Primary Etiologic Event Research Articles

Retrospective Analysis of Fibromyalgia: Exploring the Interplay Between Various Triggers and Fibromyalgia's Severity.

This study aimed to explore the diverse etiological factors associated with fibromyalgia (FM), including trauma, stress, infections, and head injuries, and investigate their potential correlation with FM severeness manifestation, aiming to discern FM subgroups. The study was a retrospective analysis, conducted with data of 182 FM patients. Each patient's medical history was analyzed to identify a primary etiological event preceding FM. Following this, correlations were examined between each etiology group and different measurements, such as the impact of FM on overall function, widespread pain, depression, anxiety, and cognitive impairments. Cluster analysis was conducted to distinguish between groups of symptoms and functioning. Contrary to the initial hypothesis, no direct association between a specific trigger and symptom manifestation was identified. However, cluster analyses revealed 2 distinct profiles based on symptom severity. Emotional trauma emerged as a potential contributor to heightened symptom severity, impacting overall function and cognitive abilities. Emotional trauma and stress are crucial factors exacerbating FM symptoms, highlighting the importance of managing these elements in FM patients. This study underscores the complexity of FM, necessitating a nuanced understanding of its etiology and symptomatology. We recommend a multidisciplinary treatment approach that includes assessing and addressing chronic stress and trauma and incorporating stress management interventions to improve patient outcomes.

Bone marrow failure may be caused by chromosome anomalies exerting effects on RUNX1T1 gene

BackgroundThe majority of the cases of bone marrow failure syndromes/aplastic anaemias (BMFS/AA) are non-hereditary and considered idiopathic (80–85%). The peripheral blood picture is variable, with anaemia, neutropenia and/or thrombocytopenia, and the patients with idiopathic BMFS/AA may have a risk of transformation into a myelodysplastic syndrome (MDS) and/or an acute myeloid leukaemia (AML), as ascertained for all inherited BMFS. We already reported four patients with different forms of BMFS/AA with chromosome anomalies as primary etiologic event: the chromosome changes exerted an effect on specific genes, namely RUNX1, MPL, and FLI1, leading to the disease.ResultsWe report two further patients with non-hereditary BM failure, with diagnosis of severe aplastic anaemia and pancytopenia caused by two different constitutional structural anomalies involving chromosome 8, and possibly leading to the disorder due to effects on the RUNX1T1 gene, which was hypo-expressed and hyper-expressed, respectively, in the two patients. The chromosome change was unbalanced in one patient, and balanced in the other one.ConclusionsWe analyzed the sequence of events in the pathogenesis of the disease in the two patients, including a number of non-haematological signs present in the one with the unbalanced anomaly. We demonstrated that in these two patients the primary event causing BMFS/AA was the constitutional chromosome anomaly. If we take into account the cohort of 219 patients with a similar diagnosis in whom we made cytogenetic studies in the years 2003–2017, we conclude that cytogenetic investigations were instrumental to reach a diagnosis in 52 of them. We postulate that a chromosome change is the primary cause of BMFS/AA in a not negligible proportion of cases, as it was ascertained in 6 of these patients.

MyD88 Deficiency Ameliorates β-Amyloidosis in an Animal Model of Alzheimer's Disease

The accumulation of β-amyloid protein (Aβ) in the brain is thought to be a primary etiologic event in Alzheimer's disease (AD). Fibrillar Aβ plaques, a hallmark of AD abnormality, are closely associated with activated microglia. Activated microglia have contradictory roles in the pathogenesis of AD, being either neuroprotective (by clearing harmful Aβ and repairing damaged tissues) or neurotoxic (by producing proinflammatory cytokines and reactive oxygen species). Aβ aggregates can activate microglia by interacting with multiple toll-like receptors (TLRs), the pattern-recognition receptors of the innate immune system. Because the adapter protein MyD88 is essential for the downstream signaling of all TLRs, except TLR3, we investigated the effects of MyD88 deficiency (MyD88(-/-)) on Aβ accumulation and microglial activation in an AD mouse model. MyD88 deficiency decreased Aβ load and microglial activation in the brain. The decrease in Aβ load in an MyD88(-/-) AD mouse model was associated with increased and decreased protein expression of apolipoprotein E (apoE) and CX3CR1, respectively, compared with that in an MyD88 wild-type AD mouse model. These results suggest that MyD88 deficiency may reduce Aβ load by enhancing the phagocytic capability of microglia through fractalkine (the ligand of CX3CR1) signaling and by promoting apoE-mediated clearance of Aβ from the brain. These findings also suggest that chronic inflammatory responses induced by Aβ accumulation via the MyD88-dependent signaling pathway exacerbate β-amyloidosis in AD.

Renin‐Angiotensin‐Aldosterone System in Diabetes and Hypertension

Activation of the renin-angiotensin-aldosterone system (RAAS) is the primary etiologic event in the development of hypertension in people with diabetes mellitus. Modulation of the RAAS has been shown to slow the progression and even cause regression of the microvascular and macrovascular complications associated with diabetes mellitus. Early pharmacotherapy with agents that decrease RAAS activation in the adipose tissue have had a dramatic impact on the prevalence of diabetes related complications. Recent data show that preventing the development of "angry fat" can prevent not just hypertension but also type 2 diabetes mellitus and its associated complications. This review updates what is known about angry fat and the role of RAAS inhibition in preventing the metabolic sequelae of local RAAS activation.

Diffuse and uncontrolled vascular smooth muscle cell proliferation in rapidly progressing pediatric moyamoya disease

Moyamoya disease is a rare stroke syndrome of unknown etiology resulting from stenosis or occlusion of the supraclinoid internal carotid artery (ICA) in association with an abnormal vascular network in the basal ganglia. Although the highest incidence of moyamoya disease is in pediatric patients, pathology reports have been primarily limited to adult samples and describe occlusive fibrocellular lesions in the intimae of affected arteries. We describe the case of a young girl with primary moyamoya disease who presented at 18 months of age with right hemiparesis following an ischemic stroke. Angiography showed stenosis of the distal left ICA, left middle cerebral artery, and right ICA. An emergent left-sided dural inversion was performed. Recurrent strokes and alternating hemiplegia necessitated a right dural inversion 6 months later. Nonetheless, her aggressive disease proved uniquely refractory to surgical revascularization, and she succumbed to recurrent strokes and neurological deterioration at 2.5 years of age. Pathological specimens revealed a striking bilateral occlusion of the anterior carotid circulation resulting from intimal proliferation of smooth muscle cells (SMCs). Most strikingly, the ascending aorta and the superior mesenteric artery demonstrated similar intimal proliferation, along with SMC proliferation in the media. The systemic pathology involving multiple arteries in this extremely young child, the first case of its kind available for autopsy, suggests that globally uncontrolled SMC proliferation, in the absence of environmental risk factors and likely resulting from an underlying genetic alteration, may be a primary etiologic event leading to moyamoya disease.

Benign paroxysmal positional vertigo after decompression sickness: a first case report and review of the literature

Benign paroxysmal positional vertigo is a common cause of vertigo. We describe a previously unreported case of this clinical entity in a young, fit recreational water diver, having experienced decompression illness. Full recovery occurred after hyperbaric recompression therapy, and he remained symptom free on 6-week follow-up. We review the literature and discuss the pathogenesis of benign paroxysmal positional vertigo, proposing that semicircular canal nitrogen bubble formation could have been the primary etiological event leading to this condition.

Respiratory chain dysfunction in skeletal muscle does not cause insulin resistance

Insulin resistance in skeletal muscle is a characteristic feature of diabetes mellitus type 2 (DM2). Several lines of circumstantial evidence suggest that reduced mitochondrial oxidative phosphorylation capacity in skeletal muscle is a primary defect causing insulin resistance and subsequent development of DM2. We have now experimentally tested this hypothesis by characterizing glucose homeostasis in tissue-specific knockout mice with progressive respiratory chain dysfunction selectively in skeletal muscle. Surprisingly, these knockout mice are not diabetic and have an increased peripheral glucose disposal when subjected to a glucose tolerance test. Studies of isolated skeletal muscle from knockout animals show an increased basal glucose uptake and a normal increase of glucose uptake in response to insulin. In summary, our findings indicate that mitochondrial dysfunction in skeletal muscle is not a primary etiological event in DM2.

Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia.

Abnormal oligodendrocyte function has been postulated as a primary etiological event in schizophrenia. Oligodendrocyte lineage transcription factor 2 (OLIG2) encodes a transcription factor central to oligodendrocyte development. Analysis of OLIG2 in a case-control sample (n = approximately 1,400) in the U.K. revealed several SNPs to be associated with schizophrenia (minimum P = 0.0001, gene-wide P = 0.0009). To obtain independent support for this association, we sought evidence for genetic interaction between OLIG2 and three genes of relevance to oligodendrocyte function for which we have reported evidence for association with schizophrenia: CNP, NRG1, and ERBB4. We found interaction effects on disease risk between OLIG2 and CNP (minimum P = 0.0001, corrected P = 0.008) for interaction with ERBB4 (minimum P = 0.002, corrected P = 0.04) but no evidence for interaction with NRG1. To investigate the biological plausibility of the interactions, we sought correlations between the expression of the genes. The results were similar to those of the genetic interaction analysis. OLIG2 expression significantly correlated in cerebral cortex with CNP (P < 10(-7)) and ERBB4 (P = 0.002, corrected P = 0.038) but not NRG1. In mouse striatum, Olig2 and Cnp expression also was correlated, and linkage analysis for trans-effects on gene expression suggests that each locus regulates the other's expression. Our data provide strong convergent evidence that variation in OLIG2 confers susceptibility to schizophrenia alone and as part of a network of genes implicated in oligodendrocyte function.

AUTONOMIC AND HEMODYNAMIC ACTIVITY IN SEPSIS

Objectives: The aim is to evaluate early hemodynamic patterns of patients with severe sepsis and septic shock and compare/contrast the effects of sepsis as a primary etiologic event versus sepsis as a secondary complication after trauma, surgery etc. with simultaneously monitored sympathetic (SNS) and parasympathetic nervous system (PSNS) activities measured by the variability of the heart rate (HR) and respiratory rate (RR). Setting: Level 1 university-run trauma service in a public hospital. Methods: Non-invasively monitored the early hemodynamic patterns in 208 severely septic patients beginning shortly after admission to the emergency department (ED). Simultaneously, monitored and compared the spectrum of HR and RR variability patterns, as markers of autonomic activity, with temporal hemodynamic patterns in 73 of these septic patients. The HR variability was measured to evaluate the low frequency area (LFa), which reflects SNS. The high frequency area (RFa) is indicative of PSNS activity. The LFa/RFa, reflects the relationship of SNS to PSNS. Concurrent noninvasive hemodynamic monitoring consisting of: a) cardiac output by bioimpedance, HR, and mean arterial pressure (MAP) to reflect cardiac function, b) pulse oximetry (SapO2) to reflect changes in pulmonary function, and c) transcutaneous oxygen (PtcO2) indexed to the FiO2 as a marker of tissue perfusion/oxygenation. Results: Non-survivors had higher LFa and RFa values than the survivors did. The increased RFa preceded the increases in LFa in non-survivors and a higher percentage of sympathetic activity. These changes were more marked when measured before sedation and pain medication. In survivors, these patterns were associated with increased cardiac index (CI), and HR, normal MAP, SapO2, and normal tissue perfusion indicated by PtcO2/FiO2 ratios. Nonsurvivors had relatively normal CI, hypotension, tachycardia, poor tissue perfusion, borderline SapO2, and reduced oxygen delivery. Conclusions: In the period immediately after ED admission of patients with sepsis increased ANS activity was observed more pronounced in non-survivors. This ANS activity was associated with increased HR, MAP, and CI, and a tendency toward reduced tissue perfusion/oxygenation. INTRODUCTION The aims were to evaluate early hemodynamic patterns of surviving and nonsurviving patients with severe sepsis and septic shock. Second, to compare these hemodynamic patterns with simultaneously monitored sympathetic (SNS) and parasympathetic nervous system (PSNS) activities measured by the variability of the heart rate (HR) and respiratory rate (RR); collectively known as autonomic nervous system (ANS) monitoring. Third, to compare and contrast the effects of sepsis as a primary etiologic event versus sepsis as a secondary complication after trauma, surgery, and other acute illnesses with simultaneously monitored SNS and PSNS activities measured by ANS monitoring. The present study: a) describes the patterns of sympathetic and parasympathetic activities in acute sepsis, b) relates these to the evolving temporal hemodynamic patterns, and c) describes these autonomic and hemodynamic interactions in sepsis as a primary disease, and as a complication of trauma and surgery. Rivers et al (11) showed improved outcome in septic patients with goal-directed therapy started in the emergency department (ED) based on minimally invasive monitoring. Multiple continuously monitored noninvasive hemodynamic values used in the present study provided an integrated approach to major circulatory components: cardiac, pulmonary, and tissue perfusion functions (6,8,12-21). Simultaneous measurements of hemodynamics with ANS activity provide a unique opportunity to study the role of ANS activity in the hemodynamic responses to various clinical septic conditions alone and in combination with surgery, trauma, or other acute emergencies.

Neurofilaments in diabetic neuropathy

This review discusses the role of abnormal neurofilament (NF) expression, processing, and structure as an etiological factor in diabetic neuropathy. Diabetic sensory and autonomic neuropathy in humans is associated with a spectrum of structural changes in peripheral nerve that includes axonal degeneration, paranodal demyelination, and loss of myelinated fibers-- the latter is probably the result of a dying-back of distal axons. NF filaments are composed of three subunit proteins, NFL, NFM, and NFH, and are major constituents of the axonal cylinder. It is clear that any abnormality in synthesis, delivery, or processing of these critical proteins could lead to severe impairments in axon structure and function. This article describes mechanisms of synthesis, phosphorylation, and delivery of NF and discusses how these processes may be abnormal in diabetics. The pathological alterations in the ganglion and preipheral nerve that occur in sensory and autonomic neuropath will be outlined and related to possible abnormal processing of NF. A major focus is the role or aberrant NF phosphorylation and its possible involvement in the imparied delivery of NF to the distal axon. Identification of stress-activated protein kinases (SAPKs) as NF kinases is discussed in detail and it is proposed that hyperglycemia-induced activation of SAPKs may be a primary etiological event in diabetic neuropathy.

Leber hereditary optic neuropathy: Potential opportunities/potential pitfalls for drug therapy of optic nerve degenerative disorders

Leber hereditary optic neuropathy (LHON) is an inherited form of bilateral optic atrophy in which the primary etiologic event is a mutation in the mitochondrial genome. The primary mitochondrial mutation is necessary—but not sufficient—for manifestation of the optic neuropathy, and secondary genetic and/or epigenetic risk factors are also involved. There is broad agreement that mutations at mtDNA nucleotides 3460, 11778, and 14484 are primary LHON mutations and that they account for 95% of the classic LHON cases in Caucasians of northern European descent. It appears that these three primary LHON mutations are associated with respiratory-chain dysfunction, but the derangement may be relatively subtle and/or vary among different tissues. The optic neuropathy involves a loss of central vision due to degeneration of the retinal ganglion cells and optic nerve axons that subserve central vision. The specific pattern of neurodegeneration in LHON may arise from a mitochondrial “chokepoint” in the region of the optic nerve that spans the nerve head and lamina cribosa. It is hypothesized that in the acute phase, a respiratory-chain dysfunction “crisis” leads to axoplasmic stasis and swelling, initially in the chokepoint, thereby blocking ganglion cell function and causing loss of vision. In some LHON patients, this loss of function is reversible in a subset of ganglion cells and a substantial recovery of vision occurs. However, in other patients, a cell death pathway (probably apoptotic) is activated, with subsequent extensive degeneration of the retinal ganglion cell layer and optic nerve with an irreversible loss of vision. The complex etiology of LHON may allow therapeutic intervention at any one of several steps, but there are also potential pitfalls. Drug Dev. Res. 46:34–43, 1999. © 1999 Wiley-Liss, Inc.

Leber hereditary optic neuropathy: respiratory chain dysfunction and degeneration of the optic nerve.

Leber hereditary optic neuropathy (LHON) is an inherited form of bilateral optic atrophy in which the primary etiological event is a mutation in the mitochondrial genome. The optic neuropathy involves a loss of central vision due to degeneration of the retinal ganglion cells and optic nerve axons that subserve central vision. The primary mitochondrial mutation is necessary, but not sufficient, for manifestation of the optic neuropathy and secondary genetic and/or epigenetic risk factors are also involved, although they are poorly defined at the present time. There is broad agreement that mutations at nucleotides 3460, 11,778 and 14,484 are primary LHON mutations, but there may also be other rare primary mutations. It appears that the three primary LHON mutations are associated with respiratory chain dysfunction, but the derangement may be relatively subtle. There is also debate on whether there are mitochondrial mutations that have a secondary etiological or pathogenic role in LHON. The specific pattern of neurodegeneration in LHON may arise from a 'chokepoint' in the optic nerve in the region of the nerve head and lamina cribosa and which may be more severe in those LHON family members who become visually affected. It is hypothesized that the respiratory chain dysfunction leads to axoplasmic stasis and swelling, thereby blocking ganglion cell function and causing loss of vision. In some LHON patients, this loss of function is reversible in a substantial number of ganglion cells, but in others, a cell death pathway (probably apoptotic) is activated with subsequent extensive degeneration of the retinal ganglion cell layer and optic nerve.

Leber hereditary optic neuropathy: Mitochondrial mutations and degeneration of the optic nerve

The predominant manifestation of Leber hereditary optic neuropathy (LHON) is a sudden and usually severe bilateral loss of central vision, most often in the mid-20s, that is due to a degeneration of the ganglion cell layer and optic nerve. LHON is an inherited form of blindness in which a mutation in the mitochondrial genome (mtDNA) is the primary etiological event. More than 95% of the LHON pedigrees in peoples of Northern European descent harbor one of the three mitochondrial mutations at nucleotides 3460, 11,778 and 14,484, although there are other rare primary mutations. In addition, there may be mtDNA mutations that have a secondary etiological role. The penetrance of the optic neuropathy is incomplete in LHON families, and males are affected much more often then females. The incomplete penetrance indicates that secondary etiological factors are necessary for the development of the optic neuropathy, although they are poorly understood at the present time. Several types of studies suggest that optic nerve function in LHON patients is impaired in the presymptomatic phase, probably as a result of a mitochondrial respiratory chain abnormality, although visual acuity is not compromised. In some family members, the presence of secondary etiological factors triggers a wave of optic nerve dysfunction in which vision is lost (the acute phase). Depending upon the particular primary LHON mutation that the patient carries, a variable proportion of the dysfunctional ganglion cells and optic nerve axons die during the atrophic phase, probably through an apoptotic pathway. In 11,778 LHON patients, retinal ganglion cell degeneration occurs almost without exception, and recovery of vision is extremely rare. In contrast, activation of the cell death pathway is less frequent, or less extensive, in 14,484 LHON patients and there is often a substantial recovery of vision.

Leber hereditary optic neuropathy: how do mitochondrial DNA mutations cause degeneration of the optic nerve?

Leber hereditary optic neuropathy (LHON) is an inherited form of bilateral optic atrophy in which the primary etiological event is a mutation in the mitochondrial genome. The optic neuropathy involves a loss of central vision due to degeneration of the retinal ganglion cells and optic nerve axons that subserve central vision. The primary mitochondrial mutation is necessary--but not sufficient--for development of the optic neuropathy, and secondary genetic and/or epigenetic risk factors must also be present although they are poorly defined at the present time. There is broad agreement that mutations at nucleotides 3460, 11778, and 14484 are primary LHON mutations, but there may also be other rare primary mutations. It appears that the three primary LHON mutations are associated with respiratory chain dysfunction, but the derangements may be relatively subtle. There is also debate on whether there are mitochondrial mutations that have a secondary etiological or pathogenic role in LHON. The specific pattern of the optic neuropathy may arise from a "chokepoint" in the optic nerve in the region of the nerve head and lamina cribosa, and which may be more severe in those LHON family members who become visually affected. It is hypothesized that the respiratory chain dysfunction leads to axoplasmic stasis and swelling, thereby blocking ganglion cell function and causing loss of vision. In some LHON patients, this loss of function is reversible in a substantial number of ganglion cells, but in others, a cell death pathway (probably apoptotic) is activated with subsequent extensive degeneration of the retinal ganglion cell layer and optic nerve.

Which is the primary etiologic event in Otsuka Long-Evans Tokushima Fatty rats, a model of spontaneous non—insulin-dependent diabetes mellitus, insulin resistance, or impaired insulin secretion?

To identify the primary disorder causing diabetes mellitus in a model rat (Otsuka Long-Evans Tokushima Fatty [OLETF]) with non-insulin-dependent diabetes mellitus (NIDDM), we studied the temporal relationship between insulin resistance and impairment of pancreatic β-cell function. Groups of 28 male OLETF rats and male nondiabetic control Long-Evans Tokushima Otsuka (LETO) rats were given an intravenous (IV) glucose and glucagon tolerance test (IVGTT) and hyperinsulinemic euglycemic clamp tests at 10, 16, 24, and 40 weeks of age. After the euglycemic clamp test, abdominal fat was measured and the pancreas was examined histologically. At 16 weeks of age, insulin-mediated whole-body glucose uptake as measured by the hyperinsulinemic euglycemic clamp technique was significantly reduced in OLETF rats (glucose infusion rate [GIR], 40.9 ± 4.2 μmol/kg - min) as compared with LETO rats (78.4.± 6.9). On the other hand, plasma insulin responses to glucose and glucagon in OLETF rats were higher than those in LETO rats at 16 and 24 weeks of age, but clearly decreased at 40 weeks of age (Σimmunoreactive insulin [IRI] to glucagon, 8.81 ± 1.81 v 27.32 ± 4.59 nmol · min in OLETF and LETO rats, respectively, P < .01). Abdominal fat deposition was significantly greater in OLETF rats than in LETO rats at all ages tested except 10 weeks. Pancreatic islets of OLETF rats became enlarged and fibrotic. These results demonstrated that insulin resistance preceded impairment of pancreatic β-cell function in OLETF rats, and that insulin resistance seemed closely related to fat deposition in the abdominal cavity.

Malignant hyperthermia in dogs

Summary Malignant hyperthermia (mh) is an anesthetic agent-induced hypermetabolic state. Human beings and several other animal species, including dogs, have been described to be genetically predisposed to development of mh. The halothane-triggered mh syndrome was characterized in genetically predisposed dogs, and in vitro contracture sensitivity of biopsied gracilis muscle exposed to halothane and caffeine was quantitated. Within 1 hour of halothane administration, each mh-susceptible dog developed rapid increases in CO2 production and rectal temperature. Reversal of the hypermetabolic state was achieved when halothane was discontinued and dantrolene sodium was given iv. Biopsied gracilis muscle from mh-susceptible dogs had abnormal in vitro contracture responses to halothane and caffeine. These findings were consistent with those observed for mh-susceptible human beings and pigs in which a loss in regulation of muscle cell Ca++ is believed to be the primary etiologic event for induction of mh.

Paradoxical increase in heart rate before conversion to sinus rhythm in patients with recent-onset atrial fibrillation

patients during vasodepressor syncope. It reached a value previously reported only in patients with septic shock.2 The pathophysiology of vasodepressor syncope is very complex. In the early phase, primary peripheral vasodilation probably predominates; subsequently, other mechanisms may be involved, such as lack of compensatory increase in cardiac rate and output, impairment of venous constriction and reflex-mediated vasodilation of skeletal muscle bed.’ Inhibition of the neuroadrenergic system may be an important factor. In fact, vasodepressor syncope can be experimentally induced by sudden interruption of sympathetic discharge.5 Moreover, norepinephrine activity does not increase during vasodepressor syncope3 Endogenous opioid peptides may inhibit the sympathetic system either centrally or peripherally.2-4~7*8 Moreover, endorphins may have a negative inotropic and chronotropic cardiac influence, reduce reflex discharge of cardiac or peripheral receptors, and exaggerate the response of J pulmonary receptors.214$7,8 In our study, no independent measure of sympathetic activity was obtained. We also did not examine the effect of administration of naloxone or other opioid antagonists on the occurrence of syncope. However, the fact that hunger, fatigue and painful stimulation may induce vasodepressor syncope,’ as well as modify plasma fi endorphin activity,9,10 suggests some link between opioid peptides and vasodepressor syncope. This is supported by our data. Whether increase of plasma @ endorphins during vasodepressor syncope is a primary etiologic event or a secondary phenomenon warrants further investigation.