Pathophysiological Hypotheses Research Articles

Nano-formulations for the Management of Epilepsy: Synthetic and Herbal Drug Perspectives

Introduction: Epilepsy is a multifaceted neurological disorder impacting many individuals globally. Although the main treatment method is through medicines, many patients do not respond to existing drugs. This has spurred extensive research for new therapeutic targets and drug delivery methods. Inflammation and oxidative stress have been associated with the development and progression of epilepsy. Nanomedicine-based treatments focussing on these pathways could provide a promising way to enhance treatment results. Objective: This review aims to provide insights into enhancing antiepileptic therapy through the development of nanoformulations of synthetic and herbal drugs. Methods: A comprehensive review of existing literature was conducted to evaluate the potential of nanoformulations in improving the delivery and efficacy of antiepileptic drugs. The review covers the pathophysiological hypotheses of epilepsy, including the glutamatergic, GABAergic, oxidative stress, and neuroinflammation hypotheses, and examines the role of neurotransmitter imbalances in seizure activity. Results: Nanoformulations offer promising advantages for epilepsy treatment by enhancing drug delivery across the blood-brain barrier, reducing required dosages, and minimizing side effects. The utilization of nanoparticles can improve the bioavailability and targeting of AEDs, potentially leading to better seizure control. However, challenges such as ensuring biocompatibility and optimizing nanoparticle characteristics remain. Conclusion: While significant progress has been made in understanding epilepsy and developing treatments, the disorder continues to pose challenges. Nanoformulations represent a promising area of research that could lead to more effective and targeted therapies for epilepsy, although further studies are needed to address the associated challenges and fully realize their potential.

Melatonin in Alzheimer's Disease: Literature Review and Therapeutic Trials.

There are currently no effective treatments to prevent, halt, or reverse Alzheimer's disease (AD), the most common cause of dementia in older adults. Melatonin, a relatively harmless over-the-counter supplement, may offer some benefits to patients with AD. Melatonin is known for its sleep-enhancing properties, but research shows that it may provide other advantages as well, such as antioxidant and anti-amyloidogenic properties. Clinical trials for melatonin use in AD have mixed results but, overall, show modest benefits. However, it is difficult to interpret clinical research in this area as there is little standardization to guide the administration and study of melatonin. This review covers basic biology and clinical research on melatonin in AD focusing on prominent hypotheses of pathophysiology of neurodegeneration and cognitive decline in AD (i.e., amyloid and tau hypotheses, antioxidant and anti-inflammation, insulin resistance and glucose homeostasis, the cholinergic hypothesis, sleep regulation, and the hypothalamic-pituitary-adrenal axis and cortisol). This is followed by a discussion on pending clinical trials, considerations for future research protocols, and open questions in the field.

Gastrointestinal ultrasound in the critically ill: A narrative review and a proposal for a protocol.

Critically ill patients are at risk of presenting with gastrointestinal dysfunction at intensive care unit admission or during their stay. However, identifying gastrointestinal dysfunction is difficult because clinical evaluation is frequently nonspecific and validated biomarkers are lacking. In this context, ultrasound of the digestive tract may help to identify gastrointestinaldysfunction. In this narrative review, we summarize available evidence and propose a protocol for assessment of the gastrointestinal tract with ultrasound. First, we report available evidence from use of four available protocols: the gastrointestinal and urinary tract sonography protocol, the acute gastrointestinal injury ultrasound score, the transabdominal gastrointestinal ultrasoundprotocol, and the Lai protocol, each addressing somewhat different aspects. Outputs from these protocols have been associated with clinical scores of gastrointestinal failure, feeding intolerance, and 28-day mortality. Second, we describe the potential pitfalls of using ultrasound in the critically ill, such as obesity, abdominal dressings, or the presence of intraluminal gas. Third, we suggest perspectives of ultrasound in monitoring the response to enteral nutrition and for early identification of nonocclusive mesenteric ischemia. Fourth, we propose a structured protocol for gastrointestinal ultrasound describing all the different structures that should be evaluated and provide detailed guidance for a clockwise abdominal examination. In conclusion, the use of a specific and structured protocol might help to identify patients presenting with gastrointestinal dysfunction, guide nutrition, and allow the proposal of pathophysiological hypotheses (complications of enteral nutrition, intra-abdominal infection, bowel ischemia, etc.). The benefit of using a structured protocol requires further investigation.

Autism spectrum disorder-like behaviors induced by hyper-glutamatergic NMDA receptor signaling through hypo-serotonergic 5-HT1A receptor signaling in the prefrontal cortex in mice exposed to prenatal valproic acid.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by repetitive behaviors, social deficits, and cognitive impairments. Maternal use of valproic acid (VPA) during pregnancy is associated with an increased risk of ASD in offspring. The prevailing pathophysiological hypothesis for ASD involves excitation/inhibition (E/I) imbalances and serotonergic dysfunction. Here, we investigated the association between glutamatergic-serotonergic neuronal interactions and ASD-like behaviors in mice exposed to prenatal VPA. Prenatal VPA exposure induced excessive repetitive self-grooming behavior and impaired social behavior and object recognition memory in young adult period. Prenatal VPA mice showed hyper-glutamatergic function (increase in basal extracellular glutamate levels and CaMKII phosphorylation) and hypo-serotonergic function (decrease in 5-hydroxyindoleacetic acid and stimulation-induced serotonin [5-HT] release, but an increase in 5-HT transporter expression) in the prefrontal cortex. Treatment with a low-affinity NMDA receptor antagonist (memantine), a selective 5-HT reuptake inhibitor (fluoxetine), and a 5-HT1A receptor agonist (tandospirone) attenuated both the increase in CaMKII phosphorylation and ASD-like behavior of prenatal VPA mice. Opto-genetic activation of the serotonergic neuronal system attenuated impairments in social behavior and object recognition memory in prenatal VPA mice. WAY-100635-a 5-HT1A receptor antagonist-antagonized the effect of fluoxetine on impaired social behavior and object recognition memory. These results suggest that E/I imbalance and ASD-like behavior are associated with hypo-serotonergic receptor signaling through 5-HT1A receptors in prenatal VPA mice.

Inflammatory Myopathies and Autoimmune Gluten-related Disorders: A Scoping Review of Pathophysiological Interconnections and Hypothesis.

Anecdotal reports describe patients with concurrent idiopathic inflammatory myopathy (IIM) and celiac disease (CeD) in whom the introduction of a gluten-free diet led to dramatic improvement of myositis. We first systematically reviewed all peer-reviewed publications on concomitant IIM and duodenal biopsy-verified CeD. The collected evidence was suggestive of associations between myositis disease activity and gluten exposure in some patients with IIM-CeD. To investigate possible explanations for the observations, an exploratory review of basic pathophysiological relationships between IIM and gluten-related disorders was performed using a combined strategy of systematic and non-systematic literature searches and forward and backward citation tracking. The investigations revealed close pathophysiological associations between IIM and the autoimmune gluten-related disorders CeD, dermatitis herpetiformis, and gluten ataxia. Common traits include shared genetic predisposition through HLA-DQ2.5/-DQ8, disease activity-associated autoantibodies, histopathological parallels with inflammatory cell infiltrates, and similarly distributed structural homologous transglutaminases (TGs). HLA-DQ2.5-restricted gluten-specific CD4+ T cells of a rare, uniform phenotype are reported in CeD and connective tissue disease. Expanded T-cell clones with identical phenotypes and CDR3β motifs indicate the presence of a continuous, antigen-driven T-cell response. The investigations revealed that the main components involved in the adaptive immune response in the CeD gut may be present in HLA-DQ2.5+/-DQ8+ IIM muscle. The collected evidence supports the notion that in some genetically predisposed patients with IIM, gluten may act as an exogenous antigen driving myositis. Further Research/Clinical Implications: To test the above hypothesis, clinical trials combined with immunological studies are needed. Meanwhile, the inclusion of HLA-DQ typing may be justified, and subsequent small-intestinal biopsies in HLA-DQ2.5/8+ individuals with IIM.

BMP4 and Temozolomide Synergize in the Majority of Patient-Derived Glioblastoma Cultures.

One of the main causes of poor prognoses in patient with glioblastoma (GBM) is drug resistance to current standard treatment, which includes chemoradiation and adjuvant temozolomide (TMZ). In addition, the concept of cancer stem cells provides new insights into therapy resistance and management also in GBM and glioblastoma stem cell-like cells (GSCs), which might contribute to therapy resistance. Bone morphogenetic protein-4 (BMP4) stimulates astroglial differentiation of GSCs and thereby reduces their self-renewal capacity. Exposure of GSCs to BMP4 may also sensitize these cells to TMZ. A recent phase I trial has shown that local delivery of BMP4 is safe, but a large variation in survival is seen in these treated patients and in features of their cultured tumors. We wanted to combine TMZ and BMP4 (TMZ + BMP4) therapy and assess the inter-tumoral variability in response to TMZ + BMP4 in patient-derived GBM cultures. A phase II trial could then benefit a larger group of patients than those treated with BMP4 only. We first show that simultaneous treatment with TMZ + BMP4 is more effective than sequential treatment. Second, when applying our optimized treatment protocol, 70% of a total of 20 GBM cultures displayed TMZ + BMP4 synergy. This combination induces cellular apoptosis and does not inhibit cell proliferation. Comparative bulk RNA-sequencing indicates that treatment with TMZ + BMP4 eventually results in decreased MAPK signaling, in line with previous evidence that increased MAPK signaling is associated with resistance to TMZ. Based on these results, we advocate further clinical trial research to test patient benefit and validate pathophysiological hypothesis.

The forensic aspects of suicide and neurotrophin factors: a research study.

Introduction: Suicide represents a significant public health problem whose neurobiology is not yet fully understood. In many cases, suicidal behavior and psychiatric spectrum disorders are linked, in particular, to major depression. An emerging pathophysiological hypothesis underlines the role of neurotrophic factors, proteins involved in neurogenesis, in synaptic plasticity in response to stressors. Our research aims to evaluate the degree of expression of brain neurotrophic factor (BDNF) in brain areas involved in depressive disorder in suicidal subjects. Furthermore, we want to evaluate the expression of glial cell line-derived neurotrophic factor (GDNF) in suicidal subjects. Methods: We selected twenty confirmed cases of suicide among subjects with a clinical history of depressive pathology and possible psychopharmacological treatment, compared to ten controls of individuals who died of non-suicidal causes. For all selected cases and controls, immunohistochemical investigations were performed using a panel of antibodies against the BDNF and GDNF antigens on samples from the various brain areas. Results and discussion: The results show that BDNF was under-expressed in the cerebral parenchyma of subjects who died by suicide compared to controls, while there was an overexpression of GDNF in suicide victims, these data could be useful for a clinical application as potential markers for suicidal risk, to assess the severity of depression and development of specific pharmacological therapies for depression.

Cardiac amyloidosis and aortic stenosis: what do we know?

Aortic valve stenosis and cardiac amyloidosis, particularly transthyretin-related, often coexist and share a common clinical and demographic profile. Several pathophysiological hypotheses have been proposed regarding the causes of this association, neither of which fully substantiated in practice. The key to detect the coexistence of cardiac amyloidosis and aortic valve stenosis lies in clinical suspicion. It is possible to hypothesize concurrent cardiac amyloidosis in patients with aortic valve stenosis with the aid of clinical, electrocardiographic, echocardiographic, and extracardiac "red flags". Subsequent non-invasive diagnostic steps are often sufficient to establish a definitive diagnosis. The early diagnosis of this condition is pivotal since the presence of dual pathology worsens patient's prognosis, especially without intervention. Available data on treatment show a better outcome in terms of survival and cardiovascular events in patients undergoing percutaneous correction of valvular heart disease rather than medical therapy alone, regardless of the presence of cardiac amyloidosis. Furthermore, it seems that cardiac amyloidosis does not impact survival after transcatheter aortic valve replacement, even if higher rates of rehospitalizations have been described. Indeed, percutaneous treatment of valvular heart disease is currently considered the primary therapeutic option. Subsequently a disease-modifying treatment for transthyretin amyloidosis may be considered in order to delay disease progression and improve outcomes, even if specific data are still lacking.

Renal implications of pneumoperitoneum in laparoscopic surgery: mechanisms, risk factors, and preventive strategies.

Pneumoperitoneum, which is established for laparoscopic surgery, has systemic implications on the renal system and may contribute to acute kidney injury or postoperative renal dysfunction. Specifically, when the pressure exceeds 10 mmHg, pneumoperitoneum decreases renal blood flow, leading to renal dysfunction and temporary oliguria. The renal effects of pneumoperitoneum stem from both the direct effects of increased intra-abdominal pressure and indirect factors such as carbon dioxide absorption, neuroendocrine influences, and tissue damage resulting from oxidative stress. While pneumoperitoneum can exacerbate renal dysfunction in patients with pre-existing kidney issues, preserving the function of the remaining kidney is crucial in certain procedures such as laparoscopic live donor nephrectomy. However, available evidence on the effects of pneumoperitoneum on renal function is limited and of moderate quality. This review focuses on exploring the pathophysiological hypotheses underlying kidney damage, mechanisms leading to oliguria and kidney damage, and fluid management strategies for surgical patients during pneumoperitoneum.

A comprehensive assessment of toxoplasmosis and its dormant impact on psychotic disorders (Review).

Toxoplasmosis is a pathological condition induced by the parasite, Toxoplasma gondii (T. gondii), which has a notable affinity for the cellular components of the central nervous system. Over the decades, the relationship between toxoplasmosis and the development of psychiatric disorders has generated profound interest within the scientific community. Whether considering immunocompetent or immunocompromised patients, epidemiological studies suggest that exposure to T. gondii may be associated with a higher risk of certain psychiatric disorders. However, there are extensive debates regarding the exact nature of this association and how T. gondii is involved in the pathogenesis of these disorders. Toxoplasmosis has long been considered an asymptomatic infection among immunocompetent patients. However, there appears to be an association between chronic brain infection with T. gondii and alterations in patient neuronal architecture, neurochemistry and behavior. The present review aimed to compile statements and pathophysiological hypotheses regarding the potential association between toxoplasmosis and psychotic disorders. Further research is necessary for understanding the potential relationship of T. gondii infection and psychotic disorders.

Associations between antipsychotics-induced weight gain and brain networks of impulsivity

Given the unpredictable rapid onset and ubiquitous consequences of weight gain induced by antipsychotics, there is a pressing need to get insights into the underlying processes at the brain system level that will allow stratification of “at risk” patients. The pathophysiological hypothesis at hand is focused on brain networks governing impulsivity that are modulated by neuro-inflammatory processes. To this aim, we investigated brain anatomy and functional connectivity in patients with early psychosis (median age: 23 years, IQR = 21–27) using anthropometric data and magnetic resonance imaging acquired one month to one year after initiation of AP medication. Our analyses included 19 patients with high and rapid weight gain (i.e., ≥5% from baseline weight after one month) and 23 patients with low weight gain (i.e., <5% from baseline weight after one month). We replicated our analyses in young (26 years, IQR = 22–33, N = 102) and middle-aged (56 years, IQR = 51–62, N = 875) healthy individuals from the general population. In early psychosis patients, higher weight gain was associated with poor impulse control score (β = 1.35; P = 0.03). Here, the observed brain differences comprised nodes of impulsivity networks - reduced frontal lobe grey matter volume (Pcorrected = 0.007) and higher striatal volume (Pcorrected = 0.048) paralleled by disruption of fronto-striatal functional connectivity (R = −0.32; P = 0.04). Weight gain was associated with the inflammatory biomarker plasminogen activator inhibitor-1 (β = 4.9, P = 0.002). There was no significant association between increased BMI or weight gain and brain anatomy characteristics in both cohorts of young and middle-aged healthy individuals. Our findings support the notion of weight gain in treated psychotic patients associated with poor impulse control, impulsivity-related brain networks and chronic inflammation.

The emerging neuroimmune hypothesis of bipolar disorder: An updated overview of neuroimmune and microglial findings.

Bipolar disorder (BD) is a severe and multifactorial disease, with onset usually in young adulthood, which follows a progressive course throughout life. Replicated epidemiological studies have suggested inflammatory mechanisms and neuroimmune risk factors as primary contributors to the onset and development of BD. While not all patients display overt markers of inflammation, significant evidence suggests that aberrant immune signaling contributes to all stages of the disease and seems to be mood phase dependent, likely explaining the heterogeneity of findings observed in this population. As the brain's immune cells, microglia orchestrate the brain's immune response and play a critical role in maintaining the brain's health across the lifespan. Microglia are also highly sensitive to environmental changes and respond to physiological and pathological events by adapting their functions, structure, and molecular expression. Recently, it has been highlighted that instead of a single population of cells, microglia comprise a heterogeneous community with specialized states adjusted according to the local molecular cues and intercellular interactions. Early evidence has highlighted the contribution of microglia to BD neuropathology, notably for severe outcomes, such as suicidality. However, the roles and diversity of microglial states in this disease are still largely undermined. This review brings an updated overview of current literature on the contribution of neuroimmune risk factors for the onset and progression of BD, the most prominent neuroimmune abnormalities (including biomarker, neuroimaging, exvivo studies) and the most recent findings of microglial involvement in BD neuropathology. Combining these different shreds of evidence, we aim to propose a unifying hypothesis for BD pathophysiology centered on neuroimmune abnormalities and microglia. Also, we highlight the urgent need to apply novel multi-system biology approaches to characterize the diversity of microglial states and functions involved in this enigmatic disorder, which can open bright perspectives for novel biomarkers and therapeutic discoveries.

Involvement of gut microbiota in multiple sclerosis-review of a new pathophysiological hypothesis and potential treatment target.

Multiple sclerosis (MS) is a chronic inflammatory disease that leads to demyelination and damage to the central nervous system. It is well known, the significance of the involvement and influence of the immune system in the development and course of MS. Nowadays, more and more studies are demonstrating that an important factor that affects the action of the immune system is the gut microbiota. Changes in the composition and interrelationships in the gut microbiota have a significant impact on the course of MS. Dysbiosis affects the disease course mainly by influencing the immune system directly but also by modifying the secreted metabolites and increasing mucosal permeability. The essential metabolites affecting the course of MS are short-chain fatty acids, which alter pro- and anti-inflammatory responses in the immune system but also increase the permeability of the intestinal wall and the blood-brain barrier. Dietary modification alone can have a significant impact on MS. Based on these interactions, new treatments for MS are being developed, including probiotics administration, supplementation of bacterial metabolites, fecal microbiota transplantation, and dietary changes. Further studies may serve to develop new drugs and therapeutic approaches for MS.

Virtual brain twins: from basic neuroscience to clinical use.

Virtual brain twins are personalized, generative and adaptive brain models based on data from an individual's brain for scientific and clinical use. After a description of the key elements of virtual brain twins, we present the standard model for personalized whole-brain network models. The personalization is accomplished using a subject's brain imaging data by three means: (1) assemble cortical and subcortical areas in the subject-specific brain space; (2) directly map connectivity into the brain models, which can be generalized to other parameters; and (3) estimate relevant parameters through model inversion, typically using probabilistic machine learning. We present the use of personalized whole-brain network models in healthy ageing and five clinical diseases: epilepsy, Alzheimer's disease, multiple sclerosis, Parkinson's disease and psychiatric disorders. Specifically, we introduce spatial masks for relevant parameters and demonstrate their use based on the physiological and pathophysiological hypotheses. Finally, we pinpoint the key challenges and future directions.

Epidemiology of Schmorl's Node in the Thoracic Spine: A Subtype Analysis.

Retrospective observational study. To describe the epidemiology of Schmorl's nodes (SN) of primarily developmental cause (SNd) and SN of primarily acquired cause (SNa) separately in the thoracic spine in subjects aged 35 to 90 years old. The epidemiology of SN and its relationship with age and gender remain controversial. On the basis of a pathophysiological hypothesis and the different morphologic characteristics, two subtypes of SN may exist and should be considered separately. Chest CT scans of subjects who came to our institution for health checks aged 35 to 90 years old were retrospectively reviewed. The presence or absence of SN was recorded for each thoracic vertebra. The SNs were further classified into SNd and SNa. The prevalence, location, and relationship with age, gender, and bone mineral density (BMD) were evaluated separately for the two subtypes. Of the 848 subjects (407 female, mean age: 53±12.2yr) included, 15.7% had SNs. Of the 303 SNs, 49.2% were SNd, and 48.5% were SNa. Aging increased the prevalence of SNa, while it was not related to the prevalence of SNd. Males had significantly more SNd than females (11.3% vs. 4.7%, P <0.001), while the prevalence of SNa was not different between the two genders (10.2% vs. 9.1%, P =0.666). A similar distribution of SNd and SNa among thoracic vertebral levels was appreciated, with T9 most frequently involved. Subjects with SNa had lower lumbar BMD than controls ( P =0.006), while no significant difference in BMD was found between subjects with SNd and controls ( P =0.166). The clinical characteristics of SN differ based on the developmental and acquired subtypes, including the relationship with age, gender, and BMD. The subtypes may be considered distinct clinical entities as a result.

Hepatofugal portal flow is highly predictive of acute-on-chronic liver failure: a new hemodynamic patho-physiological hypothesis

Hepatofugal portal flow is highly predictive of acute-on-chronic liver failure: a new hemodynamic patho-physiological hypothesis

Recalibrating the Why and Whom of Animal Models in Parkinson Disease: A Clinician's Perspective.

Animal models have been used to gain pathophysiologic insights into Parkinson's disease (PD) and aid in the translational efforts of interventions with therapeutic potential in human clinical trials. However, no disease-modifying therapy for PD has successfully emerged from model predictions. These translational disappointments warrant a reappraisal of the types of preclinical questions asked of animal models. Besides the limitations of experimental designs, the one-size convergence and oversimplification yielded by a model cannot recapitulate the molecular diversity within and between PD patients. Here, we compare the strengths and pitfalls of different models, review the discrepancies between animal and human data on similar pathologic and molecular mechanisms, assess the potential of organoids as novel modeling tools, and evaluate the types of questions for which models can guide and misguide. We propose that animal models may be of greatest utility in the evaluation of molecular mechanisms, neural pathways, drug toxicity, and safety but can be unreliable or misleading when used to generate pathophysiologic hypotheses or predict therapeutic efficacy for compounds with potential neuroprotective effects in humans. To enhance the translational disease-modification potential, the modeling must reflect the biology not of a diseased population but of subtypes of diseased humans to distinguish What data are relevant and to Whom.

Altered expression of long non-coding RNAs NRON and SNHG11 in patients with ischemic stroke

BackgroundLong non-coding RNAs, known as LncRNAs, have demonstrated a robust association with the pathogenesis of stroke. NRON and SNHG are among the most extensively studied lncRNAs in the context of atherosclerosis and inflammatory conditions. Given the absence of a current pathophysiological hypothesis regarding the potential relevance of the SNHG family and NRON lncRNAs in ischemic stroke (IS), this study aimed to investigate the altered expression of NRON and SNHG11 following atherosclerotic ischemic stroke (AIS) and their potential association with the risk of AIS.MethodsBlood samples were collected from 65 AIS patients (with large artery atherosclerosis or small vessel disease) and 65 controls. The expression levels of NRON and SNHG11 were assessed within the first 24 h following the stroke using quantitative real-time PCR.ResultsNRON expression exhibited a significant decrease in patients compared to controls, while no substantial difference was observed in the expression level of SNHG11 between the two groups. Furthermore, logistic regression analysis revealed a significant negative association between NRON expression and the risk of AIS (adjusted odds ratio = 0.70; 95% confidence interval 0.55–0.89, P = 0.004).ConclusionsThese findings suggest that NRON may play a role in the pathogenesis of AIS and could potentially serve as a biomarker for the disease. To fully comprehend the mechanism underlying the association between NRON and AIS and to explore its potential therapeutic implications, further investigation is warranted.

The Story behind the Mask: A Narrative Review on Hypomimia in Parkinson's Disease.

Facial movements are crucial for social and emotional interaction and well-being. Reduced facial expressions (i.e., hypomimia) is a common feature in patients with Parkinson's disease (PD) and previous studies linked this manifestation to both motor symptoms of the disease and altered emotion recognition and processing. Nevertheless, research on facial motor impairment in PD has been rather scarce and only a limited number of clinical evaluation tools are available, often suffering from poor validation processes and high inter- and intra-rater variability. In recent years, the availability of technology-enhanced quantification methods of facial movements, such as automated video analysis and machine learning application, led to increasing interest in studying hypomimia in PD. In this narrative review, we summarize the current knowledge on pathophysiological hypotheses at the basis of hypomimia in PD, with particular focus on the association between reduced facial expressions and emotional processing and analyze the current evaluation tools and management strategies for this symptom, as well as future research perspectives.

ASIA syndrome and the nociceptive storm: A case report of a refractory headache and a pathophysiological hypothesis

ASIA syndrome and the nociceptive storm: A case report of a refractory headache and a pathophysiological hypothesis