Pathogenic Hypothesis Research Articles

Experimental Models of Posterior Reversible Encephalopathy Syndrome: A Review From Pathophysiology to Therapeutic Targets.

Posterior reversible encephalopathy syndrome (PRES) is a clinical and radiological entity characterized by nonspecific symptomatology (eg, headache, visual disturbances, encephalopathy, and seizures) and classically cortical and subcortical vasogenic edema predominantly affecting the parietooccipital region. PRES etiologies are usually dichotomized into toxic PRES (eg, antineoplastic drugs, illicit drugs) and clinical condition-associated PRES (eg, acute hypertension, dysimmune disorders). Although the pathophysiology of PRES remains elusive, 2 main pathogenic hypotheses have been suggested: cerebral hyperperfusion due to acute hypertension and cerebral hypoperfusion related to endothelial dysfunction. Research into the pathogenesis of PRES has emerged through the development of animal models in the last decade. The motivation for developing a suitable PRES model is 2-fold: to fill in knowledge gaps of the pathophysiological mechanisms involved, and to open new perspectives for clinical assessment of pharmacological targets to improve therapeutic management of PRES. All current models of PRES have a hypertensive background, on which other triggers (acute hypertension, inflammatory, drug toxicity) have been added to address specific facets of PRES (eg, seizures). The initial model consisted in inducing a reduced uterine perfusion pressure that mimics preeclampsia, a leading cause of PRES. More recently, a model of stroke-prone spontaneously hypertensive rats on high-salt diet, originally developed for hypertensive small vessel disease and vascular cognitive impairment, has been studied in PRES. This review aims to discuss, depending on the research objective, the benefits and limitations of current experimental approaches and thus to define the desirable characteristics for studying the pathophysiology of PRES and developing new therapies.

Using 7T MRI to study hippocampal structures in Alzheimer’s disease and post‐SARS‐CoV2 infection

AbstractBackground7T MRI allows implementation of high‐resolution quantitative susceptibility mapping (QSM) which can be used to assess the cerebral microvascular/hypoperfusion pathogenic hypothesis in Alzheimer’s disease (AD) and in the post‐SARS‐CoV2 setting to explore if there may be similarities in brain changes in these two conditions. The magnetic susceptibility (reflective of tissue iron) of hippocampal subfields was assessed in patients with 1) CSF‐Amyloidß‐status AD; 2) mild COVID‐19 over 6 months previously (Cv); 3) severe COVID‐19 with ICU admission >6 months previously (ICU‐Cv); and 4) age‐matched healthy controls (HC).Methods33 participants (10 HC, 14 Cv, 9 ICU‐Cv) for the COVID study and 24 participants (14 AD, 11HC) from AD patients with confirmed CSF‐Amyloidß levels, aged 42‐79, were scanned on a 7T scanner with the following protocol T2* GRE for the AD groups (0.7×0.7×0.7mm3,TE/TR = 20/31ms) and T2* multi‐echo GRE for the Cv groups (0.38×0.38×0.75mm3,TE1/TE2/TR = 8.2/18.4/24ms). Data were processed using QSMbox1 to produce susceptibility maps. PSIR (0.55×0.55×0.55mm3,TE/TR = 3.1/6.9ms) and T2‐weighted FSE (0.38×0.39×1.5mm3, TE/TR = 117/5900ms) images were used to segment the hippocampal subfields (Figure 1)2. One‐way analyses were used in SPSS for comparison between the HC group and each of the Cv, ICU‐Cv, and AD groups.ResultsThere was no change in susceptibility for the whole hippocampus between AD and HC, but there was a significant difference for the DG subfield (p = 0.045), Figure 2. For COVID patients, there was a significant difference between the susceptibility of the whole hippocampus in the ICU‐Cv group (p = 0.035), but not in the Cv group (p = 0.788), Figure 3, compared to HC. In subfield analyses there was a trend towards decreased susceptibility in the subiculum, an area known to be affected by Alzheimer pathology, in the ICU‐Cv group (p = 0.032) compared to HC.ConclusionThe lower susceptibility within the hippocampal structures observed in AD and ICU‐Cv patients may reflect less iron either from cerebral hypoperfusion or vascular injuries in AD or additionally result from sequelae of hypoxaemia in ICU‐Cv. The study provides preliminary evidence of detectable in vivo microstructural changes in hippocampal subfields in both AD and post‐COVID settings. Funding: Medical Research Council, UK (MR/T005580/1); National Institute of Health, USA (1R56AG074467‐01)

Narrative Review: Pathogenesis of the Inflammatory Response and Intestinal Flora in Depression.

Depression, as a common mental illness that is often accompanied by suicidal and homicidal behaviors, is one of the most important diseases in the medical field that requires urgent attention. The pathogenesis of depression is complex, and the current therapeutic drugs such as tricyclic antidepressants (TCAs), monoamine oxidase inhibitors, and secondary serotonin reuptake inhibitors have certain shortcomings. The inflammatory factor hypothesis, one of the pathogenesis of depression, suggests that inflammatory response is a key factor leading to the occurrence and development of depression, and that overactivation of inflammatory factors such as NLRP3, Toll-like receptor 4, and IDO leads to immune-system dysfunction and depression. The other pathogenic hypothesis, the gut flora hypothesis, has also been the focus of recent research. The gut flora may work together with inflammatory factors to cause depression. The approach to treating depression has been by altering the gut flora through drugs or probiotics. However, effective and clear treatment methods are lacking. In this study, by exploring the involvement of intestinal flora and inflammatory factors in the pathogenesis of depression, we found that improving the intestinal flora can affect inflammatory factors and, therefore, provide research ideas for the development of novel drugs to treat depression.

Polymyalgia rheumatica: An update (Review).

Polymyalgia rheumatica (PMR) is a chronic inflammatory disease which affects the connective vascular tissue, characterized by pain accompanied by morning stiffness, predominantly of the neck muscles, hip and shoulder girdle. Usually, patients with this disease are >50 years of age and biological inflammatory syndrome is present with an increase in both the erythrocyte sedimentation rate and C-reactive protein levels, aspects similar to giant cell arteritis. The aim of the present review was to depict the current pathogenic hypothesis, diagnostic and treatment approach for patients with PMR, and novelties since the development of the currently used 2012 European League Against Rheumatism and American College of Rheumatology provisional classification criteria. PMR is a prevalent disease that can occasionally prove difficult to diagnose and treat. Possibly, the most abundant type of evidence and data revealed over the past decade have been acquired through musculoskeletal imaging, with implications in diagnosis, disease monitoring and relapse, prognosis and changes with treatment. Further research on pathophysiology is required to gain a deeper understanding of the underlying processes, which will serve as the foundation for future personalized treatments. In addition, there is an increasing demand for improved diagnostic techniques, which should include a further development of various imaging modalities, in order to provide accurate diagnosis and appropriate therapy.

Autonomic dysfunction in systemic sclerosis: A scoping review

IntroductionOver the years several lines of evidence have implied a pathological involvement of autonomic nervous system (ANS) in systemic sclerosis (SSc). However, the relationship between autonomic dysfunction and SSc is not yet fully understood. The aims of this scoping review were to map the research done in this field and inform future research to investigate pathogenic hypotheses of ANS involvement. MethodsWe performed a scoping review of publications collected through a literature search of MEDLINE and Web of Science databases, looking for dysautonomia in SSc. We included original data from papers that addressed ANS involvement in SSc regarding pathogenesis, clinical presentation and diagnostic tools. Results467 papers were identified, 109 studies were selected to be included in the present review, reporting data from a total of 2742 SSc patients. Cardiovascular system was the most extensively investigated, assessing heart rate variability with 24 h HolterECG or Ewing's autonomic tests. Important signs of dysautonomia were also found in digital vasculopathy, gastrointestinal system and SSc skin, assessed both with non-invasive techniques and histologically. Research hypotheses mainly regarding the relationship between sympathetic system – ischemia and the role of neurotrophins were then developed and discussed. ConclusionWe described the currently available evidence on pathogenesis, clinical presentation and diagnostic assessment of dysautonomia in SSc patients. A strong influence of ANS deregulation on SSc clearly emerges from the literature. Future research is warranted to clarify the mechanisms and timing of autonomic dysfunction in SSc.

A unique transgenic model that expressing Aβ oligomers: PS1V97L mutation discovered from Chinese Alzheimer’s disease families

AbstractBackgroundTransgenic mouse models are important tools for studying the pathogenesis of Alzheimer’s Disease (AD) and drug development. Commonly used models are constructed from early‐onset AD mutations in the Caucasian population, and are usually overexpression or knock‐in of multiple pathogenic gene mutations. However, they are not consistent with the genetic characteristics in real world where single gene mutation occurs most of the time. Furthermore, AD transgenic mouse models have been mostly depending on a few institutions/companies and limited by intellectual property protection.MethodWe systematically summarized the research progress of a transgenic mouse model based on a single gene mutation (PS1V97L) found uniquely in Chinese familial AD, as well as the underling mechanisms such as Aβ oligomers (AβO) self‐replication (figure 1). We further compared them with other single‐transgene models, and summarized the preliminary findings of several drugs targeting AβO.ResultPS1V97L transgenic mice showed age‐related AD phenotypes such as Aβ accumulation, tau phosphorylation, neurofibrillary tangles, gliosis, synaptic degeneration and cognitive impairment (figure 2). The unique characteristics of this model is the aggregation of interneuronal AβO in cortex and hippocampus, but no plaques formed up to 24 months. Other mechanisms of PS1V97L model include oxidative stress, inflammation, abnormal energy metabolism, and alterations in AD‐related signaling pathways, such as PI3K/Akt and Nrf2/ARE pathways. Several drugs including sulforaphane, honokiol, tenuifolin, isoliquiritigenin, ginsenoside, butylphthalide and oxiracetam were found effective in PS1V97L mouse model as well as rat and cell models based on AβO mechanism.ConclusionAlthough carrying only one mutation, PS1V97L transgenic mouse model can mimic almost all AD pathological phenotypes, and supports AβO pathogenic hypothesis. It provides important basic and translational tool for exploring the upstream mechanisms, risk factors, and multi‐target drug development in AD.

Clinical and Dermoscopic Features of Winer's Nodular Solitary Calcinosis

Aims: Solitary nodular calcinosis of Winer is a rare and benign form of localized idiopathic cutaneous calcinosis. Its dermoscopic features may be useful for early diagnosis, but have never been described in the literature to our knowledge.
 Case Report: A 5-year-old child presented to our clinic with a 2 years history of a painless keratotic and warty nodule located in the helix of the right ear. A wart was suspected and treated without any improvement. Dermoscopy was performed and showed peripheral white deposits suggestive of Winer's calcinosis, motivating an excision whose histological examination confirmed the diagnosis.
 Discussion: The subepidermal calcified nodule has been rarely described in the literature. It is not known to be associated with a disorder of phosphocalcium metabolism or other systemic diseases. Pathogenic hypotheses include calcification of preexisting skin structures, mast cell degranulation with secondary calcinosis, or prior trauma. Surgical excision with histopathological confirmation is necessary to show the dermal calcium deposits, which are usually amorphous and granular and may be surrounded by a lymphohistiocytic infiltrate or giant cells. Nevertheless, dermatoscopic evaluation can aid in rendering a timely diagnosis by showing these whitish dermal deposits.
 Conclusion: The diagnosis of Winer's nodular calcinosis has always been based on histology, but the dermoscopy described here for the first time is so suggestive that it can be used to save time and exclude other differential diagnoses.

Pathogenesis of chronic chikungunya arthritis: Resemblances and links with rheumatoid arthritis.

Chikungunya virus (CHIKV) infection results from transmission by the mosquito vector. Following an incubation period of 5-7 days, patients develop an acute febrile illness, chikungunya fever (CHIKF), characterized by high fevers, maculopapular rash, headaches, polyarthritis/arthralgias, myalgias, nausea, vomiting, and diarrhea. Joint pain is often severe, and most often involves the hands, the wrists, the ankles, and the metatarsal-phalangeal joints of the feet. Many patients recover within several weeks, but up to 50% develop chronic joint pain and swelling for more than 12 weeks, then we refer to these symptoms as chronic chikungunya arthritis (CCA). The pathogenesis of CCA is not well understood. In this article, we suggest that mesenchymal stem cells (MSCs) may play an important role in this pathogenesis. This heterogeneous group of multipotent cells, morphologically similar to fibroblasts, may undergo epigenetic changes capable of generating aberrant progenies. However, we believe that there is no need for a latent infection. In our pathogenic hypothesis, CHIKV infection of MSCs would cause epigenetic changes both in MSCs themselves and in their progenies, without the need for reactivation of dormant viruses.

Sirenomelia

Sirenomelia is a rare and fatal congenital defect characterized by varying degrees of lower limb fusion, thoracolumbar spinal anomalies, sacrococcygeal agenesis, genitourinary, and anorectal atresia.There is a strong association with maternal diabetes where relative risk is 1:200-250 and up to 22% of fetuses with this anomaly will have mothers with diabetes.A 34-year-old unbooked G3P2L2 at 35 weeks 5 days of gestational age with previous two live vaginal birth was admitted in the labor room with pain in the abdomen. She had no history of prior antenatal care and belonged to a tribal community with lower socioeconomic status.She was otherwise healthy with no known history of genetic or congenital anomaly in her family. Baby not cried after birth , no activity and hypotonia present . Immediately intubated with ET NO 3 and bag and tube ventilation given and shifted to NICU and put on ACMV mode of ventilationAnomalies observed in sirenomelia are described as the most severe form of caudal regression syndrome. Fusion of the lower extremities, presence of single umbilical and persistent vitelline artery are major features of sirenomelia . Although the primary molecular defect resulting in sirenomelia remains unclear, two main pathogenic hypotheses namely the vascular steal hypothesis and the defective blastogenesis hypothesis are proposed.Sirenomelia is a rare and lethal congenital anomaly. When diagnosed antenatally, termination should be offered. However, prevention is possible and should be the goal.

Respiratory morbidity in children with tracheoesophageal fistula

: Tracheoesophageal fistula (TEF) is a common congenital anomaly of the respiratory tract that can be isolated or associated to malformations of the digestive tract. The defective lateral septation of the foregut during the embryonic period is the most commonly accepted pathogenic hypothesis. Respiratory morbidity may recognize multiple aetiologies in TEF affected children. Indeed, associated airway abnormalities, tracheomalacia and bronchomalacia, airways hyperreactivity, iatrogenic laryngeal nerve damage and gastroesophageal reflux (GER) contribute to the onset of respiratory complaints. Symptoms onset (cough and cyanosis during feeding, barky cough, wheeze, asthma on exertion, inhalation pneumonia) is variable and the diagnosis is often not straightforward. Combined flexible bronchoscopy and digestive endoscopy are the main diagnostic modalities, supplanted by radiographic modalities especially CT scans of the chest. Fistula ligation or endoscopic repair by using tissue or fibrin adhesive are commonly employed. Because of the association of TEF with abnormalities involving other organs and systems, a multidisciplinary approach should be considered in the management of children with TEF. Although respiratory problems are more frequent during childhood, they tend to persist into adulthood. Therefore, transition of care from paediatric to adult services is imperative.

The enigma of vascular depression in old age: a critical update.

Depression is common in older individuals and is associated with high disability and increased mortality, yet the factors predicting late-life depression (LLD) are poorly understood. The relationship between of depressive disorder, age- and disease-related processes have generated pathogenic hypotheses and provided new treatment options. LLD syndrome is often related to a variety of vascular mechanisms, in particular hypertension, cerebral small vessel disease, white matter lesions, subcortical vascular impairment, and other processes (e.g., inflammation, neuroimmune regulatory dysmechanisms, neurodegenerative changes, amyloid accumulation) that may represent etiological factors by affecting frontolimbic and other neuronal networks predisposing to depression. The "vascular depression" hypothesis suggests that cerebrovascular disease (CVD) and vascular risk factors may predispose, induce or perpetuate geriatric depressive disorders. It is based on the presence of various cerebrovascular risk factors in many patients with LLD, its co-morbidity with cerebrovascular lesions, and the frequent development of depression after stroke. Other findings related to vascular depression are atrophy of the medial temporal cortex or generalized cortical atrophy that are usually associated with cognitive impairment. Other pathogenetic hypotheses of LLD, such as metabolic or inflammatory ones, are briefly discussed. Treatment planning should consider there may be a modest response to antidepressants, but several evidence-based and novel treatment options for LLD exist, such as electroconvulsive therapy, transcranial magnetic stimulation, neurobiology-based psychotherapy, as well as antihypertension and antiinflammatory drugs. However, their effectiveness needs further investigation, and new methodologies for prevention and treatment of depression in older individuals should be developed.

Pathogenic Mechanism of Autoimmune Diabetes Mellitus in Humans: Potential Role of Streptozotocin-Induced Selective Autoimmunity against Human Islet β-Cells.

Human type 1 diabetes mellitus is a chronic autoimmune disease characterized by the selective loss of insulin-producing β-cells in pancreatic islets of genetically susceptible individuals. In this communication, a new hypothesis is postulated which is based on the observations that streptozotocin (STZ), a chemically reactive and cytotoxic compound produced by certain gram-positive bacteria, can be preferentially taken up into islet β-cells and induce cytotoxicity and autoimmunity. It is hypothesized that humans might be occasionally exposed to STZ through opportunistic infections with the STZ-producing bacteria and/or through ingestion of certain food products that contain STZ. In addition, the potential presence of the STZ-producing bacteria in the gut microbiota of some individuals might be another source of long-term STZ exposure. Because of the high chemical reactivity of STZ and its breakdown products, these chemicals can covalently modify certain cellular macromolecules (e.g., DNA and proteins), and the covalently modified cellular components would serve as new antigens, potentially capable of inducing both humoral and cellular autoimmune responses in the islets of certain individuals. In addition to STZ exposure, the eventual development of autoimmunity against STZ-exposed islet β-cells also depends critically on the genetic predisposition of the susceptible individuals plus the opportunistic presence of a conducive, strong environmental trigger, which often is presented as severe febrile viral infections subsequently inducing strong aberrant reactions of the body’s immune system. The proposed pathogenic hypothesis is supported by a considerable body of direct and indirect evidence from laboratory animal studies and clinical observations. Certainly, more experimental and clinical studies are needed to carefully further examine each of the key components of the proposed pathogenic hypothesis.

Coexistence D’un Lymphome Lymphocytique Et D’une Leucémie Myéloïde Chronique: A Propos De Deux Observations Au Togo

This paper reported two cases of lymphocytic lymphoma associated with chronic myeloid leukemia (CML) in Togo. The first association is a simultaneous coexistence of a CML with the presence of the transcript bcr-abl, in a 32-year-old woman, at chronic myelocytic stage with polyadenopathy required and lymph node biopsy concluded for lymphocytic lymphoma. The second is the case of a 30-year-old man who developed a lymphocytic lymphoma after 6years and 5 months of following CML. These two cases are comparable to other associations of acute or chronic myeloid and lymphoid blood malignancies that was previously published. Several pathogenic hypothesis were reviewed which takes responsibility for chemotherapy. Nevertheless, the diagnosis is sometimes simultaneous with the involvement of cellular oncogenes. This is a more likely clonal abnormality of the stem cell sequentially or concomitantly expressed in the cells on both lineages. To the best of our knowledge, these are the first descriptions in South-Saharan Africa.

Pathomechanisms of Vascular Depression in Older Adults.

Depression in older individuals is a common complex mood disorder with high comorbidity of both psychiatric and physical diseases, associated with high disability, cognitive decline, and increased mortality The factors predicting the risk of late-life depression (LLD) are incompletely understood. The reciprocal relationship of depressive disorder and age- and disease-related processes has generated pathogenic hypotheses and provided various treatment options. The heterogeneity of depression complicates research into the underlying pathogenic cascade, and factors involved in LLD considerably differ from those involved in early life depression. Evidence suggests that a variety of vascular mechanisms, in particular cerebral small vessel disease, generalized microvascular, and endothelial dysfunction, as well as metabolic risk factors, including diabetes, and inflammation that may induce subcortical white and gray matter lesions by compromising fronto–limbic and other important neuronal networks, may contribute to the development of LLD. The “vascular depression” hypothesis postulates that cerebrovascular disease or vascular risk factors can predispose, precipitate, and perpetuate geriatric depression syndromes, based on their comorbidity with cerebrovascular lesions and the frequent development of depression after stroke. Vascular burden is associated with cognitive deficits and a specific form of LLD, vascular depression, which is marked by decreased white matter integrity, executive dysfunction, functional disability, and poorer response to antidepressive therapy than major depressive disorder without vascular risk factors. Other pathogenic factors of LLD, such as neurodegeneration or neuroimmune regulatory dysmechanisms, are briefly discussed. Treatment planning should consider a modest response of LLD to antidepressants, while vascular and metabolic factors may provide promising targets for its successful prevention and treatment. However, their effectiveness needs further investigation, and intervention studies are needed to assess which interventions are appropriate and effective in clinical practice.

History of Preeclampsia in Patients Undergoing a Kidney Biopsy: A Biphasic, Multiple-Hit Pathogenic Hypothesis

IntroductionIt is not fully elucidated whether preeclampsia (PE) is a marker or a cause of chronic kidney disease (CKD). To test the hypothesis of a biphasic relationship between PE and CKD, we assessed PE prevalence in women who underwent a kidney biopsy.MethodsThis retrospective, observational study recruited patients who underwent a kidney biopsy after delivery in 2014 to 2019 in 3 Italian Centers (Cagliari, Bari, Messina); low-risk pregnancies observed in Cagliari served as controls. A history of PE was assessed on the clinical charts and by phone interview.ResultsIn the biopsy cohort (379 pregnancies, 205 patients; 38 PE in 32 patients), kidney biopsy shows clustering in the first 5 years after PE (11 of 32). Pre-existing CKD was detected in 8 of 11 of these cases. Focal-segmental glomerulosclerosis (FSGS) and complex lesions were found in 12 of 32 biopsies. The odds ratio (OR) of having had a PE episode, compared with 561 low-risk pregnancies, was 10.071 (95% CI: 4.859–20.875; P < 0.001); multiparity maintained a protective effect (OR: 0.208). The delivery-to-biopsy time was significantly shorter in women with PE, both considering the first or the last PE versus the first or last delivery in patients with or without PE episodes. The characteristics of PE did not differ as compared with low-risk controls.ConclusionWithin the limitation of the retrospective design, our study, quantifying the association between needing a kidney biopsy and history of PE, suggests a biphasic pattern, with a peak in the first 5 years after delivery (probably due to pre-existing diseases) and a later increase, suggesting that PE may have later played as one hit in a multiple-hit pathogenesis.

InpherNet accelerates monogenic disease diagnosis using patients’ candidate genes’ neighbors

PurposeRoughly 70% of suspected Mendelian disease patients remain undiagnosed after genome sequencing, partly because knowledge about pathogenic genes is incomplete and constantly growing. Generating a novel pathogenic gene hypothesis from patient data can be time-consuming especially where cohort-based analysis is not available. MethodsEach patient genome contains dozens to hundreds of candidate variants. Many sources of indirect evidence about each candidate may be considered. We introduce InpherNet, a network-based machine learning approach leveraging Monarch Initiative data to accelerate this process. ResultsInpherNet ranks candidate genes based on orthologs, paralogs, functional pathway members, and colocalized interaction partner gene neighbors. It can propose novel pathogenic genes and reveal known pathogenic genes whose diagnosed patient-based annotation is missing or partial. InpherNet is applied to patient cases where the causative gene is incorrectly ranked low by clinical gene-ranking methods that use only patient-derived evidence. InpherNet correctly ranks the causative gene top 1 or top 1–5 in roughly twice as many cases as seven comparable tools, including in cases where no clinical evidence for the diagnostic gene is in our knowledgebase. ConclusionInpherNet improves the state of the art in considering candidate gene neighbors to accelerate monogenic diagnosis.

Cell Line Platforms Support Research into Arthropod Immunity.

Simple SummaryMany insect and tick species are serious pests, because insects damage crop plants and, along with ticks, transmit a wide range of human and animal diseases. One way of controlling these pests is by impairing their immune system, which protects them from bacterial, fungal, and viral infections. An important tool for studying immunity is using long-lasting cell cultures, known as cell lines. These lines can be frozen and thawed at will to be used in automated tests, and they provide consistent results over years. Questions that can be asked using cell lines include: How do insects or ticks recognize when they have been infected and by what organism? What kinds of defensive strategies do they use to contain or kill infectious agents? This article reviews research with insect or tick cell lines to answer these questions, as well as other questions relating to immunity. This review also discusses future research strategies for working with cell lines.Innate immune responses are essential to maintaining insect and tick health and are the primary defense against pathogenic viruses, bacteria, and fungi. Cell line research is a powerful method for understanding how invertebrates mount defenses against pathogenic organisms and testing hypotheses on how these responses occur. In particular, immortal arthropod cell lines are valuable tools, providing a tractable, high-throughput, cost-effective, and consistent platform to investigate the mechanisms underpinning insect and tick immune responses. The research results inform the controls of medically and agriculturally important insects and ticks. This review presents several examples of how cell lines have facilitated research into multiple aspects of the invertebrate immune response to pathogens and other foreign agents, as well as comments on possible future research directions in these robust systems.

Synthesis of the Data on COVID-19 Skin Manifestations: Underlying Mechanisms and Potential Outcomes.

The incidence of coronavirus disease 2019 (COVID-19)-related skin manifestations has progressively grown, in parallel with the global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreading. The available evidence indicates that cutaneous signs are heterogeneous and can be divided as follows: a) erythematous rashes, b) lesions of vascular origin, c) vesicular rashes, d) urticarial rashes, and e) acute generalized exanthematous pustulosis (AGEP), erythema multiforme (EM) and other polymorphic/atypical reactions. Most cutaneous manifestations appear simultaneously or after respiratory and/or systemic symptoms such as fever, even if rarely urticaria has been reported as the first sign of the disease. It has been proposed that erythematous and vesicular rashes, as well as urticaria, are the result of immunological activation against Sars-CoV-2, similarly to other viral exanthems; alternatively, reactivation or co-infection of herpesviruses and drug hypersensitivity represent possible etiologic diagnosis that has to be considered. Regarding lesions of vascular origin, ischemic ones are the result of systemic hypercoagulability established in severe infections, whereas chilblains seem to be linked to the type I-interferon massively produced to halt virus replication. AGEP is triggered by drugs, whereas EM could represent a delayed immune response to the virus or a hypersensitivity reaction to drugs elicited by the inflammatory process built to fight the infection. A further pathogenic hypothesis is that the virus, or its particles detected in the skin (particularly in endothelium and eccrine glands), could be responsible for certain skin reactions, including chilblains and EM. From the available data, it appears that chilblains are correlated with younger age and less severe disease, while ischemic manifestations occur in the elderly with severe infection. In conclusion, larger studies are needed to confirm the suggested pathogenetic mechanisms of COVID-19-related skin reactions and to determine the potential prognostic significance of each one.

A Review on the Mechanism Between Different Factors and the Occurrence of Autism and ADHD.

The incidence of neurodevelopmental disorders especially in children has been on the rise in recent decades, which is possibly caused by many different factors. In order to further explain this situation and arouse enough attention, this review will specifically elaborate genetic aspects and pathogenic hypothesis of these two kinds of neurodevelopmental diseases in children, autism and attention deficit hyperactivity disorder (ADHD) while analyzing the relationship between different environmental toxins and these two disorders. The effects of these pathogenic factors such as heavy metal lead, mercury, polyvinyl chloride (PVC) and polychlorinated biphenyls (PCBs) and their strong pathogenicity will be explained in detail through literature data retrieval and analysis. In addition, other neurotransmitter such as norepinephrine (NE) and serotonin (5-HT) signaling factors coming down to these two neurodevelopmental disorders and how their abnormal concentration present in the blood as well as the completely opposite results among experimental groups and control group will be elaborated. Furthermore, other high-risk and high-exposure factors may contribute to both diseases, such as alcohol and smoking abuse among parents, air pollutants PM2.5 and PM10 in the environment will also be discussed in the review. Since these environmental toxins and other harmful substances discussed in the paper have been linked to an increasing number of children with autism and ADHD in recent decades, from the medical perspective, this review will put forward certain succinct points to the aspects of minimizing relevant exposure or risks in clinical and daily life, as well as feasible suggestions in public health area for children, parents and prospective parents, to curb the growth of these two diseases in part by raising awareness in the population and reducing unnecessary exposure.

The complexity of Alzheimer's disease: an evolving puzzle.

The history of Alzheimer's disease (AD) started in 1907, but we needed to wait until the end of the century to identify the components of pathological hallmarks and genetic subtypes and to formulate the first pathogenic hypothesis. Thanks to biomarkers and new technologies, the concept of AD then rapidly changed from a static view of an amnestic dementia of the presenium to a biological entity that could be clinically manifested as normal cognition or dementia of different types. What is clearly emerging from studies is that AD is heterogeneous in each aspect, such as amyloid composition, tau distribution, relation between amyloid and tau, clinical symptoms, and genetic background, and thus it is probably impossible to explain AD with a single pathological process. The scientific approach to AD suffers from chronological mismatches between clinical, pathological, and technological data, causing difficulty in conceiving diagnostic gold standards and in creating models for drug discovery and screening. A recent mathematical computer-based approach offers the opportunity to study AD in real life and to provide a new point of view and the final missing pieces of the AD puzzle.