analysis

Background Major depressive disorder (MDD) is a serious mood disorder and leading cause of disability. Despite treatment advances, approximately 30% of individuals with MDD do not achieve adequate clinical response. Better understanding the biological mechanism(s) underlying clinical response to specific psychopharmacological interventions may help fine tune treatments in order to further modulate their underlying mechanisms of action. However, little is known regarding the effect of non-pharmacological treatments (NPTs) on candidate molecular biomarker levels in MDD. This review aims to identify molecular biomarkers that may elucidate NPT response for MDD. Methods We performed a systematic review and a multilevel linear mixed-effects meta-analyses, and a meta-regression. Searches were performed in PubMed, Scopus, and PsycINFO in October 2020 and July 2021. Results From 1387 retrieved articles, 17 and six studies were included in the systematic review and meta-analyses, respectively. Although there was little consensus associating molecular biomarker levels with symptomology and/or treatment response, brain metabolites accessed via molecular biomarker-focused neuroimaging techniques may provide promising information on whether an individual with MDD would respond positively to NPTs. Furthermore, non-invasive brain stimulation interventions significantly increased the expression of neurotrophic factors (NTFs) compared to sham/placebo, regardless of add-on pharmacological treatment. Conclusions NTFs are candidate biomarkers to fine-tune NIBS for MDD treatment.publishe

Psychiatric symptoms and expression of glucocorticoid receptor gene in cocaine users: A longitudinal study

Background Chronic cocaine users (CU) display reduced peripheral expression of the glucocorticoid receptor gene (NR3C1), which is potentially involved in stress-related psychiatric symptoms frequently occurring in CU. However, it is unknown whether psychiatric symptoms and lower NR3C1 expression are related to each other and whether reduction of drug consumption reverse them. Method At baseline, NR3C1 mRNA expression was measured in 68 recreational CU, 30 dependent CU, and 68 stimulant-naïve controls. Additionally, the Revised Symptom Checklist (SCL-90R) and the Barratt Impulsiveness Scale (BIS) were assessed. At a one-year follow-up, the association between change in NR3C1 expression and psychiatric symptoms was examined in 48 stimulant-naïve controls, 19 CU who increased and 19 CU who decreased their consumption. At both test sessions, cocaine concentrations in hair samples were determined. Mixed-effects models were used to investigate how changes in drug use intensity affect severity of psychiatric symptoms and NR3C1 expression over time. Results At baseline, recreational and dependent CU displayed elevated impulsivity and considerable symptom burden across most of the SCL-90R subscales. Time-group interaction effects were found for several impulsivity scores, SCL-90R Global Severity Index, Paranoid Thoughts, and Depression subscales as well as for NR3C1 expression. Pairwise comparisons showed that decreasing CU specifically improved in these SCL-90R subscales, while their NR3C1 expression was adapted. Finally, changes in NR3C1 expression were negatively correlated with changes in impulsivity but not SCL-90R scores. Conclusion Our findings suggest that NR3C1 expression changes and some psychiatric symptoms are reversible upon reduction of cocaine intake, thus favouring abstinence-oriented treatment approaches

Reliability of a novel thermal imaging system for temperature assessment of healthy feet

Abstract Background Thermal imaging is a useful modality for identifying preulcerative lesions (“hot spots”) in diabetic foot patients. Despite its recognised potential, at present, there is no readily available instrument for routine podiatric assessment of patients at risk. To address this need, a novel thermal imaging system was recently developed. This paper reports the reliability of this device for temperature assessment of healthy feet. Methods Plantar skin foot temperatures were measured with the novel thermal imaging device (Diabetic Foot Ulcer Prevention System (DFUPS), constructed by Photometrix Imaging Ltd) and also with a hand-held infrared spot thermometer (Thermofocus® 01500A3, Tecnimed, Italy) after 20 min of barefoot resting with legs supported and extended in 105 subjects (52 males and 53 females; age range 18 to 69 years) as part of a multicentre clinical trial. The temperature differences between the right and left foot at five regions of interest (ROIs), including 1st and 4th toes, 1st, 3rd and 5th metatarsal heads were calculated. The intra-instrument agreement (three repeated measures) and the inter-instrument agreement (hand-held thermometer and thermal imaging device) were quantified using intra-class correlation coefficients (ICCs) and the 95% confidence intervals (CI). Results Both devices showed almost perfect agreement in replication by instrument. The intra-instrument ICCs for the thermal imaging device at all five ROIs ranged from 0.95 to 0.97 and the intra-instrument ICCs for the hand-held-thermometer ranged from 0.94 to 0.97. There was substantial to perfect inter-instrument agreement between the hand-held thermometer and the thermal imaging device and the ICCs at all five ROIs ranged between 0.94 and 0.97. Conclusions This study reports the performance of a novel thermal imaging device in the assessment of foot temperatures in healthy volunteers in comparison with a hand-held infrared thermometer. The newly developed thermal imaging device showed very good agreement in repeated temperature assessments at defined ROIs as well as substantial to perfect agreement in temperature assessment with the hand-held infrared thermometer. In addition to the reported non-inferior performance in temperature assessment, the thermal imaging device holds the potential to provide an instantaneous thermal image of all sites of the feet (plantar, dorsal, lateral and medial views). Trial registration Diabetic Foot Ulcer Prevention System NCT02317835, registered December 10, 201

Factors Influencing Brazilian sugar and ethanol refineries’ failure

Purpose: This study aims to examine the dimensions of organisational failure in the Brazilian sugarcane and ethanol refineries, as reported in judicial recovery plans. Design/methodology/approach: This paper follows a qualitative, inductive approach that uses content analysis to examine the details of recovery plans. Besides, a cause-and-effect relationship diagram is proposed, making it possible to identify the interconnections between the identified variables. Findings: There is evidence that organisational failures are not a linear outcome. Organisational failures are complex and occur because of several factors, often interdependent and operating at different levels. Research implications: Organisational failures basically have three interrelated levels: the macro-level (external environment); the meso-level (organisational environment); and the micro-level (associated with the decision-maker). The relationship between these levels is not trivial and involves coordinated research efforts. Practical implications: Organisations must consider all types of failure levels when developing business reorganisation plans. Reorganisation plans are more than a formal document to achieve judicial recovery, as they should incorporate strategic factors. Social implications: Failures are a regularity in organisations’ day-to-day. Understanding failure’s sources is vital to design firms’ strategies and public policies. Originality/value: The study of organisational failure involves the analysis of complex and multidimensional phenomena. Judicial recovery plans are the means for companies to get a second chance. To that end, this article addresses the sources of organisational failures through the lens of judicial plans

Neurofibromatosis

Neurofibromatosis (NF) is one of the most common genetic disorders. Inherited in an autosomal dominant fashion, this phacomatosis is classified into two genetically distinct subtypes characterized by multiple cutaneous lesions and tumors of the peripheral and central nervous system. Neurofibromatosis type 1 (NF1), also referred to as Recklinghausen's disease, affects about 1 in 3500 individuals and presents with a variety of characteristic abnormalities of the skin and the peripheral nervous system. Neurofibromatosis type 2 (NF2), previously termed central neurofibromatosis, is much more rare occurring in less than 1 in 25 000 individuals. Often first clinical signs of NF2 become apparent in the late teens with a sudden loss of hearing due to the development of bi-or unilateral vestibular schwannomas. In addition NF2 patients may suffer from further nervous tissue tumors such as meningiomas or gliomas. This review summarizes the characteristic features of the two forms of NF and outlines commonalities and distinctions between NF1 and NF2

DNA isolation protocol effects on nuclear DNA analysis by microarrays, droplet digital PCR, and whole genome sequencing, and on mitochondrial DNA copy number estimation.

Potential bias introduced during DNA isolation is inadequately explored, although it could have significant impact on downstream analysis. To investigate this in human brain, we isolated DNA from cerebellum and frontal cortex using spin columns under different conditions, and salting-out. We first analysed DNA using array CGH, which revealed a striking wave pattern suggesting primarily GC-rich cerebellar losses, even against matched frontal cortex DNA, with a similar pattern on a SNP array. The aCGH changes varied with the isolation protocol. Droplet digital PCR of two genes also showed protocol-dependent losses. Whole genome sequencing showed GC-dependent variation in coverage with spin column isolation from cerebellum. We also extracted and sequenced DNA from substantia nigra using salting-out and phenol / chloroform. The mtDNA copy number, assessed by reads mapping to the mitochondrial genome, was higher in substantia nigra when using phenol / chloroform. We thus provide evidence for significant method-dependent bias in DNA isolation from human brain, as reported in rat tissues. This may contribute to array "waves", and could affect copy number determination, particularly if mosaicism is being sought, and sequencing coverage. Variations in isolation protocol may also affect apparent mtDNA abundance

Klinische Bedeutung der Bestimmung der Bindung von Trijodthyronin an Serumproteine mittels Dextran-Gel-Filtration

Neben den bewährten älteren Verfahren zur Bestimmung des proteingebundenen127Jods und des Radiojodumsatzes hat sich die gleichzeitige Bestimmung des sog. freien und des proteingebundenen Anteils an in vitro mit Serum inkubiertem L-Trijodthyronin-131Jod mittels Dextran-Gel-Filtration klinisch zur Differentialdiagnose von Hyperthyreose und Euthyreose bewährt. Bei Ausnützung der Verdrängung von proteingebundenem L-Trijodthyronin-131Jod durch nichtmarkiertes Hormon und bei Variation der Dextran-Gel-Menge in der Säule bietet die Methode gute Differenzierungsmöglichkeiten auch für die Schilddrüsenfunktionszustände Euthyreose und Hypothyreose. Bei dem Verfahren wird der Patient nicht mit radioaktivem Jod belastet, ein für die Kinderklinik wichtiger Gesichtspunkt. Manche Störfaktoren, die den131Jodspeicherungstest und die Bestimmung des proteingebundenen Jods (PB127I) verfälschen, haben keinen Einfluß auf die mit der Dextran-Gel-Filtration untersuchten Proteinbindungsverhältnisse für L-Trijodthyronin-131Jod. So hat sich das Verfahren für die Untersuchung von Patienten mit operativ oder durch131Jodbehandlung verkleinerten Schilddrüsen, mit endokrinem Exophthalmus und in Fällen mit vorausgegangener Jodgabe, z. B. in Form von Kontrastmitteln, besonders bewährt. Mit der Bestimmung des sog. freien L-Trijodthyronin-131Jods wird ein physiologisch und pathogenetisch wichtiger Parameter der Schilddrüsenfunktion ermittelt. Die klinische Bedeutung der Bestimmung der Bindungs-und Transportverhältnisse für Trijodthyronin mittels Dextran-Gel-Filtration wird diskutiert.In addition to conventional methods of assay of protein bound iodine (PB127I) and of131iodine turnover in the thyroid, the simultaneous determination of socalled free and protein bound 1-triiodothyronine-131I, added in vitro to serum, using dextran gel filtration was found to be clinically helpful for diagnosis of euthyroidism and hyperthyroidism. Employing discharge effects of non-labelled triiodothyronine on protein bound 1-triiodothyronine-131I and varying the amount of dextran gel in the columns, the method provides reasonably good differentiation of euthyroid and hypothyroid states. No radioactive iodine is given to patients during this procedure, a fact of importance for pediatriciens. Some factors, that influence131iodine uptake or PB127I levels, do not disturb protein binding of 1-triiodothyronine-131I as determined by dextran gel filtration. The latter method was found to be especially useful for the examination of patients with surgically, or by therapy with131iodine dissected thyroid glands, with endocrine exophthalmos, and in cases of previous iodine administration (e.g. X-ray procedures). Determination of socalled free 1-triiodothyronine-131I provides information about a factor of physiological and pathogenetical significance, its clinical meaning is discussed

The Endocrine Disruptor Mono-(2-Ethylhexyl) Phthalate Affects the Differentiation of Human Liposarcoma Cells (SW 872)

Esters of phthalic acid (phthalates) are largely used in industrial plastics, medical devices, and pharmaceutical formulations. They are easily released from plastics into the environment and can be found in measurable levels in human fluids. Phthalates are agonists for peroxisome proliferator-activated receptors (PPARs), through which they regulate translocator protein (TSPO; 18 kDa) transcription in a tissue-specific manner. TSPO is a drug- and cholesterol-binding protein involved in mitochondrial respiration, steroid formation, and cell proliferation. TSPO has been shown to increase during differentiation and decrease during maturation in mouse adipocytes. The purpose of this study was to establish the effect of mono-(2-ethylhexyl) phthalate (MEHP) on the differentiation of human SW 872 preadipocyte cells, and examine the role of TSPO in the process. After 4 days of treatment with 10 µM MEHP, we observed changes in the transcription of acetyl-CoA carboxylase alpha, adenosine triphosphate citrate lyase, glucose transporters 1 and 4, and the S100 calcium binding protein B, all of which are markers of preadipocyte differentiation. These observed gene expression changes coincided with a decrease in cellular proliferation without affecting cellular triglyceride content. Taken together, these data suggest that MEHP exerts a differentiating effect on human preadipocytes. Interestingly, MEHP was able to temporarily increase TSPO mRNA levels through the PPAR-α and β/δ pathways. These results suggest that TSPO can be considered an important player in the differentiation process itself, or alternatively a factor whose presence is essential for adipocyte development

Replacement of Retinyl Esters by Polyunsaturated Triacylglycerol Species in Lipid Droplets of Hepatic Stellate Cells during Activation

Activation of hepatic stellate cells has been recognized as one of the first steps in liver injury and repair. During activation, hepatic stellate cells transform into myofibroblasts with concomitant loss of their lipid droplets (LDs) and production of excessive extracellular matrix. Here we aimed to obtain more insight in the dynamics and mechanism of LD loss. We have investigated the LD degradation processes in rat hepatic stellate cells in vitro with a combined approach of confocal Raman microspectroscopy and mass spectrometric analysis of lipids (lipidomics). Upon activation of the hepatic stellate cells, LDs reduce in size, but increase in number during the first 7 days, but the total volume of neutral lipids did not decrease. The LDs also migrate to cellular extensions in the first 7 days, before they disappear. In individual hepatic stellate cells. all LDs have a similar Raman spectrum, suggesting a similar lipid profile. However, Raman studies also showed that the retinyl esters are degraded more rapidly than the triacylglycerols upon activation. Lipidomic analyses confirmed that after 7 days in culture hepatic stellate cells have lost most of their retinyl esters, but not their triacylglycerols and cholesterol esters. Furthermore, we specifically observed a large increase in triacylglycerol-species containing polyunsaturated fatty acids, partly caused by an enhanced incorporation of exogenous arachidonic acid. These results reveal that lipid droplet degradation in activated hepatic stellate cells is a highly dynamic and regulated process. The rapid replacement of retinyl esters by polyunsaturated fatty acids in LDs suggests a role for both lipids or their derivatives like eicosanoids during hepatic stellate cell activation