Manifestations In Tissues Research Articles

Prevalence of oral manifestations in soft tissues during early childhood in Brazilian children

This study aimed at assessing the prevalence of soft tissue oral manifestations in children during early childhood, according to age group, gender, and site in the oral cavity, and at correlating these oral manifestations with systemic alterations. A cross-sectional study was conducted involving 586 children from 0 to 3 years of age (12.4 ± 11.8 months), 316 (53.9%) male and 270 (46.1%) female, in the city of Mauá, SP, Brazil. Examination was performed by a single examiner (Kappa Index = 0.90) according to World Health Organization criteria (WHO, 1997).The prevalence of oral manifestations in the soft tissues of children during early childhood was 34.8%. The age group showing statistical significance was 0-1 months old (56.4%). Epstein's pearls were significantly present (43.2%) in 0-1-month-old babies, and gingivitis in 12-24-month-olds (15.9%). The palate was the most affected region (16.7%). Infectious alterations were the most prevalent systemic alteration (20%). An association was observed between the presence of systemic alterations and the occurrence of oral manifestations. The prevalence of oral manifestations was 34.8%, regardless of gender, and was manifested mostly in 0-1-month-old babies. The palate was the most prevalent region, and the majority of oral manifestations were associated with systemic alterations.

Fibrillin-1 directly regulates osteoclast formation and function by a dual mechanism

Mutations in the fibrillin-1 gene give rise to a number of heritable disorders, which are all characterized by various malformations of bone as well as manifestations in other tissues. However, the role of fibrillin-1 in the development and homeostasis of bone is not well understood. Here, we examined the role of fibrillin-1 in regulating osteoclast differentiation from primary bone-marrow-derived precursors and monocytic RAW 264.7 cells. The soluble N-terminal half of fibrillin-1 (rFBN1-N) strongly inhibited osteoclastogenesis, whereas the C-terminal half (rFBN1-C) did not. By contrast, when rFBN1-N was immobilized on calcium phosphate, it did not affect osteoclastogenesis but modulated osteoclast resorptive activity, which was evident by a larger number of smaller resorption pits. Using a panel of recombinant sub-fragments spanning rFBN1-N, we localized an osteoclast inhibitory activity to the 63 kDa subfragment rF23 comprising the N-terminal region of fibrillin-1. Osteoclastic resorption led to the generation of small fibrillin-1 fragments that were similar to those identified in human vertebral bone extracts. rF23, but not rFBN1-N, was found to inhibit the expression of cathepsin K, matrix metalloproteinase 9 and Dcstamp in differentiating osteoclasts. rFBN1-N, but not rF23, exhibited interaction with RANKL. Excess RANKL rescued the inhibition of osteoclastogenesis by rFBN1-N. By contrast, rF23 disrupted RANKL-induced Ca(2+) signaling and activation of transcription factor NFATc1. These studies highlight a direct dual inhibitory role of N-terminal fibrillin-1 fragments in osteoclastogenesis, the sequestration of RANKL and the inhibition of NFATc1 signaling, demonstrating that osteoclastic degradation of fibrillin-1 provides a potent negative feedback that limits osteoclast formation and function.

Much more than thrombosis and pregnancy loss: The antiphospholipid syndrome as a ‘systemic disease’

Antiphospholipid syndrome is an auto-immune disorder characterised by recurrent thrombosis, pregnancy losses and the presence of antiphospholipid antibodies. Although it was initially considered an auto-immune coagulopathy, it is now clear that it is a complex and systemic disease. A large number of manifestations in different organs and tissues (cardiac, pulmonary, neurological, renal, cutaneous, haematologic, gastrointestinal, ocular, skeletal and endocrinologic) have been described in these patients. A small group of patients can have a microvascular involvement, which is the most common pathological finding in patients affected by the catastrophic variant of the syndrome. A strong relationship exists between the antiphospholipid syndrome and systemic lupus erythematosus, as demonstrated by common clinical, serological and genetic features and by the few but possible cases evolving from the first disease into the second one over years. Finally, the systemic nature of the antiphospholipid syndrome and the understanding of the mechanisms of antiphospholipid-mediated damage suggest a role of immunomodulation beyond anticoagulation in the therapeutic approach to the disease.

Accurate and Simple Measurement of the Pro-inflammatory Cytokine IL-1β using a Whole Blood Stimulation Assay

Inflammatory processes resulting from the secretion of soluble mediators by immune cells, lead to various manifestations in skin, joints and other tissues as well as altered cytokine homeostasis. The innate immune system plays a crucial role in recognizing pathogens and other endogenous danger stimuli. One of the major cytokines released by innate immune cells is Interleukin (IL)-1. Therefore, we utilize a whole blood stimulation assay in order to measure the secretion of inflammatory cytokines and specifically of the pro-inflammatory cytokine IL-1β(1, 2, 3). Patients with genetic dysfunctions of the innate immune system causing autoinflammatory syndromes show an exaggerated release of mature IL-1β upon stimulation with LPS alone. In order to evaluate the innate immune component of patients who present with inflammatory-associated pathologies, we use a specific immunoassay to detect cellular immune responses to pathogen-associated molecular patterns (PAMPs), such as the gram-negative bacterial endotoxin, lipopolysaccharide (LPS). These PAMPs are recognized by pathogen recognition receptors (PRRs), which are found on the cells of the innate immune system (4, 5, 6, 7). A primary signal, LPS, in conjunction with a secondary signal, ATP, is necessary for the activation of the inflammasome, a multiprotein complex that processes pro-IL-1β to its mature, bioactive form (4, 5, 6, 8, 9, 10). The whole blood assay requires minimal sample manipulation to assess cytokine production when compared to other methods that require labor intensive isolation and culturing of specific cell populations. This method differs from other whole blood stimulation assays; rather than diluting samples with a ratio of RPMI media, we perform a white blood cell count directly from diluted whole blood and therefore, stimulate a known number of white blood cells in culture (2). The results of this particular whole blood assay demonstrate a novel technique useful in elucidating patient cohorts presenting with autoinflammatory pathophysiologies.

Compound Heterozygous Desmoplakin Mutations Result in a Phenotype with a Combination of Myocardial, Skin, Hair, and Enamel Abnormalities

Desmoplakin (DP) anchors the intermediate filament cytoskeleton to the desmosomal cadherins and thereby confers structural stability to tissues. In this study, we present a patient with extensive mucocutaneous blisters, epidermolytic palmoplantar keratoderma, nail dystrophy, enamel dysplasia, and sparse woolly hair. The patient died at the age of 14 years from undiagnosed cardiomyopathy. The skin showed hyperplasia and acantholysis in the mid- and lower epidermal layers, whereas the heart showed extensive fibrosis and fibrofatty replacement in both ventricles. Immunofluorescence microscopy showed a reduction in the C-terminal domain of DP in the skin and oral mucosa. Sequencing of the DP gene showed undescribed mutations in the maternal and paternal alleles. Both mutations affected exon 24 encoding the C-terminal domain. The paternal mutation, c.6310delA, leads to a premature stop codon. The maternal mutation, c.7964 C to A, results in a substitution of an aspartic acid for a conserved alanine residue at amino acid 2655 (A2655D). Structural modeling indicated that this mutation changes the electrostatic potential of the mutated region of DP, possibly altering functions that depend on intermolecular interactions. To conclude, we describe a combination of DP mutation phenotypes affecting the skin, heart, hair, and teeth. This patient case emphasizes the importance of heart examination of patients with desmosomal genodermatoses.

Telomeres and marrow failure

Telomeres, repeat sequences at the ends of chromosomes, are protective chromosomal structures highly conserved from primitive organisms to humans. Telomeres inevitably shorten with every cell cycle, and telomere attrition has been hypothesized to be fundamental to normal senescence of cells, tissues, and organisms. Molecular mechanisms have evolved to maintain their length and protective function; telomerase (TERT) is a reverse transcriptase enzyme that uses an RNA molecule (TERC) as the template to elongate the 3' ends of telomeres. Shelterin is a collection of DNA-binding proteins that cover and protect telomeres. The recent discovery of inherited mutations in genes that function to repair telomeres as etiologic in a range of human diseases, which have clinical manifestations in diverse tissues, including the hematopoietic tissue, suggests that defects in telomere repair and protection can cause organ failure. Dyskeratosis congenita is the prototype of telomere diseases; it is characterized by bone marrow failure, mucocutaneous abnormalities, pulmonary fibrosis, liver cirrhosis, and increased susceptibility to cancer, including acute myeloid leukemia. Aplastic anemia, acute myeloid leukemia, and idiopathic pulmonary fibrosis also are associated with inherited mutations in telomere repair or protection genes. Additionally, telomere defects associate with predisposition to hematologic malignancy and epithelial tumors. Telomere erosion is abnormally rapid in patients with mutations in telomerase genes but also after hematopoietic stem cell transplant, and telomeres are naturally shorter in older individuals-all conditions associated with higher rates of malignant diseases. In human tissue culture, short telomeres produce end-to-end chromosome fusion, nonreciprocal translocations, and aneuploidy.

The “brain–skin connection”: nerve growth factor-dependent pathways for stress-induced skin disorders

Keywords CNS.NGF.CRF.MastcellsStress can precipitate or exacerbate certain neuroinflamma-tory manifestations in peripheral tissues, including the skin.Indeed, stress may trigger or aggravate skin diseases, such asatopic dermatitis, psoriasis, urticaria, and alopecia areata ortotalis. The precise mechanisms leading to stress-induced or-aggravated skin disorders have just begun to be understood.Thus, recent experimental evidence reveals that distinctneuroendocrine pathways of the brain and the skin areintricately intertwined. This so-called “brain–skin connec-tion” represents an exciting new area of investigation [5].Mouse models are now available for the detailed mechanisticinvestigation of the effects of stress on skin diseases.The stress system in the brain and the periphery includesthe hypothalamic–pituitary–adrenal (HPA) axis and thearousal and sympathetic systems (Fig. 1). When activatedby stress, the stress system leads to several behavioral, neu-roendocrine,autonomic,andimmunechangesthatarepartofthe adaptive response [1]. Besides the classic stress-relatedneurohormones of the stress system [corticotropin-releasinghormone (CRH), arginine-vasopressin, adrenocorticotropichormone, glucocorticoids and the catecholamines norepi-nephrine and epinephrine], additional mediators, such asnerve growth factor (NGF) and several cytokines, havebeen identified as important players of the stress response.Circulating NGF levels are increased in patients withinflammatory skin diseases, such as psoriasis [7].Mast cells are involved in the development of allergicand late-phase inflammation reactions [2]. They are alsoimplicated in nonallergic inflammation, as they releaseseveral proinflammatory cytokines, such as tumor necrosisfactor and other inflammatory mediators (Table 1). Mastcells are located perivascularly in close proximity toperipheral neuron terminals, including both those ofpostganglionic sympathetic and sensory [dorsal root ganglia(DRG) neurons] neurons originating in the sympathetic andDRG, respectively (Fig. 1). Skin mast cells produce CRHand express CRH receptors type 1 [4, 6]. They can beactivated by many neuropeptides secreted by postganglion-ic sympathetic and sensory neurons, especially peripheralCRH, substance P (SP), and calcitonin gene-related peptide(CGRP), in response to stress, or by inflammatorymediators. Stress-induced or -aggravated neuroinflamma-tory skin conditions have been associated with mast cellactivation and degranulation. Similarly, we have previouslyshown that stress induces intracranial mast cell activation,through the sequential action of CRH and sensory neuro-peptides [9], and that CRH degranulates skin mast cells andincreases vascular permeability [8].In a murine model of stress involving exposure ofC57BL/6 mice to sound stress, Joachim et al. [3] in thisissue of the Journal provide evidence that stress, orintracutaneous injection of recombinant NGF mimickingthe skin’s response to stress, up-regulate the percentage ofSP

Salmonella intestinal perforation: (27 perforations in one patient, 14 perforations in another) Are the goal posts changing?

The pathology of salmonellosis after a faeco-oral transmission was first clearly described by Jenner in 1850. Over the years, the pathological manifestations in different tissues of the body have been described. The ileum is however mostly involved leading to enlarged Peyer's patches, ulceration, and sometimes bleeding and perforation. Efforts at control have largely been improvement in public water supply, safe disposal of waste, and general public health measures. Despite these measures, intestinal perforation from salmonellosis remains the commonest cause of emergency operation in children above 3 years. The incidence continues to rise, so also the mortality, despite new antibiotics and improvement in facilities in the hospitals. Even more disturbing is that we now see more perforations per patient, and more involvement of the colon. Three recently managed patients with multiple ileal/colonic perforations were reviewed. Presenting problems, delay in referral, choice of antibiotics and postoperative complications were noted. One patient had 27 perforations and another 14 perforations. Both survived. Is salmonella changing? Are our patients changing? Is the environment changing? Are the goal posts changing? This article details our recent experience with this dreadful disease, reviews the new literature and makes suggestions for the way forwards.<br>

Oropharyngeal leprosy in art, history, and medicine

Advanced lesions of the face, nasopharynx, and oropharynx have played an important role in the medical and social history of Hansen’s disease. Renaissance artists included detailed portrayals of these lesions in some of their paintings, a testimony not only to their artistic skill and powers of observation but also to the common presence of these patients in European cities and towns of the period. The disease is now understood as a broad immunologic spectrum of host responses to Mycobacterium leprae , with a variety of clinical and pathologic manifestations in nerve, soft tissues, and bone. This review incorporates the findings of 2 extraordinary studies (one from Europe and the other from Japan) of pharyngeal and facial lesions. In the 1950s, studies of skeletal remains from the churchyard of a Danish leprosarium revealed a triad of maxillofacial lesions unique to leprosy and designated facies leprosa . In pre–World War II Japan, before effective treatment had been discovered, a prominent otorhinolaryngologist studying oropharyngeal and nasopharyngeal lesions prepared watercolor illustrations of the natural progression of untreated Hansen’s disease. As a result of effective antimicrobial therapy, such advanced lesions are now rarely seen, but the presenting signs and symptoms of leprosy still occasionally arise in the nasal and oral mucosa. The nasopharynx and oropharynx may be important early sites of inoculation and infection by M leprae , and they require additional emphasis in worldwide efforts toward early diagnosis and treatment of Hansen’s disease. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:463-70)

Connexin32 and X-linked Charcot-Marie-Tooth disease.

The discovery that X-linked Charcot-Marie-Tooth disease (CMTX) is caused by mutations in connexin32 (Cx32)1 has united the fields of molecular genetics, neurology, and gap junction biology by demonstrating the importance of Cx32 in myelinating Schwann cells. The lack of overt clinical manifestations in other tissues that express Cx32 suggests the existence of compensatory mechanisms elsewhere that are absent in peripheral nerve. Determining the mechanism by which Cx32 mutations cause the phenotype of CMTX will contribute to the understanding of the function of the myelin sheath and elucidate the role of Cx32 in other tissues.

Necklace-like detachment of endothelial cell layer from arterial wall under low-calcium condition

The diversified morphological manifestations in various tissues and organs obtained by administration of differing amounts of calcium chelating agents were reported in previous papers (Yamaguchi et al 1981 a & b; 1982; 1990; 1993). In our recent research described here, administration of a moderate dose of Na2EDTA over the short term demonstrated necklace-like detachment from the arterial wall without disruption of the endothelial cell chain. Intercellular spaces in the media just beneath the detached endothelial cell layer was stained strongly with colloidal iron staining. Electron microscopic observation revealed that the detached endothelial cells showed a lot of elongated anchoring villi from the basal surface, usually seen at the luminal surface, adhered to the degenerative and thin flattened internal elastic lamellae. The alteration of the colloidal iron staining of the vascular wall under the low-calcium condition is suggested to be induced by loosening of the molecular structure of glycosaminoglycans (GAGs) as well as glycoproteins (GPs), comprising the important component of the intercellular matrix and elastic lamellae, which would induce a change in their pasty or viscous character. This would be an accelerative factor for detachment of endothelial cells. Moreover, the lack of the waving of the internal elastic lamellae, trapping of endothelial cytoplasmic processes among them, would play the decisive role in the total detachment of the endothelial cell layer. On the other hand, the low-calcium condition did not adversely influence the joining of endothelial cells. The pathognomatic mechanism will be discussed, with a comparison made to the angiolytic changes provoked by a large amount of Na2EDTA.

Induction of ovalbumin and conalbumin synthesis in immature chick oviducts by ethionine.

PROLONGED feeding of rats with ethionine results in a high frequency of hepatic carcinoma. Ethionine induces other pathological manifestations in other organs and tissues of experimental animals1, and some of its effects can be reversed rapidly by the administration of methionine. At the molecular level ethionine induces a rapid decrease in hepatic ATP concentration2–4, followed by inhibition of RNA5 and protein synthesis6. The decrease in ATP concentration is due to formation of S-adenosyl-ethionine7, an inhibitor of tRNA methyltransferases8,9, and so tRNA isolated from the liver of rats injected with adenine and ethionine is hypomethylated10,11. It is well established that several eukaryotic mRNAs are methylated on the 5′ terminus and that such modification is essential for translation12,13. To study the mechanism of methylation we attempted to produce a specific methyl-deficient mRNA by the administration of ethionine. To monitor the effectiveness of the deprivation of methyl groups the synthesis of hormone-induced ovalbumin in immature chick oviducts was followed. Administration of oestrogen to immature chicks causes cytodifferentiation and growth of the primitive oviduct14–17. The tubular gland cells synthesise ovalbumin, conalbumin, ovomucoid and lysozyme which comprise 85–90% of the egg-white proteins18. The continuous presence of oestrogen is required for sustained synthesis of these proteins in immature chicks; withdrawal of oestrogen is accompanied by a gradual decline in cell-specific protein synthesis as well as in the weight of the oviduct and the RNA content of the tissue17. But, the tubular gland cells in the oviduct magnum during withdrawal are retained although they do not synthesise cell-specific secretory proteins17,19. Readministration of hormone to chicks after withdrawal (secondary stimulation) results in restoration of cell-specific protein synthesis without concomitant need for DNA synthesis17. During these studies ethionine unexpectedly simulated the effects of the injection of oestrogen for secondary stimulation.