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PubMed2000

Pathogenesis and progression of human pancreatic fibrosis.

Fibrosis of the pancreas is one of the representative histopathological findings in cases of chronic pancreatitis. The pathogenesis and progression of pancreatic fibrosis are not yet fully understood. In this article, the pathogenesis, mechanism, and progression of pancreatic fibrosis are briefly reviewed based on our previous and most recent reports. Pancreatic fibrosis was classified into interlobular and intralobular types. In chronic alcoholic pancreatitis cases, fibrosis was mainly found in the interlobular, or perilobular, areas in a form of nodular pancreatitis. As for the mechanism of interlobular fibrosis, incomplete obstruction of the pancreatic duct and the appearance of the cells expressing alpha-smooth muscle actin, which is a marker for myofibroblasts, played an important role. In contrast, in intralobular fibrosis, alcohol intake was shown to have an effect in the initial stage of periacinar collagenization through the activation of myofibroblasts and severe damage to acinar cells. Progression of fibrosis occurred due to both duct obstruction and interlobular fibrosis admixed with myofibroblast proliferation. Therefore, myofibroblasts play an important role in both the mechanism and progression of pancreatic fibrosis.

Fibrosis↗
PubMed2001

Pathogenesis of acne.

Acne vulgaris is a skin disorder of the sebaceous follicles that commonly occurs in adolescence and in young adulthood. The major pathogenic factors involved are hyperkeratinization, obstruction of sebaceous follicles resulting from abnormal keratinization of the infundibular epithelium, stimulation of sebaceous gland secretion by androgens, and microbial colonization of pilosebaceous units by Propionibacterium acnes, which promotes perifollicular inflammation. The clinical presentation of acne can range from a mild comedonal form to severe inflammatory cystic acne of the face, chest, and back. At the ultrastructural level, follicular keratinocytes in comedones can be seen to possess increased numbers of desmosomes and tonofilaments, which result in ductal hypercornification. The increased activity of sebaceous glands elicited by androgen causes proliferation of P. acnes, an anaerobe present within the retained sebum in the pilosebaceous ducts. The organism possesses a ribosome-rich cytoplasm and a relatively thick cell wall, and produces several biologically active mediators that may contribute to inflammation, for instance, by promoting leukocyte migration and follicular rupture. In inflamed lesions, numerous neutrophils and macrophages infiltrate around hair follicles and sometimes phagocytose P. acnes. To examine the participation of neurogenic factors in the pathogenesis of acne, we quantitatively assessed the effects of neuropeptides on the morphology of sebaceous glands in vitro using electron microscopy. Substance P, which can be elicited by stress, promoted the development of cytoplasmic organelles in sebaceous cells, stimulated sebaceous germinative cells, and induced significant increases in the area of sebaceous glands. It also increased the size of individual sebaceous cells and the number of sebum vacuoles for each differentiated sebaceous cell, all of which suggests that substance P promotes both the proliferation and the differentiation of sebaceous glands. In this review, we introduce the general concept of pathogenic factors involved in acne, including typical electron microscopic findings and recent evidence of stress-induced exacerbation of acne from a neurological point of view. An improved understanding of the pathogenesis of acne should lead to a rational therapy to successfully treat this skin disease.

Acne Vulgaris↗
PubMed2004

Genetic and environmental factors in the pathogenesis of Huntington's disease.

Huntington's disease is a fatal inherited disorder in which there is progressive neurodegeneration in specific brain areas, mainly the striatum and cerebral cortex, producing motor, cognitive, and psychiatric symptoms. The trinucleotide repeat mutation involved is common to many other brain diseases, which may therefore involve similar mechanisms of pathogenesis. We are beginning to understand how a CAG trinucleotide repeat expansion in the disease gene, encoding an expanded polyglutamine tract, induces neuronal dysfunction and symptomatology in Huntington's disease. Recent evidence that environmental factors modify the onset and progression of neurodegeneration has shed new light on Huntington's disease and other devastating brain diseases. This review focuses on genetic mediators, environmental modulators, and associated gene-environment interactions in the pathogenesis of Huntington's disease.

Animals↗
PubMed2003

Friedreich ataxia-update on pathogenesis and possible therapies.

Friedreich ataxia is the most-common inherited ataxia. Since the causative genetic basis was described in 1996, much has been learnt about the pathogenesis from human, animal, and yeast studies. This has led to the development of rational therapeutic approaches. In this review, the current state of knowledge regarding the pathogenesis of Friedreich ataxia is presented and possible therapeutic strategies based on this knowledge are discussed.

Animals↗
PubMed2003

Diabetic muscular infarction: emphasis on pathogenesis.

Diabetic muscular infarction is a rare complication of diabetes. It usually occurs in those with target organ involvement of diabetes, generally affecting one or a group of muscles of the thigh, and can recur. The pathogenesis of the disease is still not clear. Here we report an unusual case of extensive muscle involvement of both thighs and calves, with special emphasis on pathogenesis.

Adult↗
PubMed2006

Whole-body electrolyte-free water clearance: derivation and clinical utility in analyzing the pathogenesis of the dysnatremias.

The total exchangeable sodium (Na(e)), total exchangeable potassium (K(e)), and total body water (TBW) are the major determinants of the plasma water sodium concentration ([Na(+)](pw)). The relationship between [Na(+)](pw) and Na(e), K(e), and TBW was empirically determined by Edelman et al., where: [Na(+)](pw) = 1.11(Na(e) + K(e))/TBW - 25.6 (Eq. 1). According to Eq. 1, changes in the mass balance of Na(+), K(+), and H(2)O will therefore result in changes in the [Na(+)](pw). Historically, in evaluating the pathogenesis of the dysnatremias, free water clearance (FWC) and electrolyte-free water clearance (EFWC) have been used to evaluate the pathophysiology of the dysnatremias. However, such analyses are only valid when there is no concomitant input and non-renal output of Na(+), K(+), and H(2)O. Since the classic FWC and EFWC formulas fail to account for the input and non-renal output of Na(+), K(+), and H(2)O, these formulas cannot be used to evaluate the pathogenesis of the dysnatremias or to predict the directional change in the [Na(+)](pw). In this article, we have addressed this limitation by deriving a new formula, termed whole-body electrolyte-free water clearance (WB-EFWC), which calculates whole-body electrolyte-free water clearance for a given mass balance of Na(+), K(+), and H(2)O, rather than simply the urinary component (FWC, EFWC formulas). Unlike previous formulas, which consider only the renal component of electrolyte-free water clearance, WB-EFWC accounts for all sources of input and output of Na(+), K(+), and H(2)O, and will therefore be helpful in conceptually understanding the basis for changes in the [Na(+)](pw) in patients with the dysnatremias.

Body Water↗
PubMed2005

Non-hypothalamic cluster headache: the role of the greater occipital nerve in cluster headache pathogenesis.

Cluster headache is marked by its circadian rhythmicity and the hypothalamus appears to have a significant influence over cluster pathogenesis. However, as not all cluster patients present in the same manner and not all respond to the same combination of medications, there is likely a nonhypothalamic form of cluster headache. A patient is presented who began to develop cluster headaches after receiving bilateral greater occipital nerve (GON) blockade. His headaches fit the IHS criteria for cluster headache but had some irregularities including frequent side shifting of pain, irregular duration and time of onset and the ability of the patient to sit completely still during a headache without any sense of agitation. This article will suggest that some forms of cluster headache are not primarily hypothalamic influenced and that the GON may play a significant role in cluster pathogenesis in some individuals.

Afferent Pathways↗
PubMedDate not supplied

Protein misfolding disorders: pathogenesis and intervention.

Newly synthesized proteins in the living cell must go through a folding process to attain their functional structure. To achieve this in an efficient fashion, all organisms, including humans, have evolved a large set of molecular chaperones that assist the folding as well as the maintenance of the functional structure of cellular proteins. Aberrant proteins, the result of production errors, inherited or acquired amino acid substitutions or damage, especially oxidative modifications, can in many cases not fold correctly and will be trapped in misfolded conformations. To rid the cell of misfolded proteins, the living cell contains a large number of intracellular proteases, e.g. the proteasome, which together with the chaperones comprise the cellular protein quality control systems. Many inherited disorders due to amino acid substitutions exhibit loss-of-function pathogenesis because the aberrant protein is eliminated by one of the protein quality control systems. Examples are cystic fibrosis and phenylketonuria. However, not all aberrant proteins can be eliminated and the misfolded protein may accumulate and form toxic oligomeric and/or aggregated inclusions. In this case the loss of function may be accompanied by a gain-of-function pathogenesis, which in many cases determines the pathological and clinical features. Examples are Parkinson and Huntington diseases. Although a number of strategies have been tried to decrease the amounts of accumulated and aggregated proteins, a likely future strategy seems to be the use of chemical or pharmacological chaperones with specific effects on the misfolded protein in question. Positive examples are enzyme enhancement in a number of lysosomal disorders.

Animals↗
PubMed2006

The role of the human DNA mismatch repair gene hMSH2 in DNA repair, cell cycle control and apoptosis: implications for pathogenesis, progression and therapy of cancer.

The cellular DNA mismatch repair (MMR) pathway, involving the DNA mismatch repair genes MLH1 and MSH2, detects and repairs DNA replication errors. Defects in MSH2 and MLH1 account for most cases of hereditary non-polyposis colorectal cancer as well as for sporadic colorectal tumors. Additionally, increased expression of MSH2 RNA and/or protein has been reported in various malignancies. Loss of DNA MMR in mammalian cells has been linked to resistance to certain DNA damaging agents including clinically important cytotoxic chemotherapeutics. Due to other functions besides its role in DNA repair, that include regulation of cell proliferation and apoptosis, MSH2 has recently been shown to be of importance for pathogenesis and progression of cancer. This review summarizes our present understanding of the function of MSH2 for DNA repair, cell cycle control, and apoptosis and discusses its importance for pathogenesis, progression and therapy of cancer.

Apoptosis↗
PubMed2005

Selection of optimal host strain for molecular pathogenesis studies on Cryptococcus gattii.

Encapsulated yeast, Cryptococcus gattii (Cg) is a primary and emerging fungal pathogen in North America. It has a predilection for invading the central nervous system of both healthy and immunocompromised humans and animals. Recently, we initiated molecular pathogenesis studies in Cg strain NIH444 (ATCC 32609). In this report, we compared the biology and pathogenic potential of NIH444 to those of WM276, an Australian environmental isolate that is being used for the whole genome-sequencing project. Our data indicated that NIH444 is comparatively more virulent in a mouse model of cryptococcosis than is WM 276. We found robust mating of NIH444, and no mating of WM276, when tested against Cg MATa strain, NIH198. WM276 but not NIH444 was defective in filamentation and sporulation (haploid fruiting). Interestingly, NIH444 has a VGII/AFLP6 genotype similar to that of the genotype of the recent outbreak strains from Vancouver Island, British Columbia, Canada. Additionally, comparisons of nucleotide sequences of various genes also showed differences between NIH444 and WM276. Based on these observations, we conclude that NIH444 should remain the strain of choice for understanding Cg pathogenesis, especially on the North American continent.

Animals↗
PubMed2004

Molecular pathogenesis of meningiomas.

Meningiomas are common central nervous system tumors that originate from the meningeal coverings of the brain and the spinal cord. Most meningiomas are slowly growing benign tumors that histologically correspond to World Health Organization (WHO) grade I. However, certain rare histological variants (clear cell, chordoid, papillary, and rhabdoid), as well as atypical (WHO grade II) and anaplastic (WHO grade III) meningiomas show a more aggressive biological behavior and are clinically associated with a high risk of local recurrence and a less favorable prognosis. This review summarizes the most important features of meningioma pathology and provides an up-to-date overview about the molecular mechanisms involved in meningioma initiation and progression. Current data indicate that meningioma initiation is closely linked to the inactivation of one or more members of the highly conserved protein 4.1 superfamily, including the neurofibromatosis type 2 gene product merlin/schwannomin, protein 4.IB (DAL-1) and protein 4.1R. The genetic alterations in atypical meningiomas are complex and involve losses on 1p, 6q, 10, 14q and 18q, as well as gains on multiple chromosomes. The relevant genes are still unknown. Anaplastic meningiomas show even more complex genetic alterations, including frequent alteration of the CDKN2A, p14ARF, and CDKN2B tumor suppressor genes at 9p21, as well as gene amplification on 17q23. A better understanding of the molecular mechanisms involved in meningioma pathogenesis may not only lead to the identification of novel diagnostic and prognostic marker but will also facilitate the development of new pathogenesis-based therapeutic strategies.

Animals↗
PubMed2006

The role of citrullinated proteins suggests a novel mechanism in the pathogenesis of multiple sclerosis.

The pathogenesis of MS is unknown. In our studies, we have demonstrated an important role for citrullinated myelin basic protein (MBP). The accompanying loss of positive charge compromises the ability of MBP to interact with the lipid bilayer. The conversion of arginine to citrulline in brain is carried out by an enzyme peptidyl arginine deiminase (PAD) 2. The amount of PAD 2 in brain was increased in MS normal-appearing white matter. The mechanism responsible for this increase involved hypomethylation of the promoter region in the PAD 2 gene in MS, but no change (compared to normal) was found in thymus tissue DNA from the same MS patients. In addition, no change was observed in other neurological diseases, including Alzheimer's, Parkinson's, and Huntington's. We propose that citrullinated MBP, resulting from elevated levels of PAD 2 represents an important biochemical pathway in the pathogenesis of MS.

Apoptosis↗
PubMed2005

The role of urine osmolality and ions in the pathogenesis of primary enuresis nocturna and in the prediction of responses to desmopressin and conditioning therapies.

Aim of the study was to determine the role of nocturnal and daytime urine volume, osmolality and ion excretions in the pathogenesis of primary monosymptomatic enuresis nocturna (PMEN) and in the prediction of response to desmopressin and conditioning therapies. Fifty-five children with PMEN between the ages 5 and 15 years were included to the study. The patients were randomly divided into three groups Group 1: Twenty enuretics having intranasal desmopressin 1x 20 microg treatment for 2 months Group 2: Twenty enuretics having conditioning therapy for 2 months. Group 3: Fifteen enuretics having intranasal izotonic solutions as placebo. The control group consisted of 15 healthy children. Urine osmolality, sodium, potassium, chloride, magnesium and creatinine levels were investigated in both daytime and nighttime urines. Fractional sodium, potassium, magnesium, chloride excretions were calculated. Wilcoxon, Mann-Whitney U, Kruskal-Wallis, Chi-square, Student's t and Pearson correlation tests were performed. The ratio of night/daytime urine osmolality was significantly decreased in enuretic children. In addition, the ratio of night/daytime urine Cl and K excretions were also significantly decreased in enuretics. Response rate to desmopressin and conditioning treatments were statistically higher than placebo control. The difference between response rates of desmopressin and conditioning therapies was not found statistically significant. Pretreatment values of urine volume osmolality and ions were not observed as predictive factors in response to desmopressin or conditioning therapy. In conclusion, nightly decreased potassium and chloride excretions were found to have a role in the pathogenesis of primary enuresis nocturna. Urine volume, osmolality and ion excretions are not suggested to be used in the prediction of response to desmopressin and conditioning therapies.

Adolescent↗
PubMed2003

Dietary factors in the pathogenesis of asthma and chronic obstructive pulmonary disease.

This review focuses on the role of dietary factors in the pathogenesis of asthma and chronic obstructive pulmonary disease. Reduced pulmonary function and indicators of airway obstruction have been shown to be strong indicators of mortality; therefore, a link with diet in the pathogenesis of these diseases would have important public health implications. The results of the studies identified in the review suggest that people who have a diet rich in fruit and vegetables have a lower risk of poor respiratory health, and that this may be due to the antioxidant nutrients these foods contain. On the basis of the evidence, it seems justified to promote a healthy diet, high in fruits, vegetables, and whole grain foods and low in alcohol and fatty foods, as set out in existing guidelines for prevention of cardiovascular disease and cancer, to protect respiratory health in both children and adults.

Asthma↗
PubMed2003

Update on the pathogenesis of diabetic neuropathy.

Peripheral diabetic neuropathy (PDN) affects up to 60% to 70% of diabetic patients, and is the leading cause of foot amputation. The pathogenesis of PDN involves multiple mechanisms. The findings obtained in 1999 to 2003 support the role of previously established mechanisms such as increased aldose reductase activity, nonenzymatic glycation or glyco-oxidation, activation of protein kinase C, enhanced oxidative stress, impaired neurotrophic support, and reveal the importance of new downstream effectors of oxidative injury. Those include mitogen-activated protein kinases and poly (ADP-ribose) polymerase that are activated by diabetes, and contribute to such neuropathic changes as motor and sensory nerve conduction deficits, decreased nerve blood flow, and energy failure. Further studies are needed to understand the role of other signaling pathways as well as interactions among previously discovered mechanisms in the pathogenesis of PDN.

Diabetic Angiopathies↗
PubMed2002

The pathogenesis of inflammatory bowel disease: translational implications for clinicians.

Research in the pathogenesis of inflammatory bowel disease (IBD) has dramatically broadened our understanding of these complex disorders. These clinical manifestations result from a dysregulated immune response in the presence of luminal bacteria. Recent identification of mutations in the NOD2 gene, a protein involved in the sensing of bacteria, offers genetic support for the model of perturbed host-microbial interactions in Crohn's disease. Several immunologic pathways have been identified that play a role in maintaining gut immune homeostasis. Abnormal expression of proinflammatory, deleterious cytokines such as tumor necrosis factor-a and interferon-g results in direct and indirect tissue damage. The search for specific causative microbial agents in IBD continues to be intense. This paper describes the advances in our understanding of IBD pathogenesis, with an emphasis on how this information is translated into patient care. The next stage of research will take advantage of such molecular biologic techniques to identify new pathogenetic mechanisms and targets for therapy tailored to individual patients.

Animals↗
PubMed2006

The role of RAS in the pathogenesis of preeclampsia.

Preeclampsia is a hypertensive disorder that is unique to pregnancy, with consistent involvement of the kidney. The renin-angiotensin system (RAS) has been implicated in the pathogenesis of preeclampsia. In the gravid state, in addition to the RAS in the kidney, there is a tissue-based RAS in the uteroplacental unit. Increased renin expression in human preeclampsia and in transgenic mouse models with a human preeclampsia-like syndrome shows that activation of the uteroplacental RAS, with angiotensin II entering the systemic circulation, may mediate the pathogenesis of preeclampsia. Vascular maladaptation in preeclampsia with increased vasomotor tone, endothelial dysfunction, and increased sensitivity to angiotensin II and norepinephrine in manifest preeclampsia may be explained on the basis of angiotensin II-mediated mechanisms through angiotensin receptor type I (AT1) activation. Recently, novel angiotensin II-related biomolecular mechanisms have been described in preeclampsia. These include AT1 and bradykinin B2 receptor heterodimerization and the production of autoantibody against AT1. Various organ systems with predilection for involvement in preeclampsia are sites of tissue-based RAS. Angiotensin II-mediated mechanisms may explain the primary clinicopathologic features of preeclampsia. In this review, these various aspects are critically examined and an integrated concept on the role of RAS in preeclampsia is presented.

Angiotensin II↗
PubMed2002

Pathogenesis, Therapy, and Prevention of Meningococcal Sepsis.

Neisseria meningitidis (meningococcus), an exclusive pathogen of humans, is the cause of sepsis (meningococcemia) and meningitis, often in otherwise healthy individuals. Several hundred thousand cases of meningococcal disease occur worldwide each year, a number that is frequently accentuated by epidemic outbreaks. In recent years, significant advances, fueled by new molecular approaches and genome sequencing projects, have improved our understanding of the pathogenesis of meningococcal disease and have led to progress in the development of the next generation of meningococcal vaccines. However, the mortality of meningococcal disease remains 10% to 15% for all cases, and is up to 40% in patients with severe sepsis. This review summarizes current knowledge of the pathogenesis, therapy, and prevention of meningococcal disease with emphasis on meningococcal sepsis.

Journal Article↗