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Parkinson’s disease has been recently redefined clinically and its underlying molecular biology determined. Although it is a neurodegenerative disease, loss of neurons is largely focal rather than large scale; symptoms are caused more by neurochemical deficits and dysfunctional cells than cell loss. The two main pathologic features are loss of dopamine neurons in the substantia nigra of the midbrain and the more widespread aggregation of a-synuclein in certain vulnerable neurons in the brain. Several triggers can cause the molecular cascade that kills dopamine neurons and makes the a-synuclein protein fibrilize and aggregate initially in brainstem neurons, including genetic variants and post-translational modification of the protein. The disease is slowly progressive with the propagation of aggregates from vulnerable synapses to the entire neuron, then from one neuron to other neurons and glial cells. Different propagation mechanisms have been identified for these different brain cells that work in concert to sustain the slow disease process. Current therapeutic delivery of dopamine or deep brain stimulation temporarily relieve the symptoms with disease-modifying treatments now able to be trialled due to identifying the underlying molecular biology.
It is estimated that more than one-tenth of adults aged ≥60 years are now classified as having sarcopenic obesity (SO), a clinical condition characterised by the concurrent presence of sarcopenia (low muscle mass and weakness) and obesity (excessive fat mass). Independently, sarcopenia and obesity are associated with a high risk of numerous adverse health outcomes including CVD and neurological conditions (e.g. dementia), but SO may confer a greater risk, exceeding either condition alone. This imposes a substantial burden on individuals, healthcare systems and society. In recent years, an increasing number of observational studies have explored the association between SO and the risk of CVD; however, results are mixed. Moreover, the pathophysiology of SO is governed by a complex interplay of multiple mechanisms including insulin resistance, inflammation, oxidative stress, hormonal shifts and alteration of energy balance, which may also play a role in the occurrence of various CVD. Yet, the exact mechanisms underlying the pathological connection between these two complex conditions remain largely unexplored. The aim of this review is to examine the association between SO and CVD. Specifically, we seek to: (1) discuss the definition, epidemiology and diagnosis of SO; (2) reconcile previously inconsistent findings by synthesising evidence from longitudinal studies on the epidemiological link between SO and CVD and (3) discuss critical mechanisms that may elucidate the complex and potentially bidirectional relationships between SO and CVD.
We examined whether cannabis use contributes to the increased risk of psychotic disorder for non-western minorities in Europe.
Methods
We used data from the EU-GEI study (collected at sites in Spain, Italy, France, the United Kingdom, and the Netherlands) on 825 first-episode patients and 1026 controls. We estimated the odds ratio (OR) of psychotic disorder for several groups of migrants compared with the local reference population, without and with adjustment for measures of cannabis use.
Results
The OR of psychotic disorder for non-western minorities, adjusted for age, sex, and recruitment area, was 1.80 (95% CI 1.39–2.33). Further adjustment of this OR for frequency of cannabis use had a minimal effect: OR = 1.81 (95% CI 1.38–2.37). The same applied to adjustment for frequency of use of high-potency cannabis. Likewise, adjustments of ORs for most sub-groups of non-western countries had a minimal effect. There were two exceptions. For the Black Caribbean group in London, after adjustment for frequency of use of high-potency cannabis the OR decreased from 2.45 (95% CI 1.25–4.79) to 1.61 (95% CI 0.74–3.51). Similarly, the OR for Surinamese and Dutch Antillean individuals in Amsterdam decreased after adjustment for daily use: from 2.57 (95% CI 1.07–6.15) to 1.67 (95% CI 0.62–4.53).
Conclusions
The contribution of cannabis use to the excess risk of psychotic disorder for non-western minorities was small. However, some evidence of an effect was found for people of Black Caribbean heritage in London and for those of Surinamese and Dutch Antillean heritage in Amsterdam.
This chapter provides a basic introduction to virology, dealing with the history of viruses, taxonomy, virus replication stages (attachment, entry, uncoating, transcription, translation, assembly and release). It also deals with the immune response to viruses, including innate immune response, adaptive immunity, cell-mediated response, antibody-mediated response, viral pathogenesis, viral tropisms, viral spread, viral persistence, viral virulence and host factors.
Shaken baby syndrome (SBS) is well accepted by child abuse paediatricians as an explanation for the triad when parents/caregivers can provide no explanation. There is mounting evidence on many fronts that SBS is not a valid or well-defined diagnosis, and that many cases of SBS have medical causes or are from accidental short falls. An incorrect SBS diagnosis has far-reaching implications for the alleged perpetrator, the family, the child, and society. The three most compelling reasons to doubt the existence of SBS are: multiple biomechanical studies show that shaking cannot produce nearly the forces needed to cause the triad; sutopsy studies of most infants with alleged SBS do not show microscopic findings of trauma, but rather of hypoxia; retinal hemorrhages - once thought pathognomonic of shaking through vitreous retraction - are seen wherever there is an abrupt and significant rise in intracranial pressure and are highly unlikely to be caused by shaking. This review also provides observations that question the existence of SBS and the underlying psychological reasons why SBS proponents do not accept the compelling evidence that puts the diagnosis of SBS into question.
Timothy syndrome (TS), characterised by multiple system malfunction especially the prolonged corrected QT interval and synchronised appearance of hand/foot syndactyly, is an extremely rare disease affecting early life with devastating arrhythmia. In this work, firstly, the various mutations in causative gene CACNA1C encoding cardiac L-type voltage-gated calcium channel (LTCC), regard with the genetic pathogeny and nomenclature of TS are reviewed. Secondly, the expression profile and function of CACNA1C gene encoding Cav1.2 proteins, and its gain-of-function mutation in TS leading to multiple organ disease phenotypes especially arrhythmia are discussed. More importantly, we focus on the altered molecular mechanism underlying arrhythmia in TS, and discuss about how LTCC malfunction in TS can cause disorganised calcium handling with excessive intracellular calcium and its triggered dysregulated excitation–transcription coupling. In addition, current therapeutics for TS cardiac phenotypes including LTCC blockers, beta-adrenergic blocking agents, sodium channel blocker, multichannel inhibitors and pacemakers are summarised. Eventually, the research strategy using patient-specific induced pluripotent stem cells is recommended as one of the promising future directions for developing therapeutic approaches. This review updates our understanding on the research progress and future avenues to study the genetics and molecular mechanism underlying the pathogenesis of devastating arrhythmia within TS, and provides novel insights for developing therapeutic measures.
In the present world a significant threat to human health is posed by zoonotic diseases. Helminth parasites of ruminants are one of the most common zoonotic organisms on the planet. Among them, trichostrongylid nematodes of ruminants, found worldwide, parasitize humans in different parts of the world with varying rates of incidence, particularly among rural and tribal communities with poor hygiene, pastoral livelihood and poor access to health services. In the Trichostrongyloidea superfamily, Haemonchus contortus, Teladorsagia circumcincta, Marshallagia marshalli, Nematodirus abnormalis and Trichostrongylus spp. are zoonotic in nature. Species of the genus Trichostrongylus are the most prevalent gastrointestinal nematode parasites of ruminants that transmit to humans. This parasite is prevalent in pastoral communities around the world and causes gastrointestinal complications with hypereosinophilia which is typically treated with anthelmintic therapy. The scientific literature from 1938 to 2022 revealed the occasional incidence of trichostrongylosis throughout the world with abdominal complications and hypereosinophilia as the predominant manifestation in humans. The primary means of transmission of Trichostrongylus to humans was found to be close contact with small ruminants and food contaminated by their faeces. Studies revealed that conventional stool examination methods such as formalin-ethyl acetate concentration or Willi's technique combined with polymerase chain reaction-based approaches are important for the accurate diagnosis of human trichostrongylosis. This review further found that interleukin 33, immunoglobulin E, immunoglobulin G1, immunoglobulin G2, immunoglobulin M, histamine, leukotriene C4, 6-keto prostaglandin F1α, and thromboxane B2 are vital in the fight against Trichostrongylus infection with mast cells playing a key role. This review focuses on the prevalence, pathogenicity and immunological aspects of Trichostrongylus spp. in humans.
During your call duty, a 29-year-old primigravida at 19+2 weeks’ gestation by early ultrasound dating presents to the obstetrics emergency assessment unit of your hospital center with a one-week history of dyspnea. She has not refilled her asthma treatments, as she was busy changing residences. The patient converses well, without signs of distress.
During your call duty, a healthy 40-year-old primigravida with a spontaneous dichorionic pregnancy presents, accompanied by her husband, to the obstetric emergency assessment unit of your hospital center at 33+1 weeks’ gestation with new-onset abdominal pain and vomiting after a two-day history of nausea and general malaise. She has no obstetric complaints, and fetal viabilities are ascertained upon presentation. Her face appears yellow tinged relative to her last clinical visit one week ago. You recall that routine prenatal laboratory investigations, aneuploidy screening, morphology surveys of the male fetuses, and serial sonograms have all been unremarkable.
Microorganisms distributed in our tissues and fluids make up the human microbiota. During our lifetime, gastrointestinal microbiota acts as an important modulator of brain development and, in turn, adult behavior and health. Immune response may be triggered by gut microbiota, releasing mediators that penetrate the blood-brain barrier (BBB).
Objectives
Understanding if gut microbiota can influence schizophrenia pathogenesis. Clarifying how gut microbiota can influence schizophrenia treatment, and vice-versa.
Methods
PubMed database search, with “gut microbiota and schizophrenia” keyword expression. Eight articles published in the last ten years were selected among the most recent best match results. Reference lists of articles were reviewed to identify additional articles.
Results
There could be an association between the development of gut microbiota starting during pregnancy and schizophrenia pathogenesis, through an immune-mediated process. Schwarz et al. (2018) investigated the differences in faecal microbiota between individuals with first-episode psychosis and controls. They found psychotic patients to have an increased amount of Lactobacillus bacteria. Yuan et al. (2018) studied microbiota changes in patients with schizophrenia, before and after treatment. Individuals diagnosed with schizophrenia had less faecal Bifidobacterium, Escherichia coli and Lactobacillus. After treatment with risperidone, there was a significant increase in the amount of fecal Bifidobacterium and E. Coli.
Conclusions
Microorganisms living inside our gastrointestinal tract are vital for proper central nervous system (CNS) development. Patients with schizophrenia have anomalies in the composition of the microbiota. It remains unclear if microbiota changes after treatment further influence the course of the disease.
Necrotic enteritis (NE), caused by Clostridium perfringens (CP), is one of the most common of poultry diseases, causing huge economic losses to the poultry industry. This review provides an overview of the pathogenesis of NE in chickens and of the interaction of CP with the host immune system. The roles of management, nutrition, probiotics, and vaccination in reducing the incidence and severity of NE in poultry flocks are also discussed.
Endometriosis is a chronic oestrogen-dependent condition that affects 10% of women from puberty to menopause. It is characterised by the presence and proliferation of endometrial-like cells outside the uterine cavity, generally within the pelvis. Endometriosis can present as superficial or deep peritoneal lesions, ovarian endometrioma or deep rectovaginal disease. The two hallmark symptoms of endometriosis are pelvic pain and infertility resulting in poor quality of life. There is no correlation between the extent of the disease and severity of symptoms. The true prevalence of the condition is not known, as it requires a laparoscopy to confirm the diagnosis. It is found in up to 30% of women with infertility and in 45% of those with pelvic pain. While there are several theories of pathogenesis, an interplay of genetic, hormonal, environmental and immunological factors is implicated in the development of endometriosis in susceptible women. Symptoms are managed with a combination of hormonal treatment and laparoscopic ablation or excision of lesions for pain and usually assisted reproduction for infertility. Endometriosis is prone to recurrence after treatment, requiring multiple contacts with healthcare and repeat surgery. Management of endometriosis requires an individualised approach based on the woman’s age, predominant symptoms and priorities, which are subject to change over time.
The bone marrow (BM) is a frequent site of haematogenous spread for all types of cancer. Metastatic spread of disseminated tumour cells (DTCs) to the BM is detected in 0.2 to 12% of patients with solid tumours [1]. The variability in incidence is related to the incidence of the primary tumour and its homing behaviour [2]. Common primary tumours affecting the BM are listed below (Table 17.1).
It was reported that about 10% of people suffer from painful knee arthritis, and a quarter of them were severely disabled. The core activities of daily living were severely limited by knee osteoarthritis (KOA). In order to reduce knee pain and prolong the life of the knee joint, there has been an increasing demand on the development of exoskeletons, for prevention and treatment. The course of KOA was closely related to the biomechanics of knee joint, and the pathogenesis was summarized based on the biomechanics of knee joint. For the prevention and clinical treatment, exoskeletons are classified into three categories: prevention, treatment, and rehabilitation after the operation. Furthermore, the design concepts, actuators, sensors, control strategies, and evaluation criteria were presented. Finally, the shortcomings and limitations were summarized. It is useful for researchers to develop suitable exoskeletons in the future.
Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare tumor-like lesion with unknown pathogenesis. It is likely under-reported due to diagnostic challenges including the nonspecific radiographic features, lack of diagnostic markers, and often asymptomatic nature of the lesions.
Methods:
We performed detailed examination of 11 CAPNON specimens diagnosed by histopathology, with the help of electron microscopy and immunohistochemistry.
Results:
Electron microscopy revealed the presence of fibrillary materials consistent with neurofilaments. In addition to some entrapped axons at the periphery of CAPNONs, we discovered that all specimens stained positive for neurofilament-light (NF-L) within the granular amorphous cores, but not neurofilament-phosphorylated (NF-p). CAPNONs also showed variable infiltration of CD8+ T-cells and a decreased ratio of CD4/CD8+ T-cells, suggesting an immune-mediated process in the pathogenesis of CAPNON.
Conclusion:
NF-L and CD4/CD8 immunostains may serve as diagnostic markers for CAPNON and shed light on its pathogenesis.
We have learned a lot about infections of the mammary gland of dairy cows from experimental investigations of the pathogenesis of the various diseases. The understanding gained has contributed to huge successes in reducing the prevalence of infection in properly managed dairy herds. Now descriptive studies using DNA technologies reject previous concepts of mammary gland sterility by default. Bacteria, at least markers of genes, of many genera are reported even from absolutely healthy mammary glands. This may be a technological artefact. No direct evidence exists because experimental studies of infection are no longer fashionable. A regeneration of the lost arts in the pathogenesis of infection is essential to separate truth from conjecture and deal with coming challenges from rapidly changing farm systems and the reduction in access to antimicrobial drugs. In this Opinion Paper I argue for a return to experimental approaches that construct hypotheses, and then test them, in intramammary disease research.
Experiences of childhood trauma (CT) are associated with increased psychological vulnerability. Past research suggests that CT might alter stress processing with a subsequent negative impact on mental health. However, it is currently unclear how different domains of CT exert effects on specific subjective experiences of stress during adulthood.
Methods
In the present study, we used network analysis to explore the complex interplay between distinct domains of CT and perceived stress in a large, general-population sample of middle-aged adults (N = 1252). We used a data-driven community-detection algorithm to identify strongly connected subgroups of items within the network. To assess the replicability of the findings, we repeated the analyses in a second sample (N = 862). Combining data from both samples, we evaluated network differences between men (n = 955) and women (n = 1159).
Results
Results indicate specific associations between distinct domains of CT and perceived stress. CT domains reflecting a dimension of deprivation, i.e. experiences of neglect, were associated exclusively to a stress network community representing low perceived self-efficacy. By contrast, CT associated with threat, i.e. experiences of abuse, was specifically related to a stress community reflecting perceived helplessness. Our results replicated with high accordance in the second sample. We found no difference in network structure between men and women, but overall a stronger connected network in women.
Conclusions
Our findings emphasize the unique role of distinct domains of CT in psychological stress processes in adulthood, implying opportunities for targeted interventions following distinct domains of CT.
Only with the completion of the life cycles of Fasciola hepatica in 1883 and 30 years later those of Schistosoma japonicum (1913), Schistosoma haematobium and Schistosoma mansoni (1915) did research on schistosomiasis really get underway. One of the first papers by Cawston in 1918, describing attempts to establish the means of transmission of S. haematobium in Natal, South Africa, forms the historical perspective against which to judge where we are now. Molecular biology techniques have produced a much better definition of the complexity of the schistosome species and their snail hosts, but also revealed the extent of hybridization between human and animal schistosomes that may impact on parasite adaptability. While diagnostics have greatly improved, the ability to detect single worm pair infections routinely, still falls short of its goal. The introduction of praziquantel ~1982 has revolutionized the treatment of infected individuals and led directly to the mass drug administration programmes. In turn, the severe pathological consequences of high worm burdens have been minimized, and for S. haematobium infections the incidence of associated squamous cell carcinoma has been reduced. In comparison, the development of effective vaccines has yet to come to fruition. The elimination of schistosomiasis japonica from Japan shows what is possible, using multiple lines of approach, but the clear and present danger is that the whole edifice of schistosome control is balanced on the monotherapy of praziquantel, and the development of drug resistance could topple that.
The CXCR3 chemokine CXCL10 or IFN-γ inducible protein 10 (IP-10) has been identified as an important biomarker of cerebral malaria (CM) mortality in children. Studies in mouse malaria infection models have shown that CXCL10 blockade alleviates brain intravascular inflammation and protects infected mice from CM. Despite the key role that CXCL10 plays in the development of CM, the leucocytic sources of CXCL10 in response to human malaria are not known. Here we investigated CXCL10 responses to Plasmodium falciparum in peripheral blood mononuclear cells (PBMCs). We found that PBMCs from malaria-unexposed donors produce CXCL10 in response to P. falciparum and that this response is IFN-γ-dependent. Moreover, CD14+ monocytes were identified as the main leucocytic sources of CXCL10 in peripheral blood, suggesting an important role for innate immune responses in the activation of this pathway involved in the development of symptomatic malaria.