In situ cytokine immune responses in acute disseminated encephalomyelitis: insights into pathophysiologic mechanisms

Acute disseminated encephalomyelitis (ADEM) is thought to be an autoimmune disorder of the central nervous system in which myelin is targeted. Pathological studies on closely related human diseases (eg, multiple sclerosis) and on animal models for these demyelinating disorders have suggested the involvement of cytokines. Studies on peripheral immunocytes and on cerebrospinal fluid revealed the presence of cytokine-mediated responses in ADEM. We carried out this neuroimmunopathologic exploration and report for the first time the in situ expression of "inflammatory" cytokines in ADEM. Moreover, we note a particular spatial and molecular pattern whereby tumor necrosis factor-alpha and interleukin (IL)-1beta are intensely expressed, whereas IL-6 is absent. Differential expression at different levels of the neuraxis was also noticed. Our findings suggest that these cytokines, reported to be toxic to myelin, are implicated in the molecular cascade, resulting in the neural damage. These observations might provide insights into molecular pathways involved in the immunopathogenesis of ADEM and might open new horizons in neuroimmunomodulation and anticytokine treatment.     

Cough and angioedema from angiotensin-converting enzyme inhibitors: new insights into mechanisms and management

PURPOSE OF REVIEW: Angiotensin-converting enzyme inhibitors are widely prescribed for hypertension and heart failure. These drugs are commonly associated with cough, and are less commonly associated with angioedema, which may be potentially life threatening. This review describes data that extend our understanding of the mechanisms of these reactions, and provides guidance about clinical management. RECENT FINDINGS: For patients who develop angioedema from angiotensin-converting enzyme inhibitors, recent data are reassuring that the majority of such patients can tolerate angiotensin-II receptor blockers. These data support earlier conclusions that most patients with angiotensin-converting enzyme inhibitor-induced cough can tolerate angiotensin-II receptor blockers. Limited case reports suggest that in acute angioedema induced by angiotensin-converting enzyme inhibitors, patients refractory to standard treatment may benefit from the infusion of fresh frozen plasma. SUMMARY: Although data are incomplete, it appears that angiotensin-converting enzyme inhibitors cause cough and angioedema through a cascade of effects that begins with the accumulation of kinins, and then involves arachidonic acid metabolism and nitric oxide generation. Most patients who develop either cough or angioedema from angiotensin-converting enzyme inhibitors can tolerate angiotensin-II receptor blocking agents.     

A model for cardiomyocyte cell death: Insights into mechanisms of oncosis

It is now known that there are at least two basic patterns of cell injury progressing to cell death: cell injury with swelling, known as oncosis, and cell injury with shrinkage, known as apoptosis. Both types of cell death are “programmed” in the sense that the genetic information and many of the enzymes and other factors pre-exist in the cell. Previous investigation has pointed to cardiomyocyte ischemic injury evolving as the oncotic pattern of injury, although apoptosis has also been implicated. This study was designed, using a unique cell model system, to gain insight into the molecular events of anticancer agent-induced cardiomyocyte injury. Cardiomyocytes exposed for 2 h to 1.5 μg/ml sanguinarine consistently displayed the morphology of apoptosis in over 80% of cells, whereas a higher dose of 25 μg/ml at 2 h yielded the pattern of oncosis in over 90% of cells. Microarray analysis revealed altered expression of 2514 probes in sanguinarine-induced oncosis and 1643 probes in apoptosis at a level of significance of p < 0.001. Some of the inductions such as perforin were found to be higher than 11-fold in oncosis. When perforin was blocked by perforin-specific siRNA we found a reduction in oncotic cell death. These results strengthen the notion that oncosis is not representative of nonspecific necrosis, but constitutes a genetically controlled form of “programmed cell death”; and also that oncosis might represent a pathogenetic mechanism of cardiomyocyte injury. This is also the first demonstration of the involvement of perforin in cardiomyocyte oncosis.     

Hereditary vibratory angioedema: Confirmation of histamine release in a type of physical hypersensitivity

A new syndrome called hereditary vibratory angioedema (HVA), characterized by pyruritis and angioedema at the site of a vibratory stimulus, was recently reported as a model of nonimmunologic immediate hypersensitivity. The biochemical mediator of this syndrome was not defined initially. This study now demonstrates that in vivo histamine release occurs in conjunction with the local and systemic clinical manifestations following a controlled vibratory stimulus. Histamine is suggested as the major mediator in this inherited physical hypersensitivity state.     

心力衰竭分子治疗机制探讨

过去的20余年中,由于人们对心力衰竭（心衰）发病的细胞分子机制的理解,并相应制订出了有效的治疗方法,从而使心衰逐渐转变成一种慢性病。但是,心衰尤其是慢性心衰仍然是心源性死亡的主要原因。     

Tumor-related thrombotic pulmonary microangiopathy: review of pathologic findings and pathophysiologic mechanisms

We report a middle-aged woman who died 2 days after presenting with dyspnea and severe pulmonary hypertension of unknown etiology. Her symptoms were highly suggestive of pulmonary embolism, but clinical evaluations for that disease yielded negative results. Autopsy revealed a Krukenberg tumor of the left ovary, representing metastatic gastric carcinoma from an occult primary lesion. Although the lungs exhibited no gross evidence of pulmonary emboli or neoplasia, microscopic examination revealed diffuse microscopic metastases in the pulmonary arterial vasculature. The pulmonary arteries exhibited fibrocellular intimal proliferation with smooth muscle colonization of the luminal neoplastic lesions and associated microthrombi. This disease entity, known as tumor-related thrombotic pulmonary microangiopathy, results in generalized microvascular obliteration and subsequent pulmonary hypertension. It is a rare condition that is distinct from ordinary pulmonary thromboembolism and primary pulmonary hypertension. Tumor-related thrombotic pulmonary microangiopathy should be considered diagnostically by the autopsy pathologist in cases of rapidly evolving pulmonary hypertension in a middle-aged or elderly individual, or respiratory failure of unknown cause, especially if there is a history of a visceral malignancy.     

Insights into molecular mechanisms of contact hypersensitivity gained from gene knockout studies

Contact hypersensitivity (CHS), a dendritic-cell (DC)-dependent, T-cell-mediated skin immune response to reactive haptens, has been a subject of intense research for many years. The molecular mechanisms underlying CHS are complicated and are not fully understood. During the past few years, varieties of gene-targeted knockout mice have been used in the study of CHS. Such studies have contributed significantly to our understanding of the mechanisms responsible for the initiation of CHS. This review focuses on insights into molecular requirements for CHS gained from knockout studies.     

Novel recessive BFSP2 and PITX3 mutations: Insights into mutational mechanisms from consanguineous populations

PurposeDesignating mutations as recessive or dominant is a function of the effect of the mutant allele on the phenotype. Genes in which both classes of mutations are known to exist are particularly interesting to study because these mutations typically define distinct pathogenic mechanisms at the molecular level.MethodsWe studied two consanguineous families with different eye phenotypes and used a combination of candidate gene analysis and homozygosity mapping to identify the underlying genetic defects.ResultsIn one family, a novel BFSP2 mutation causes autosomal recessive diffuse cortical cataract with scattered lens opacities, and in another, a novel PITX3 mutation causes an autosomal recessive severe form of anterior segment dysgenesis and microphthalmia.ConclusionWe show that BFSP2 and PITX3, hitherto known to cause eye defects only in a dominant fashion, can also present recessively. The likely null nature of both mutations and lack of manifestation in heterozygotes strongly argues for a mechanism other than loss of function in the previously reported dominant mutations in these two genes. Thus, study of consanguineous populations has the additional advantage of not only identifying novel recessive genes but also defining the mutational mechanism of dominant disorders.     

Stress and telomere shortening: Insights from cellular mechanisms

Short telomeres confer risk of degenerative diseases. Chronic psychological stress can lead to disease through many pathways, and research from in vitro studies to human longitudinal studies has pointed to stress-induced telomere damage as an important pathway. However, there has not been a comprehensive model to describe how changes in stress physiology and neuroendocrine pathways can lead to changes in telomere biology. Critically short telomeres or the collapse of the telomere structure caused by displacement of telomere binding protein complex shelterin elicit a DNA damage response and lead to senescence or apoptosis. In this narrative review, we summarize the key roles glucocorticoids, reactive oxygen species (ROS) and mitochondria, and inflammation play in mediating the relationship between psychological stress and telomere maintenance. We emphasis that these mediators are interconnected and reinforce each other in positive feedback loops. Telomere length has not been studied across the lifespan yet, but the initial setting point at birth appears to be the most influential point, as it sets the lifetime trajectory, and is influenced by stress. We describe two types of intergenerational stress effects on telomeres – prenatal stress effects on telomeres during fetal development, and ‘telotype transmission” –the directly inherited transmission of short telomeres from parental germline. It is clear that the initial simplistic view of telomere length as a mitotic clock has evolved into a far more complex picture of both transgenerational telomere influences, and of interconnected molecular and cellular pathways and networks, as hallmarks of aging where telomere maintenance is a key player interacting with mitochondria. Further mechanistic investigations testing this comprehensive model of stress mediators shaping telomere biology and the telomere-mitochondrial nexus will lead to better understanding from cell to human lifespan aging, and could lead to anti-aging interventions.     

Current update on cellular and molecular mechanisms of hereditary angioedema

ObjectiveTo provide an update on the molecular mechanisms of hereditary angioedema (HAE).Data SourcesMEDLINE and PubMed databases were searched to identify pertinent articles using the following key terms: hereditary angioedema, angioedema, C1 inhibitor, bradykinin, contact system, factor XII, mechanism, pathophysiology, severity, permeability, and estrogen.Study SelectionsArticles were selected based on their relevance to the subject matter.ResultsAlthough the biochemical basis of “classic” HAE is known to result from C1 esterase inhibitor (C1INH) deficiency, a new form, HAE with normal C1INH, has been identified. HAE types I and II are caused by mutations in the SERPING1 gene that result in decreased plasma levels of functional C1INH. In HAE with normal C1INH, mutations in the F12 gene have been identified in a subset of individuals, but the genetic defect remains unknown in most patients. The primary mediator of swelling in HAE is bradykinin, a product of the plasma contact system that increases vascular permeability. HAE disease severity is highly variable and may be influenced by polymorphisms in other genes and other factors, such as hormones, trauma, stress, and infection.ConclusionHereditary angioedema is a heterogeneous disorder with a complex pathophysiology. Implicated genes include SERPING1 and FXII in patients with HAE from C1INH deficiency and HAE with normal C1INH levels, respectively. Disease severity is highly variable.     

Insights into the uterus

A better understanding of the mechanisms that generate and modulate uterine contractility is needed if progress is to be made in the prevention or treatment of problems in labour. Dysfunctional labour describes the condition when uterine contractility is too poor to dilate the cervix, and it is the leading cause of emergency Caesarean sections. Recently, insight has been gained into a possible causal mechanism for dysfunctional labour. Study of the physiological mechanisms that produce excitation in the uterus, the subsequent Ca(2)(+) signals and biochemical pathway leading to contraction has underpinned this progress. In this review, I give an account of excitation-contraction signalling in the myometrium and explore the implications of recent findings concerning lipid rafts for these processes. I also discuss how changes of pH are fundamentally enmeshed in uterine activity and biochemistry and explore the effect that pH changes will have on human myometrium. Finally, I present the evidence that acidification of the myometrium is correlated with dysfunctional labour and suggest the processes by which it is occurring. It is only by gaining a better understanding of uterine physiology and pathophysiology that progress will be made and research findings translated into clinical benefit for women and their families.     

Urorectal septum malformation sequence: Insights into pathogenesis

We characterize the urorectal septum malformation sequence (URSMS) in discordant fetal lambs and relate it to the human syndromes with which URSMS is associated. We found abnormal external genitalia, imperforate anus, and fistulous connections between the rectum, bladder, and vagina. Discordance among the dizygous twins eliminated teratogens as a likely etiologic factor. We summarize the relevant literature and propose a molecular model for the pathogenesis of the URSMS, in which alterations in sonic hedgehog and homeobox genes lead to caudal mesodermal deficiency during blastogenesis.     

Studies of the mechanisms of bradykinin generation in hereditary angioedema plasma

BACKGROUND: Factor XII-dependent bradykinin formation is thought to be responsible for the swelling associated with the various forms of C1 inhibitor deficiency, and complement activation is augmented during attacks of swelling. OBJECTIVES: To further elucidate the interactions of the kinin-forming cascade that lead to complement activation during attacks of swelling and to determine whether fibrinolysis is augmented as well. METHODS: We compared spontaneous and kaolin-induced activation of normal plasma with the plasma of patients with hereditary angioedema. RESULTS: Hereditary angioedema plasma demonstrated augmented factor XII activation, production of factor XIIf, prekallikrein activation, and high-molecular-weight kininogen cleavage, and, as a result, bradykinin formation was markedly increased. Baseline levels of C4a and plasmin-alpha 2 antiplasmin complexes increased, and, on activation with kaolin, levels increased further. CONCLUSIONS: All parameters indicative of activation of the bradykinin-forming cascade are activated in hereditary angioedema plasma vs normal plasma. Production of factor XIIf, demonstrated for the first time in whole plasma, may be responsible for C1 activation based on C4a production. The factor XII-dependent fibrinolytic cascade is also activated.     

New Insights into Disintegrin Metalloproteases

Inflammation Research -