Pathophysiological Hypotheses Research Articles

The Microbiome in Cystic Fibrosis Pulmonary Disease.

Cystic fibrosis (CF) is a genetic disease with mutational changes leading to profound dysbiosis, both pulmonary and intestinal, from a very young age. This dysbiosis plays an important role in clinical manifestations, particularly in the lungs, affected by chronic infection. The range of microbiological tools has recently been enriched by metagenomics based on next-generation sequencing (NGS). Currently applied essentially in a gene-targeted manner, metagenomics has enabled very exhaustive description of bacterial communities in the CF lung niche and, to a lesser extent, the fungi. Aided by progress in bioinformatics, this now makes it possible to envisage shotgun sequencing and opens the door to other areas of the microbial world, the virome, and the archaeome, for which almost everything remains to be described in cystic fibrosis. Paradoxically, applying NGS in microbiology has seen a rebirth of bacterial culture, but in an extended manner (culturomics), which has proved to be a perfectly complementary approach to NGS. Animal models have also proved indispensable for validating microbiome pathophysiological hypotheses. Description of pathological microbiomes and correlation with clinical status and therapeutics (antibiotic therapy, cystic fibrosis transmembrane conductance regulator (CFTR) modulators) revealed the richness of microbiome data, enabling description of predictive and follow-up biomarkers. Although monogenic, CF is a multifactorial disease, and both genotype and microbiome profiles are crucial interconnected factors in disease progression. Microbiome-genome interactions are thus important to decipher.

Central serous chorioretinopathy: An update on risk factors, pathophysiology and imaging modalities.

Central serous chorioretinopathy (CSC) is a common form of vision loss, typically seen in working-age men. The pathophysiology behind CSC still eludes us, however significant advances have been made in understanding this disease over the last decade using information from genetic and cell-based studies and imaging modalities. This review aims to give an overview of the current pathophysiology hypotheses surrounding CSC in addition to future directions in cellular work from human induced pluripotent stem cell derived choroidal endothelial cells from CSC patients. Furthermore, this review will provide the reader with an update on the clinical aspects of CSC including risk factors, diagnostic challenges and findings from multimodal imaging.

Proposal for New Classification and Practical Use of Diuretics According to Their Effects on the Serum Chloride Concentration: Rationale Based on the "Chloride Theory".

Currently, diuretic therapy for heart failure (HF) pathophysiology is primarily focused on the sodium and water balance. Over the last several years, however, chloride (Cl) has been recognized to have an important role in HF pathophysiology, as both a prognostic marker and a possible central factor regulating the body fluid status. I recently proposed a unifying hypothesis for HF pathophysiology, called the “chloride theory”, during HF worsening and recovery, as follows. Chloride is the key electrolyte for regulating both reabsorption of tubular electrolytes and water in the kidney through the renin–angiotensin–aldosterone system and distributing body fluid in each compartment of the body. As changes between the serum Cl concentration and plasma volume are intimately associated with worsening HF and its recovery after decongestive therapy, modulation of the serum Cl concentration by careful selection and combination of various diuretics and their doses could become an attractive therapeutic option for HF. In this review, I will propose a new classification and practical use of diuretics according to their effects on the serum Cl concentration. Diuretic use according to this classification is expected to be a useful strategy for the treatment of patients with HF.

Effect of type 2 diabetes and antihyperglycemic drug therapy on signs of tumor invasion in papillary thyroid cancer.

This retrospective study investigated the association between worrisome pathological features of papillary thyroid cancer indicative of invasion and type 2 diabetes, as well as antihyperglycemic drug therapy for diabetes. The records of 14,167 patients who had undergone primary surgery for thyroid cancer were retrospectively reviewed and screened for concomitant diabetes. The diabetic and nondiabetic groups were age and gender matched, and further stratified by treatment, including five single antihyperglycemic drugs. The study population comprised 942 patients, including 471 patients each with and without diabetes. The rate of worrisome pathological features was higher in diabetic patients than in nondiabetic patients (49.26% cf. 30.57%, P < 0.001), mainly reflected by extrathyroidal extension (34.82% cf. 5.94%, P < 0.001) and lymph node metastasis (42.68% cf. 33.55%, P < 0.001). The number of lymph node metastases in those treated with acarbose (0.32) was significantly lower compared with groups given any of the other four antihyperglycemic drugs (ranging from 1.51 to 2.15; P = 0.001 to 0.05). Papillary thyroid cancer complicated with type 2 diabetes has a higher risk of invasive tumor growth. Compared with other antihyperglycemic drugs, patients with acarbose had the lowest risk of aggressive tumor growth. These results may evoke pathophysiological hypotheses to be explored in preclinical and clinical studies.

Causal relationship between influenza infection and risk of acute myocardial infarction: pathophysiological hypothesis and clinical implications.

Presently several evidences support an association between acute myocardial infarction and influenza infection. The pathophysiology rationale rests on the release of inflammation cytokines, rupture of atherosclerotic plaque, and triggering of prothrombotic events leading to coronary artery occlusion. Several observational evidences support a potential role of influenza vaccine in cardiovascular prevention. It is estimated that the efficacy of influenza vaccine in preventing myocardial infarction could range between 15% and 45%. Notwithstanding the clear recommendation of numerous guidelines concerning patients with cardiovascular diseases, vaccination rates are still low in the high-risk groups. Influenza vaccine as preventive measure of cardiovascular disease still awaits support from randomized clinical trials. Nonetheless, considering the favourable cost-efficacy and safety profile of influenza vaccination, its use should be encouraged in everyday clinical practice.

A Comprehensive Review of Over-the-counter Treatment for Chronic Migraine Headaches.

Migraine headaches are a neurologic disorder characterized by attacks of moderate to severe throbbing headache that are typically unilateral, exacerbated by physical activity, and associated with phonophobia, photophobia, nausea, and vomiting. In the USA, the overall age-adjusted prevalence of migraine in female and male adults is 22.3% and 10.8%, respectively. Migraine is a disabling disease that ranks as the 8th most burdensome disease in the world and the 4th most in women. The overarching hypothesis of migraine pathophysiology describes migraine as a disorder of the pain modulating system, caused by disruptions of the normal neural networks of the head. The activation of these vascular networks results in meningeal vasodilation and inflammation, which is perceived as head pain. The primary goals of acute migraine therapy are to reduce attack duration and severity. Current evidence-based therapies for acute migraine attacks include acetaminophen, four nonsteroidal anti-inflammatory drugs (NSAIDs), seven triptans, NSAID-triptan combinations, dihydroergotamine, non-opioid combination analgesics, and several anti-emetics. Over-the-counter medications are an important component of migraine therapy and are considered a first-line therapy for most migraineurs. These medications, such as acetaminophen, ibuprofen, naproxen, and aspirin, have shown strong efficacy when used as first-line treatments for mild-to-moderate migraine attacks. The lower cost of over-the-counter medications compared with prescription medications also makes them a preferred therapy for some patients. In addition to their efficacy and lower cost, over-the-counter medications generally have fewer and less severe adverse effects, have more favorable routes of administration (oral vs. subcutaneous injection), and reduced abuse potential. The purpose of this review is to provide a comprehensive evidence-based update of over-the-counter pharmacologic options for chronic migraines.

Biphasic Temporal Relationship between Cancers and Systemic Sclerosis: A Clinical Series from Montpellier University Hospital and Review of the Literature.

Cancer among patients with systemic sclerosis (SSc) would appear to be more prevalent than in the general population. Pathophysiological hypotheses are multiple, involving intertwined factors such as immune system antitumoral response, oxygen species dysregulation, and immunosuppressive treatments. We aimed to identify SSc patients with cancer monitored at our center, describing their clinical and immunological characteristics, such as cancer-specific outcomes. We focused in particular on the temporal relationships between cancer onset and SSc diagnosis. A retrospective study was conducted on SSc patients from Montpellier University Hospital from 2003 to 2018. Clinical characteristics and outcomes of each SSc patient with cancer were recorded. Fifty-five patients with SSc and at least one cancer was included (median age 56 years (47–66)), with a median follow-up time of 11 years (4–15). Sixty-four metachronous malignancies were identified (12 patients had two cancers). Among them, early-onset cancer occurrences (±5 years from SSc diagnosis) included 23 cancers (39% breast cancers, 13% lung cancers, and 13% gastro-intestinal tract cancers). Twenty-two cancers occurred 10 years (±5 years) after SSc diagnosis (14% breast cancers, 23% gastrointestinal (GI) tract cancers, and 18% lung cancers). Patients without any of the two autoantibodies (anti-centromere (ACA) and anti-topoisomerase (ATA-scl70) antibodies) were more prevalent in the early-onset cancer subgroup (14 vs. 6, p = 0.02). This study brought to light two peaks of cancer occurrence in SSc patients. Early-onset cancers were associated with SSc with a specific immunological signature. Late-onset cancers might be the consequence of a subtle interplay between repeated target organ inflammation, immunosuppressant use, mesenchymal cell dysfunction and subsequent genetic alterations.

Kronik Böbrek Hastalığı ile İlişkili Kaşıntı ve Hemşirelik Bakımı

Pruritus is defined as an unpleasant sensation and there are many diseases in the etiopathogenesis. Among these systemic diseases, chronic renal failure associated with pruritus is seen with a prevalence of 10-70% in end stage renal disease patients. Although there are many hypotheses about the pathophysiological mechanism of chronic renal failure associated pruritus, it is still unclear and adversely affects the patients’ life. Patients have insomnia with itching at night, fatigue, itching scratching with discomfort and social isolation problems. The negative impact of the quality of life of the patients makes assessment of the itch important and the assessment is done by both subjective and objective measurement methods and scales. While pharmacological and non-pharmacological options are included in the treatment, nursing care includes skin care precautions and practices on chronic renal failure associated pruritus. In nursing care, prevention, early detection and assessment with written and verbal scales of pruritus with record of chronic renal failure pruritus. In this review, chronic renal failure associated pruritus and prevalence, classification, pathophysiological hypothesis, impact on patients' life, assessment, treatment and nursing care will be mentioned.ce, classification, pathophysiological hypothesis, impact on patients' life, assessment, treatment and nursing care will be mentioned.

Correlation Perspectives for the Diagnosis of Idiopathic Triglyceride Deposit Cardiomyovasculopathy

Background: Triglyceride (TG) deposit cardiomyovasculopathy (TGCV) is a novel cardiovascular disorder and was recently encoded as an orphan disease in Europe (ORPHA code: 565612). Defective lipolysis results in TG accumulation in the myocardium and coronary arteries in TGCV. The myocardial washout rate (WR) of iodine-123-β-methyl iodophenyl-pentadecanoic acid (BMIPP) is an essential indicator to evaluate myocardial lipolysis in vivo. TGCV is classified into primary and idiopathic type with and without PNPLA2 mutation, respectively. Here, we present the clinical correlation perspectives of TGCV patients in Chiba, Japan, to increase the awareness of this orphan disease and facilitate its diagnosis. Methods: We enrolled 234 patients who underwent BMIPP scintigraphy between September 2015 and July 2019. The diagnosis of TGCV was made based on the criteria we reported previously. Blood smear tests were performed for TGCV classification. The distributions of TGCV in each comorbidity were investigated. Results: In total, 104 patients were diagnosed with definitive idiopathic TGCV (I-TGCV). They had various comorbid conditions, including heart failure with reduced ejection fraction and multivessel coronary artery disease requiring revascularization. Moreover, the serum TG levels in I-TGCV patients were not high, and there was no correlation between serum TG level and BMIPP WR (n=205, p-value=0.31), supporting the pathophysiological hypothesis of TGCV. Conclusion: I-TGCV patients showed multiple coexistence of coronary artery disease, heart failure of unknown etiology, or diabetes mellitus. For patients with such clinical characteristics, BMIPP scintigraphy and calculation of WR should be considered proactively for the diagnosis of TGCV.

Manifestations of cold sensitivity – a case series

ABSTRACT Objectives: To characterise cold sensitivity using a semi-structured interview, physical examination, thermal quantitative sensory testing (QST), and laser speckle contrast analysis (LASCA). Methods: Eight women and four men, ages 22–74, with cold sensitivity were interviewed and examined by an occupational physician. Thermal perception thresholds were established using QST, on the pulp of the index and little finger of the most affected hand. Skin perfusion in the dorsum of the hand was measured using LASCA, at baseline, after two-minute 12°C water immersion, and during rewarming. Results: The physical examination yielded few findings indicative of vascular or neurosensory pathology. One subject (8%) had impaired thermal perception thresholds. LASCA at baseline showed absent proximal-distal perfusion gradients in six subjects (50%), and a dyshomogeneous perfusion pattern in five (42%). Perfusion on a group level was virtually unchanged by cold stress testing (median 52.5 PU; IQR 9.0 before versus 51.3 PU; IQR 27.2 afterwards). Conclusions: Physical examination and thermal QST offered little aid in diagnosing cold sensitivity, which challenges the neurosensory pathophysiological hypothesis. LASCA indicated disturbances in microvascular regulation and could prove a useful tool in future studies on cold sensitivity.

Recent advances in the elucidation of migraine pathophysiology

Three hypotheses have been proposed so far regarding the pathophysiology of migraine: one is the "vascular theory", which posits cerebral vascular dysfunction as the etiological factor. The second is the "neuronal theory", which suggests that migraine is triggered by cortical spreading depression. The third is the "trigemino-vascular theory", which postulates that migraine is triggered by inflammation of trigeminal nerves and vessels around trigeminal ganglion cells. Nowadays, the "trigemino-vascular theory" is widely accepted. However, recent advances in imaging analysis indicate that the origin of migraine lies in a premonitory phase which precedes the aura phase. Modern imaging techniques such as functional MRI and PET reveal high activity of the hypothalamic area during the premonitory phase of migraine. These findings suggest that hypothalamic activation might be a generator of a migraine attack. On the other hand, current analyses show that the photosensitivity of migraine (photophobia) could be caused by dysfunction of the newly discovered intrinsically photosensitive retinal ganglion cells (ipRGCs). In the absence of visual signaling from rods and cones, light activation of ipRGCs expressing melanopsin photopigment is sufficient to produce photophobia during migraine. The ipRGCs project to the hypothalamus; their activation might be the trigger for migraine attacks. Significant advances in molecular biology and imaging in recent years have clarified the previous hypotheses of migraine pathophysiology.

The nosology of systemic sclerosis: how lessons from the past offer new challenges in reframing an idiopathic rheumatological disorder.

Systemic sclerosis is a rare connective tissue disease characterised by a wide range of clinical manifestations. Compared with previous sets of criteria, the 2013 American College of Rheumatology and European League Against Rheumatism (ACR/EULAR) classification of systemic sclerosis encompasses a broader and more relevant spectrum of the condition. Nonetheless, clinical and prognostic heterogeneity persists among patients fulfilling these criteria. The next task in the classification of systemic sclerosis is the development of new subset criteria that can successfully identify subgroups of patients with distinct prognostic or pathophysiological features. In this Viewpoint we describe the history of systemic sclerosis over the past century with the objective of highlighting the effect of previous nosological debates on efforts to understand and manage this disorder. Rather than seeking to present a systematic review of possible subgrouping for systemic sclerosis in relation to prognosis, we aim to clarify how nosological considerations have influenced our understanding of the cause and prognosis of this so-called idiopathic rheumatological disorder and how aetiological, prognostic, and pathophysiological hypotheses have helped to describe clusters within the disease. By reflecting on past nosological debates and endeavours, we identify challenges for the current initiative to develop a new subgrouping of systemic sclerosis.

Drug Development for Rare Paediatric Epilepsies: Current State and Future Directions.

Rare diseases provide a challenge in the evaluation of new therapies. However, orphan drug development is of increasing interest because of the legislation enabling facilitated support by regulatory agencies through scientific advice, and the protection of the molecules with orphan designation. In the landscape of the rare epilepsies, very few syndromes, namely Dravet syndrome, Lennox-Gastaut syndrome and West syndrome, have been subject to orphan drug development. Despite orphan designations for rare epilepsies having dramatically increased in the past 10years, the number of approved drugs remains limited and restricted to a handful of epilepsy syndromes. In this paper, we describe the current state of orphan drug development for rare epilepsies. We identified a large number of compounds currently under investigation, but mostly in the same rare epilepsy syndromes as in the past. A rationale for further development in rare epilepsies could be based on the match between the drug mechanisms of action and the knowledge of the causative gene mutation or by evidence from animal models. In case of the absence of strong pathophysiological hypotheses, exploratory/basket clinical studies could be helpful to identify a subpopulation that may benefit from the new drug. We provide some suggestions for future improvements in orphan drug development such as promoting paediatric drug investigations, better evaluation of the incidence and the prevalence, together with the natural history data, and the development of new primary outcomes.

Normal pressure hydrocephalus-an overview of pathophysiological mechanisms and diagnostic procedures.

Normal pressure hydrocephalus (NPH) is an important differential diagnosis of neurodegenerative diseases. The prevalence of dementia is increasing in line with the worldwide increase in life expectancy. NPH can be divided into idiopathic (iNPH) and secondary (sNPH) which is important in terms of clinical symptoms, future progress, and the outcome of possible treatment. The full clinical triad is not prevalent in all of the cases and the pathophysiology of iNPH remains unclear. Diagnosis is based on the evaluation of clinical symptoms (Hakim's triad) combined with an MRI assessment, evaluation of CSF dynamic parameters by different methods such as a tap test, lumbar infusion test (LIT), and external lumbar drainage (ELD). Despite the development of diagnostic techniques and strategies in management, NPH remains to be a challenge for the specialists despite more than 50 years of research. However, results of this research have brought new opportunities in the diagnosis, therapy, and quality of life as well as survival time of NPH patients with improved symptoms. The aim of this article is to present the pathophysiological hypotheses of NPH and an overview of the diagnostic techniques used for the evaluation of NPH patients.

The accuracy of hippocampal volumetry and glucose metabolism for the diagnosis of patients with suspected Alzheimer's disease, using automatic quantitative clinical tools.

The hippocampus is one of the earliest sites involved in the pathology of Alzheimer's disease (AD). Therefore, we specifically investigated the sensitivity and specificity of hippocampal volume and glucose metabolism in patients being evaluated for AD, using automated quantitative tools (NeuroQuant – magnetic resonance imaging [MRI] and Scenium – positron emission tomography [PET]) and clinical evaluation.This retrospective study included adult patients over the age of 45 years with suspected AD, who had undergone fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET-CT) and MRI. FDG-PET-CT images were analyzed both qualitatively and quantitatively. In quantitative volumetric MRI analysis, the percentage of the total intracranial volume of each brain region, as well as the total hippocampal volume, were considered in comparison to an age-adjusted percentile. The remaining brain regions were compared between groups according to the final diagnosis.Thirty-eight patients were included in this study. After a mean follow-up period of 23 ± 11 months, the final diagnosis for 16 patients was AD or high-risk mild cognitive impairment (MCI). Out of the 16 patients, 8 patients were women, and the average age of all patients was 69.38 ± 10.98 years. Among the remaining 22 patients enrolled in the study, 14 were women, and the average age was 67.50 ± 11.60 years; a diagnosis of AD was initially excluded, but the patients may have low-risk MCI. Qualitative FDG-PET-CT analysis showed greater accuracy (0.87), sensitivity (0.76), and negative predictive value (0.77), when compared to quantitative PET analysis, hippocampal MRI volumetry, and specificity. The positive predictive value of FDG-PET-CT was similar to the MRI value.The performance of FDG-PET-CT qualitative analysis was significantly more effective compared to MRI volumetry. At least in part, this observation could corroborate the sequential hypothesis of AD pathophysiology, which posits that functional changes (synaptic dysfunction) precede structural changes (atrophy).

Post orgasmic illness syndrome: what do we know till now?

BackgroundPeri orgasmic dysfunctions are very rare and little information exists on their diagnosis and treatment. One of these conditions is post-orgasmic illness syndrome (POIS), manifesting by a debilitating cluster of symptoms affecting men within seconds, minutes, or hours after ejaculation. The aim of this article is to do a thorough literature review about POIS, in order to elucidate the pathophysiology, the diagnosis and the management of this rare disease.ResultsUpdated literature review on Pubmed was done, using the following terms: “orgasm illness”, “post-orgasmic” and “postorgasmic illness syndrome”. The references of the 17 identified publications were also reviewed for additional 8 relevant articles that were all included in the results.POIS has 5 preliminary diagnostic criteria and criterion 1 has 7 described clusters. Pathophysiological hypotheses include: immunological phenomenon (most relevant), opioid-like withdrawal, neuroendocrine response, transient deregulation of the autonomic nervous system, hypersensitivity and disordered cytokines. Differential diagnoses include: chronic prostatitis, orgasmolepsy, benign orgasmic cephalgia, sneezing and rhinorrhea, postcoital dysphoria, post-coital asthma and rhinitis. Patients have been symptomatically treated with antihistamines, non-steroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, and benzodiazepines. A trial of hyposensitization therapy with autologous semen was successful.ConclusionPOIS is a rare condition that is underdiagnosed, most probably because of its unclear pathophysiology leading to a lack of treatment options. Further studies are warranted to investigate the prevalence, pathophysiology, and management of this debilitating condition.

Lymphocytic Colitis Associated to Systemic Lupus Erythematosus in a Young Woman

Introduction: Gastrointestinal symptoms are common in systemic lupus erythematosus (SLE) and are often difficult to interpret. Specific lupus involvement (lupus enteritis) typically affects the jejunum and ileum, whereas colonic and rectal involvement remains rare. Lymphocytic colitis (LC) associated with SLE remains exceptional and unusual. We report an original observation of LC occurring in a 35-year-old patient with SLE. Case report: 35-year-old woman, having in her medical history a Hashimoto thyroiditis diagnosed for four years and a SLE diagnosed for three years, consulted for chronic fluid diarrhea, not improved by symptomatic treatment, and associated for two weeks with rectorrhagia. Somatic examination, basic biological tests, stool culture and parasitological stool examination were without abnormalities. Colonoscopy revealed a diffuse minimal inflammatory colitis interesting the entire colon, and the pathological examination of multiple biopsies led to the diagnosis of isolated LC. She was treated with 5-amino-salicylate with good evolution. Conclusion: Our observation is, to our knowledge the third reporting the association of LC with SLE; it is characterized in addition by the young age of occurrence. This association once again comforts the hypothesis of a common pathophysiology to these two diseases mainly involving genetic predisposition, HLA susceptibility, immune disorders, and environmental factors.

Proposal for distinctive biological profilings of pre-eclampsia

The interaction between the endothelial cell and plasma biomolecules determine its dysfunction in renal disorders. In order to explore the implication of these interactions in renal failure, we used the pre-eclampsia as a model for studying renal impairment in human pathology. Our goal was to determine the weight of each immune-pathological hypothesis in the same series of patients and to find the one most associated with renal impairment. One hundred and twelve plasma samples from normotensive, hypertensive and pre-eclampsia women were analyzed according to the different explanatory hypothesis of pre-eclampsia pathophysiology: pro-calcitonin (bacterial infection hypothesis), functional AH50 and FH (alternative complement pathway–ACP hypothesis), ratio of antiangiogenicfactors sFLT-1/PLGF (anti-angiogenesis hypothesis), MDA (oxidative stress hypothesis), Il6 (inflammation hypothesis). We also took account for the season in which the sample was taken (theory of pseudo-allergy). Our results showed that, contrary to the defendants of the theory of the ACP involvement such as Z. Prohászka's and A. Lynch's teams, ACP was not associated with renal impairment ( P = 0.350). These later teams used quantitative ACP assays, whereas we used functional and interatomic tests with a higher level of evidence; this could explain this discrepancy. Unexpectedly we found that pre-eclampsia is a continuum of hypertension and normotension according to the increase in oxidative stress ( P = 0.002) and to the ratio sFLT-1/PLGF P = 0.001). This reinforces the results of the A. Ahmed's team and the StAmP trial. Interestingly, hypertension was associated with the lowest rate of pro-calcitonin compared to normotensive and pre-eclampsia women ( P = 0.001). We suggest that pre-eclampsia hypertensive women progress to renal failure when their oxidant stress levels and angiogenic ratio increase.

Liver neoplasms in methylmalonic aciduria: An emerging complication.

Methylmalonic aciduria (MMA) is an inherited metabolic disease caused by methylmalonyl-CoA mutase deficiency. Early-onset disease usually presents with a neonatal acute metabolic acidosis, rapidly causing lethargy, coma, and death if untreated. Late-onset patients have a better prognosis but develop common long-term complications, including neurological deterioration, chronic kidney disease, pancreatitis, optic neuropathy, and chronic liver disease. Of note, oncogenesis has been reported anecdotally in organic acidurias. Here, we present three novel and two previously published cases of MMA patients who developed malignant liver neoplasms. All five patients were affected by a severe, early-onset form of isolated MMA (4 mut0 , 1 cblB subtype). Different types of liver neoplasms, that is, hepatoblastoma and hepatocellular carcinoma, were diagnosed at ages ranging from infancy to adulthood. We discuss pathophysiological hypotheses involved in MMA-related oncogenesis such as mitochondrial dysfunction, impairment of tricarboxylic acid cycle, oxidative stress, and effects of oncometabolites. Based on the intriguing occurrence of liver abnormalities, including neoplasms, we recommend close biochemical and imaging monitoring of liver disease in routine follow-up of MMA patients.

Tianeptine, an atypical pharmacological approach to depression

The introduction of the first antidepressants in the 50s of the 20th century radically changed the treatment of depression, while providing information on pathophysiological aspects of this disease. New antidepressants drugs (agomelatine, tianeptine, vortioxetine) are providing data that give rise to pathophysiological hypotheses of depression that differ from the classic monoaminergic theory. In this sense, tianeptina, an atypical drug by its mechanism of differential action, contributes to clarify that in depression there is more than monoamines. Thus, tianeptine does not modify the rate of extracellular serotonin, so it does not increase or decrease the reuptake of serotonin. Chronic administration of tianeptine does not alter the density or affinity of more than a hundred classical receptors related to depression. Recently, a weak action of tianeptine on Mu opioid receptors has been described that could explain the release of dopamine in the limbic system and its participation in the modulation of glutamatergic mechanisms. These mechanisms support the hypothesis of the possible mechanism of action of this antidepressant.Tianeptine is an antidepressant, with anxiolytic properties, that can improve somatic symptoms. Tianeptine as a glutamatergic modulator, among other mechanisms, allows us to approach depression from a different point of view than other antidepressants.