Pathogenesis Of Comorbidities Research Articles

Microbial-Derived Uremic Toxins: Role in the Pathogenesis of Comorbidities in Patients with Chronic Kidney Disease

Аim: to analyze the significance of microbial-derived uremic toxins (MDUT) in the pathogenesis of comorbidities in patients with chronic kidney disease (CKD).Key findings. Increased excretion of nitrogen metabolism products into the intestines of patients with CKD is associated with uremic dysbiosis; changes in the metabolic activity of the gut microbiota and the leaky gut syndrome; which largely cause the accumulation of MDUT in the internal environment of the body: indoxyl sulfate; p-cresyl sulfate; trimethylamine-N-oxide; etc. The results of recent studies allow to consider these metabolites as an independent risk factor for adverse outcomes in people with CKD due to the progression of renal dysfunction to the terminal stage; as well as frequent cardiovascular; neurological; bone mineral; nutritional and other complications.Conclusion. MDUT are one of the key modulators of the pathogenetic relationship between the gut and kidneys. Therapeutic manipulations with intestinal microbiota can be considered a promising strategy for preventing complications associated with uremia.

Cerebellum and hippocampus abnormalities in patients with insomnia comorbid depression: a study on cerebral blood perfusion and functional connectivity.

Chronic insomnia disorder and major depressive disorder are highly-occurred mental diseases with extensive social harm. The comorbidity of these two diseases is commonly seen in clinical practice, but the mechanism remains unclear. To observe the characteristics of cerebral blood perfusion and functional connectivity in patients, so as to explore the potential pathogenesis and biological imaging markers, thereby improving the understanding of their comorbidity mechanism. 44 patients with chronic insomnia disorder comorbid major depressive disorder and 43 healthy controls were recruited in this study. The severity of insomnia and depression were assessed by questionnaire. The cerebral blood perfusion and functional connectivity values of participants were obtained to, analyze their correlation with questionnaire scores. The cerebral blood flow in cerebellum, vermis, right hippocampus, left parahippocampal gyrus of patients were reduced, which was negatively related to the severity of insomnia or depression. The connectivities of left cerebellum-right putamen and right hippocampus-left inferior frontal gyrus were increased, showing positive correlations with the severity of insomnia and depression. Decreased connectivities of left cerebellum-left fusiform gyrus, left cerebellum-left occipital lobe, right hippocampus-right paracentral lobule, right hippocampus-right precentral gyrus were partially associated with insomnia or depression. The connectivity of right hippocampus-left inferior frontal gyrus may mediate between insomnia and depression. Insomnia and depression can cause changes in cerebral blood flow and brain function. Changes in the cerebellar and hippocampal regions are the result of insomnia and depression. They reflect abnormalities in sleep and emotion regulation. That may be involved in the pathogenesis of comorbidity.

Is obstructive sleep apnea a circadian rhythm disorder?

Obstructive sleep apnea is the most common sleep-related breathing disorder worldwide and remains underdiagnosed. Its multiple associated comorbidities contribute to a decreased quality of life and work performance as well as an increased risk of death. Standard treatment seems to have limited effects on cardiovascular and metabolic aspects of the disease, emphasising the need for early diagnosis and additional therapeutic approaches. Recent evidence suggests that the dysregulation of circadian rhythms, processes with endogenous rhythmicity that are adjusted to the environment through various cues, is involved in the pathogenesis of comorbidities. In patients with obstructive sleep apnea, altered circadian gene expression patterns have been demonstrated. Obstructive respiratory events may promote circadian dysregulation through the effects of sleep disturbance and intermittent hypoxia, with subsequent inflammation and disruption of neural and hormonal homeostasis. In this review, current knowledge on obstructive sleep apnea, circadian rhythm regulation, and circadian rhythm sleep disorders is summarised. Studies that connect obstructive sleep apnea to circadian rhythm abnormalities are critically evaluated. Furthermore, pathogenetic mechanisms that may underlie this association, most notably hypoxia signalling, are presented. A bidirectional relationship between obstructive sleep apnea and circadian rhythm dysregulation is proposed. Approaching obstructive sleep apnea as a circadian rhythm disorder may prove beneficial for the development of new, personalised diagnostic, therapeutic and prognostic tools. However, further studies are needed before the clinical approach to obstructive sleep apnea includes targeting the circadian system.

Atherosclerosis, Cardiovascular Disorders and COVID-19: Comorbid Pathogenesis.

The article describes how atherosclerosis and coronavirus disease 19 (COVID-19) may affect each other. The features of this comorbid pathogenesis at various levels (vascular, cellular and molecular) are considered. A bidirectional influence of these conditions is described: the presence of cardiovascular diseases affects different individuals' susceptibility to viral infection. In turn, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can have a negative effect on the endothelium and cardiomyocytes, causing blood clotting, secretion of pro-inflammatory cytokines, and thus exacerbating the development of atherosclerosis. In addition to the established entry into cells via angiotensin-converting enzyme 2 (ACE2), other mechanisms of SARS-CoV-2 entry are currently under investigation, for example, through CD147. Pathogenesis of comorbidity can be determined by the influence of the virus on various links which are meaningful for atherogenesis: generation of oxidized forms of low-density lipoproteins (LDL), launch of a cytokine storm, damage to the endothelial glycocalyx, and mitochondrial injury. The transformation of a stable plaque into an unstable one plays an important role in the pathogenesis of atherosclerosis complications and can be triggered by COVID-19. The impact of SARS-CoV-2 on large vessels such as the aorta is more complex than previously thought considering its impact on vasa vasorum. Current information on the mutual influence of the medicines used in the treatment of atherosclerosis and acute COVID-19 is briefly summarized.

Multiple gene expression profiling suggests epithelial dysfunction in polypoid chronic rhinosinusitis.

SUMMARYChronic rhinosinusitis (CRS) is a heterogeneous inflammatory disorder resulting from a complex gene-environment interaction. Although its aetiology remains elusive, numerous studies reported gene expression alterations of factors apparently implicated in all aspects of the inflammatory response. However, most investigations are limited, unconfirmed analyses of a single gene. Moreover, studies concerning multiple gene expression analyses, usually on inflammatory mediators (e.g. cytokines), show contrasting outcomes in part due to use of heterogeneous samples or methodologies with limited power. In this scenario, our goal was to simultaneously evaluate the expression of a panel of selected genes (AQP5, MUC5AC, CAV1, LTF, COX2, PGDS, TNFα, TGFβ1, MGB1) potentially involved in CRS inflammatory mechanisms. While most of the samples collected were excluded from the analysis because of poor quality RNA, we were able to demonstrate statistically significant downregulation of the AQP5, CAV1, LTF, MGB1 genes in a specific subset of polypoid CRS (patients without typical comorbidities), which might suggest relevant underlying epithelial dysfunction. Further studies are needed to enrich our knowledge on the pathogenesis of CRS. Forthcoming approaches might utilise next-generation RNA sequencing and comprehensive bioinformatics analyses to better characterise the transcriptome profiles of CRS endotypes.

The progression of comorbidity in IL-18 transgenic chronic obstructive pulmonary disease mice model

Patients with severe COPD are known to have comorbidities such as emaciation, cor pulmonale and right heart failure, muscle weakness, hyperlipemia, diabetes mellitus, osteoporosis, muscle atrophy, arterial sclerosis, hypertension, and depression. Therefore, treatment for COPD needs to focus on these comorbidities as well as the lungs. We previously reported a new mouse model of COPD utilizing the human surfactant protein C promoter SP-C to drive the expression of mature mouse IL-18 cDNA; constitutive IL-18 overproduction in the lungs of transgenic (Tg) mice induces severe emphysematous change, dilatation of the right ventricle, and mild pulmonary hypertension with aging. In the present study, we evaluated the progression of comorbidity in our COPD model. In female Tg mice, significant weight loss was observed at 16weeks and beyond, when compared with control wild-type (WT) mice. This weight loss was suppressed in IL-13-deficient (knockout; KO) Tg mice. Muscle weight and bone mineral density were significantly decreased in aged Tg mice relative to control WT and IL-13 KO Tg mice. The aged Tg mice also showed impaired glucose tolerance. IL-18 and IL-13 may play important roles in the pathogenesis of comorbidity in COPD patients.

The changing face of acromegaly—advances in diagnosis and treatment

Acromegaly is a chronic disease characterized by the presence of a pituitary growth hormone (GH)-producing tumour, excessive secretion of growth hormone, raised levels of insulin-like growth factor I (IGF-I) and characteristic clinical presentation of acral enlargement. Over the past two decades, major advances have occurred in the understanding of some aspects of acromegaly--such as the biology of pituitary tumours, the physiology, molecular mechanisms of GH secretion and IGF-I generation, and the pathogenesis of comorbidities. Moreover, new approaches to diagnosis and surveillance (both in terms of screening and follow-up) of acromegaly have led to increases in the number of patients diagnosed with active disease, many of whom would previously have been missed. The development of sensitive assays for detecting plasma GH and IGF-I levels, as well as the widespread use of MRI for visualization of small tumours, have been major contributing factors to these improvements. Treatment advances have resulted in improved cure rates and disease control through novel neurosurgical techniques and pharmacological approaches. This Review summarizes and discusses the changes in our understanding of the epidemiology, diagnosis, treatment, and follow-up of acromegaly and its comorbidities.

CS01-01 - Comorbidity of mental and physical disorders: a central challenge for medicine of the 21st century

The recognition and treatment of the simultaneous presence of mental and physical disorders has become a central challenge for health care systems worldwide. The co-morbidity of mental and physical disorders is frequent and its consequences for the persons who have both types of disorders are numerous - ranging from a worsening of the prognosis of both disorders (and a more severe impairment and consequent disability) to the exposure to risks of inappropriate or insufficient treatment. The management of problems related to the co-morbidity of mental and physical disorders meets problems resulting from the traditional separation of psychiatry from general medicine and from the attitudes of psychiatrists and other medical specialists who have been trained in a manner reflecting similar attitudes of their teachers. It also meets problems due to insufficient knowledge about the pathogenesis of co-morbidity and the impact that co-morbidity may have on the reaction to treatment of either or both disorders that are present. The presentation will refer to epidemiological findings concerning co-morbidity of mental and physical disorders and enumerate problems that arise in care as well as possible solutions to them.

“Comorbidity” between epilepsy and headache/migraine: the other side of the same coin!

Dear Editor, We read with interest the paper by Toldo and co-workers addressing the important issue of comorbidity between epilepsy and headache/migraine [1]. In fact, although these are both chronic disorders with episodic attacks and their association has been long recognized, the common molecular mechanisms remain so far elusive [2–4]. Indeed, recent data suggest shared genetic substrates and phenotypic-genotypic correlations with mutations in some ion transporters genes, including CACNA1A, ATP1A2, SCN1A [3, 4]. In their latest study, Toldo et al. evaluated the distribution of five polymorphisms of SCN1A, the gene encoding the a-subunit of the neuronal voltage-gated sodium channel Nav1.1, in children and adolescents with headache and epilepsy compared to controls. They concluded that SCN1A is not involved in the pathogenesis of comorbidity between headache/migraine and epilepsy [1]. Despite this negative study, neuronal hyperexcitability and increased susceptibility to cortical spreading depression remain important molecular mechanisms in the pathophysiology of this association. In the coming decade it is possible that International efforts to collect large well-phenotyped samples and the current technical possibilities of massive genotyping will shed light on the genetic mechanisms involved in with headache/migraine and epilepsy. On the other hand, the role of additional, non genetic factors influencing the excitation threshold, e.g., mitochondrial dysfunction, disturbance in neurotransmitters metabolism, or inflammatory factors-alone or in combination-can not be excluded a priori [3, 4]. Indeed, any of these triggering factors, irrespective of their nature (genetically determined or not), could potentially lead to a paroxysmal and transient cortical excitability change leading to prolonged neuronal depolarization (seizure) or spreading depression (headache/migraine) [2, 3]. Among the potential practical implications arising from these observations, there is the urgent need for a revision of either International Classifications of Epilepsy and Headache disorders [2, 3, 5]. Finally, insight into the molecular mechanisms involved in the association between headache/migraine and epilepsy is crucial to identify drug targets for improving patients’ treatment.

Polymorphisms of the SCN1A gene in children and adolescents with primary headache and idiopathic or cryptogenic epilepsy: is there a linkage?

The purpose of this study was to evaluate the distribution of the polymorphisms of the SCN1A gene in a series of children and adolescents with primary headache and idiopathic or cryptogenic epilepsy compared to controls. Five non-synonymous exonic polymorphisms (1748A > T, 2656T > C, 3199A > G, 5771G > A, 5864T > C) of the SCN1A gene were selected and their genotyping was performed, by high resolution melting (HRM), in 49 cases and 100 controls. We found that among the five polymorphisms, only 3199A > G was a true polymorphism. We did not find a statistically significant difference between distribution of 3199A > G genotypes between cases and controls. We excluded the role of the SCN1A gene in the pathogenesis of comorbidity between headache (especially migraine) and epilepsy. The SCN1A gene is a major gene in different epilepsies and epilepsy syndromes; the HRM could be the new methodology, more rapid and efficacious, for molecular analysis of the SCN1A gene.