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[Pathogenesis of lesions in late age-related macular disease].

To summarize the evidence that exists concerning the pathogenesis of lesions in late age-related macular disease (AMD), we reviewed both experimental evidence and clinical observations that address these problems. There is good evidence that choroidal neovascularization is due to a change in the balance of growth factors derived from the retinal pigment epithelial basolateral plasma membrane domain (RPE). Retinal angiomatous proliferation may also have a similar pathogenesis involving the apical domain. Detachment of the RPE is likely to be a consequence of increased resistance of Bruch's membrane to water flow due to deposition of lipids. Geographic atrophy is preceded by accumulation of autofluorescent material in the RPE and possible causal relationships between the two have been demonstrated. There is increasing understanding concerning the sequence of events that lead to those lesions causing loss of central vision in AMD. Therapeutic approaches that address the underlying mechanisms are more likely to succeed than current treatment options. Such an approach has already been initiated in the management of choroidal neovascularization.

Humans↗

Apparent absence of a benign precursor lesion: implications for the pathogenesis of malignant melanoma.

This review relates concepts derived from the study of chemically induced skin cancer in animal models to the pathogenesis of malignant melanoma in humans. Most chemically induced experimental cancers in animals, including melanomas in rodents, arise within a benign precursor lesion. The initiation-promotion-progression sequence is a central concept in animal models for carcinogenesis. Many human melanomas appear to arise from epidermal melanocytes, with no associated precursor lesion. This article considers why there is no apparent precursor in many human melanomas and the consequences of this absence. Melanocyte physiology and factors that govern escape from defenses such as DNA repair, local tissue environment, and immunity presumably influence melanocyte conversion to melanoma. These factors may determine the absence of a precursor lesion in primary melanomas. In addition, it is possible that some human melanomas arise by cellular mechanisms different from those causing cancer in rodent models. Both molecular and prospective clinical studies will be required to explain this apparent paradox in the pathogenesis of melanoma. A similar approach may help to explain the origin of basal cell carcinoma and perhaps other human cancers that appear to arise directly from normal cells. From a clinical point of view, the absence of an identifiable, benign precursor lesion requires even greater emphasis on melanoma prevention. Research on mechanisms of ultraviolet carcinogenesis indicates that appropriate postexposure treatments may be useful in preventing long-term consequences of sunburn, including melanoma.

Animals↗

Sweet's syndrome: is the pathogenesis mediated by helper T cell type 1 cytokines?

BACKGROUND: The pathogenesis of Sweet's syndrome (acute febrile neutrophilic dermatosis; SS) is still not fully understood. An imbalance between helper T cell types 1 and 2 cytokine secretion patterns has been shown to be relevant in many diseases. OBJECTIVE: We assessed the serum cytokine levels (interleukin [IL]-1alpha, IL-1beta, IL-2, interferon gamma [IFN-gamma], IL-4) in patients with SS. METHODS: Eight patients with SS were analyzed for their clinical features and serum cytokine levels and compared with normal control subjects. RESULTS: In patients serum levels of IL-1alpha, IL-1beta, IL-2, and IFN-gamma were significantly elevated, whereas the IL-4 level was within the normal range. CONCLUSION: Our findings suggest that the pathogenesis of SS is probably mediated through helper T cell type 1 cytokines (IL-2, IFN-gamma) rather than helper T cell type 2 cytokines (IL-4).

Aged↗

Pathogenesis of feline diabetes mellitus.

Cats are one of the few species that develop a form of diabetes mellitus that is clinically and histologically analogous to human type 2 diabetes mellitus. Figure 9 summarizes the etiologic factors thought to be involved in the development of feline and human type 2 diabetes. The main metabolic characteristics of type 2 diabetes mellitus are impaired insulin secretion and resistance to the action of insulin in its target tissues. Impaired beta cell function occurs before histologic changes become evident. The characteristic histologic finding in cats with type 2 diabetes is deposition of amyloid in pancreatic islets. Amyloid deposition occurs before the onset of clinical signs, but does not seem to be the primary defect. Pancreatic amyloid is derived form the recently discovered pancreatic hormone amylin. Amylin is synthesized in pancreatic beta cells, and is co-stored and co-secreted with insulin. Amylin has been postulated to be involved in the pathogenesis of feline diabetes mellitus both through its metabolic effects, which include inhibition of insulin secretion and induction of insulin resistance, and via progressive amyloid deposition and beta cell degeneration. Increased amylin concentration has been documented intracellularly in cats with impaired glucose tolerance and in the plasma of diabetic cats, and supports the hypothesis that amylin is involved in the pathogenesis of type 2 diabetes. Obesity is a common finding in diabetic felines and is a contributing factor to the insulin resistance present in type 2 diabetes. Clinical signs of diabetes develop once total insulin secretion decreases to 20% to 25% of normal levels. Many diabetic cats have been treated successfully with oral hypoglycemics, but 50% to 70% of diabetic cats are insulin dependent. Based on histologic evidence, this is the result of extensive amyloid deposition and subsequent beta cell degeneration, rather than autoimmune destruction of pancreatic beta cells associated with type 1 diabetes. Alternative ways of treating type 2 diabetes currently are being investigated. Amylin antagonists recently have been proposed as a novel treatment to reverse the deleterious effects of excessive amylin concentrations. The gastrointestinal hormone glucagon-like peptide-1 may also prove useful in treating diabetic cats, because of its stimulatory effect on insulin secretion and synthesis, and the absence of significant hypoglycemic effect.

Amyloid↗

Contribution of endotracheal tubes to the pathogenesis of ventilator-associated pneumonia.

The contribution of ventilatory equipment to the pathogenesis of ventilator-associated pneumonia (VAP) is well-established but the design of endotracheal tubes has been improved only to reduce tracheal traumatization. However many factors, including the surface properties of the endotracheal tube, humidity of the ventilatory gases, ventilatory mode and nursing management result in the formation of an infective, highly viscous and adhesive layer inside of the endotracheal tube. Endotracheal tubes may contribute to the pathogenesis of VAP when infective particles of this adhesive layer are dislodged into the lower airways by shear forces imparted by the respiratory gasflow. The current state of research is reviewed and potential solutions to this problem are discussed.

Cross Infection↗

CD40 signaling and Alzheimer's disease pathogenesis.

The interaction between CD40 and its cognate ligand, CD40 ligand, is a primary regulator of the peripheral immune response, including modulation of T lymphocyte activation, B lymphocyte differentiation and antibody secretion, and innate immune cell activation, maturation, and survival. Recently, we and others have identified CD40 expression on a variety of CNS cells, including endothelial cells, smooth muscle cells, astroglia and microglia, and have found that, on many of these cells, CD40 expression is enhanced by pro-inflammatory stimuli. Importantly, the CD40-CD40 ligand interaction on microglia triggers a series of intracellular signaling events that are discussed, beginning with Src-family kinase activation and culminating in microglial activation as evidenced by tumor necrosis factor-alpha secretion. Based on the involvement of microglial activation and brain inflammation in Alzheimer's disease pathogenesis, we have investigated co-stimulation of microglia, smooth muscle, and endothelial cells with CD40 ligand in the presence of low doses of freshly solubilized amyloid-beta peptides. Data reviewed herein show that CD40 ligand and amyloid-beta act synergistically to promote pro-inflammatory responses by these cells, including secretion of interleukin-1 beta by endothelial cells and tumor necrosis factor-alpha by microglia. As these cytokines have been implicated in neuronal injury, a comprehensive model of pro-inflammatory CD40 ligand and amyloid-beta initiated Alzheimer's disease pathogenesis (mediated by multiple CNS cells) is proposed.

Alzheimer Disease↗

Peptide binding alpha1alpha2 domain of HLA-B27 contributes to the disease pathogenesis in transgenic mice.

Human spondyloarthropathies are strongly associated with a major histocompatibility complex (MHC) class I allele, HLA-B27. HLA-B27 transgenic mice and rats demonstrate many features of these diseases further confirming the role of HLA-B27 in disease. Yet the exact role of this molecule in disease pathogenesis is not clearly understood. We have previously reported spontaneous arthritis and nail disease in HLA-B27 transgenic mice lacking beta2-microglobulin (B27+beta2m(o)). These observations along with binding studies of B27 derived peptides to HLA-B27 molecule itself led to two hypotheses: (i) HLA-B27 derived peptide as a source of autoantigen; and (ii) HLA-B27 functions as an antigen presenting molecule. In this report, we confirm spontaneous disease in transgenic mice expressing a hybrid B27 molecule with alpha1alpha2 domain of B27 and alpha3 domain of mouse H-2Kd. These mice developed spontaneous arthritis and nail disease when transferred from specific pathogen free barrier facility to the conventional area. Other control mice with MHC class I transgene (e.g., HLA-B7, HLA-Cw3, and H2-Dd) did not develop such disease. In a MHC reassembly assay, binding of similar peptides to both wild type and hybrid B27 molecules was observed. In addition, the hybrid B27 molecule lacks at least one of the 3 proposed peptides from the third hypervariable (HV3) region of HLA-B27. These data strongly suggest that HLA-B27 molecule is an antigen presenting molecule rather than a peptide donor in the disease pathogenesis.

Animals↗

Overview of the pathogenesis, prophylaxis and therapeusis of viral hepatitis B, with focus on reduction to practical applications.

Hepatitis B is the most important of several hepatitis viruses of man because of the number of cases of the disease and the frequent occurrence of persistent infection that may lead to cirrhosis and cancer of the liver. The pathology of hepatitis B infection results mainly from the self-destructive cytotoxic T cell response of the host. This may be modulated by soluble pre-core e antigen of the virus that induces immune tolerance and by cytokines elaborated by cytotoxic T cells, which suppress viral replication in the infected cell. Pathogenesis of the disease is markedly influenced by viral mutations. Persistent hepatitis B virus infection may be controlled in a minority of patients by passive alpha-interferon therapy, and in a majority of patients by the nucleoside lamivudine until resistance develops. The best means to control the disease is by prevention through application of the highly effective vaccine prepared using surface antigen of the virus. It is anticipated that the gradually increasing application of the vaccine throughout the world may lead to elimination of hepatitis B as an important medical problem. This paper is intended to provide a cursory overview of the contemporary knowledge relating to pathogenesis, prophylaxis and therapeusis of human hepatitis B.

Animals↗

Critical overview and outlook: pathogenesis, prevention, and treatment of hepatitis and hepatocarcinoma caused by hepatitis B virus.

Viral hepatitis B is an enigmatic disease in which the host's own immune response to persistent viral infection may bring about host destruction through antiviral inflammatory responses which might otherwise present as a benign or inapparent disease. The simple solution to the hepatitis B problem is by immunoprophylaxis using the vaccine licensed in 1981, which prevents both infection and the late sequelae of liver cirrhosis and hepatocarcinoma. Immunotherapeutic vaccines against persistent hepatitis B infection have not been successful and new explorations are being directed to therapies which include antisense, ribozymes, gene silencing by RNA interference (RNAi) and aptamer approaches. Limited benefits from nucleoside therapy and limitations in opportunity for liver transplantation have left a large void of curative treatments. Findings with respect to e antigen tolerance provide a basis for exploration to determine whether passively administered e antigen might suppress cell-mediated immunity, creating a commensal state in which virus persists but without pathologic damage to the host. Therapy of hepatocarcinoma by conventional chemotherapy, radiation, or surgical resection and ablation gives little hope for restoration of health unless the tumor is detected very early. The large engagement of the world medical science community to develop therapeutic vaccines against cancer is now in major clinical trials to determine the hope and credibility for the immunization approach. Vaccines based on tumor peptides which are linked to heat shock proteins and directed to host dendritic cells give reason for excitement and may be the "best show in town". A new era of tumor therapy will need to be based on new discoveries in immune function which are required to pursue immunotherapy on a more rational basis. The many facets of current hepatitis B virology, pathogenesis, immunoprophylaxis, immunotherapeusis, chemotherapy, and tumor pathogenesis and therapy are discussed here, in depth, but in keeping with needed brevity.

Antineoplastic Agents↗

The molecular pathogenesis of acute promyelocytic leukaemia: implications for the clinical management of the disease.

Acute promyelocytic leukaemia (APL) is characterised by chromosomal rearrangements of 17q21, leading to fusion of the gene encoding retinoic acid receptor alpha (RARalpha) to a number of alternative partner genes (X), the most frequent of which are PML (>95%), PLZF (0.8%) and NPM (0.5%). Over the last few years, it has been established that the X-RARalpha fusion proteins play a key role in the pathogenesis of APL through recruitment of co-repressors and the histone deacetylase (HDAC)-complex to repress genes implicated in myeloid differentiation. Paradoxically, the X-RARalpha fusion protein has the potential to mediate myeloid differentiation at pharmacological doses of its ligand (all trans-retinoic acid (ATRA)), which is dependent on the dissociation of the HDAC/co-repressor complex. Arsenic compounds have also been shown to be promising therapeutic agents, leading to differentiation and apoptosis of APL blasts. It is now apparent that the nature of the RARalpha-fusion partner is a critical determinant of response to ATRA and arsenic, underlining the importance of cytogenetic and molecular characterisation of patients with suspected APL to determine the most appropriate treatment approach. Standard protocols involving ATRA combined with anthracycline-based chemotherapy, lead to cure of approximately 70% patients with PML-RARalpha-associated APL. Patients at high risk of relapse can be identified by minimal residual disease monitoring. The challenge for future studies is to improve complete remission rates through reduction of induction deaths, particularly due to haemorrhage, identification of patients at high risk of relapse who would benefit from additional therapy, and identification of a favourable-risk group, for which treatment intensity could be reduced, thereby reducing risks of treatment toxicity and development of secondary leukaemia/myelodysplasia. With the advent of ATRA and arsenic, APL has already provided the first example of successful molecularly targeted therapy; it is hoped that with further understanding of the pathogenesis of the disease, the next decade will yield further improvements in the outlook for these patients.

Animals↗

Eicosanoids in the pathogenesis of the functional and structural alterations of the kidney in diabetes.

Diabetes mellitus alters the cellular production of eicosanoids in a number of tissues, including the kidney, and these agents have in turn been implicated in the pathogenesis of diabetic nephropathy. As delineated in the streptozotocin diabetic rat (SDR) model, a preferential enhancement of glomerular synthesis of the vasodilatory prostaglandins (PGs) PGE2 and PGI2 with concurrent smaller increases in thromboxane (TX)A2 occurs within 1 week after induction of diabetes. This early alteration in glomerular synthesis of eicosanoids in the SDR has been linked to glucose-induced activation of the glomerular protein kinase C signalling system that enhances phospholipase A2 activity and, therefore, release of membrane-bound arachidonic acid for oxygenation. The preferential increase in glomerular production of vasodilatory PGs may contribute to the glomerular hyperfiltration that is characteristic of early diabetes. After more prolonged (months) diabetes in the SDR, glomerular generation and urinary excretion of thromboxane (TX) are preferentially enhanced. Studies with selective inhibitors of TX synthesis in the SDR have implicated this eicosanoid in the pathogenesis of both albuminuria and glomerular structural changes (basement membrane thickening and mesangial matrix expansion). Direct stimulation of matrix protein production has been demonstrated in cultured mesangial cells in response to both TX and high ambient concentrations of glucose. The actions of TX and glucose on mesangial cell matrix production appear to be interactive, with each signalled through distinct pathways of protein kinase C activation.

Animals↗

Molecular pathogenesis of human hepatocellular carcinoma.

Primary hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, the viral-chemical etiology as well as molecular mechanisms of HCC pathogenesis remains largely unknown. Recent studies in our laboratory have identified several potential factors that may contribute to the pathogenesis of HCC. Oxidative stress and chronic inflammation have been linked to an increased risk of liver cancer. For example, oxyradical overload diseases such as Wilson disease and hemochromatosis result in the generation of oxygen/nitrogen species that can cause mutations in the p53 tumor suppressor gene. The Hepatitis B virus X gene (HBx), a viral transactivator with oncogenic potentials, has been shown to bind to and inactivate p53-mediated apoptosis. HBx mutants derived from HCC have a diminished ability to act as a transactivator. However, they still retain the ability to bind to and abrogate p53-mediated apoptosis. The comparison of gene expression profiles between HBx-expressing primary human hepatocytes and HBV-infected liver samples by cDNA microarrays indicate a unique alteration of a subset of oncogenes and tumor suppressor genes including p53. Our studies implicate both viral and endogenous chemical processes in the etiology of HCC, and p53 may be a common target for the inactivation during liver carcinogenesis.

Carcinoma, Hepatocellular↗

Snake venom metalloproteinases: their role in the pathogenesis of local tissue damage.

The biochemical characteristics of hemorrhagic metalloproteinases isolated from snake venoms are reviewed, together with their role in the pathogenesis of the local tissue damage characteristic of crotaline and viperine snake envenomations. Venom metalloproteinases differ in their domain structure. Some enzymes comprise only the metalloproteinase domain, others have disintegrin-like and high cysteine domains and others present, besides these domains, an additional lectin-like subunit. All of them are zinc-dependent enzymes with highly similar zinc binding environments. Some metalloproteinases induce hemorrhage by directly affecting mostly capillary blood vessels. It is suggested that hemorrhagic enzymes cleave, in a highly selective fashion, key peptide bonds of basement membrane components, thereby affecting the interaction between basement membrane and endothelial cells. As a consequence, these cells undergo a series of morphological and functional alterations in vivo, probably associated with biophysical hemodynamic factors such as tangential fluid shear stress. Eventually, gaps are formed in endothelial cells through which extravasation occurs. In addition to hemorrhage, venom metalloproteinases induce skeletal muscle damage, myonecrosis, which seems to be secondary to the ischemia that ensues in muscle tissue as a consequence of bleeding and reduced perfusion. Microvessel disruption by metalloproteinases also impairs skeletal muscle regeneration, being therefore responsible of fibrosis and permanent tissue loss after snakebites. Moreover, venom metalloproteinases participate in the degradation of extracellular matrix components and play a relevant role in the prominent local inflammatory response that characterizes snakebite envenomations, since they induce edema, activate endogenous matrix metalloproteinases (MMPs) and are capable of releasing TNF-alpha from its membrane-bound precursor. Owing to their protagonic role in the pathogenesis of local tissue damage, snake venom metalloproteinases constitute relevant targets for natural and synthetic inhibitors which may complement antivenoms in the neutralization of these effects.

Animals↗

Pathogenesis of feline diabetes mellitus.

The common form of spontaneous diabetes mellitus that occurs in domestic cats bears close resemblance clinically and pathologically to human type 2 diabetes mellitus (T2DM). For example, the typical diabetic cat is obese and middle-aged, and has low but detectable circulating insulin levels. However, the most striking similarity is the occurrence of islet amyloidosis (IA) in nearly all diabetic cats and in over 90% of humans with T2DM. IA in both humans and cats is derived from islet amyloid polypeptide (IAPP, or amylin) which is a hormone produced and secreted along with insulin by the pancreatic beta cells. Since all cats and humans normally produce IAPP, additional factors must be invoked in order to explain the development of IA. Several lines of evidence support the concept that IA is caused by chronically increased stimulus for beta cells to secrete IAPP (and insulin). For example, peripheral insulin resistance such as in chronic obesity results in increased IAPP and insulin secretion. A recent study, in which diabetes mellitus was induced in cats, demonstrated that IAPP hypersecretion was induced by treatment with a sulfonylurea drug and resulted in 4/4 cats in this group developing IA. In contrast, cats treated with insulin had low IAPP secretion and minimal IA developed in 1/4 cats. Several human-IAPP transgenic mouse models, in which there is IAPP overexpression, also support the notion that prolonged high expression of IAPP leads to IA. In vitro models of IAPP overexpression also support this mechanism for IA formation and by demonstrating an association between IA formation and beta cell toxicity, suggest a linkage between IA formation and loss of beta cells in T2DM. A recent study has indicated that intermediate-sized IAPP-derived amyloid fibrils can disrupt cell membranes and therefore, may be involved in the destruction of beta cells. Striking parallels between the pathogenesis of IA and beta-amyloid plaque formation in Alzheimer's disease suggest possible parallel pathogenetic mechanisms of cell death and provide potential avenues for future studies into the pathogenesis of IA.

Amyloid↗

The role of luteinizing hormone in the pathogenesis of hyperadrenocorticism in neutered ferrets.

Four studies were performed to test the hypothesis that gonadotrophic hormones, and particularly luteinizing hormone (LH) play a role in the pathogenesis of ferrets: (I) adrenal glands of ferrets with hyperadrenocorticism were studied immunohistochemically to detect LH-receptors (LH-R); (II) gonadotrophin-releasing hormone (GnRH) stimulation tests were performed in 10 neutered ferrets, with measurement of androstenedione, 17alpha-hydroxyprogesterone and cortisol as endpoints; (III) GnRH stimulation tests were performed in 15 ferrets of which 8 had hyperadrenocorticism, via puncture of the vena cava under anesthesia; and (IV) urinary corticoid/creatinine (C/C) ratios were measured at 2-week intervals for 1 year in the same ferrets as used in study II. Clear cells in hyperplastic or neoplastic adrenal glands of hyperadrenocorticoid ferrets stained positive with the LH-R antibody. Plasma androstenedione and 17alpha-hydroxyprogesterone concentrations increased after stimulation with GnRH in 7 out of 8 hyperadrenocorticoid ferrets but in only 1 out of 7 healthy ferrets. Hyperadrenocorticoid ferrets had elevated urinary C/C ratios during the breeding season. The observations support the hypothesis that gonadotrophic hormones play a role in the pathogenesis of hyperadrenocorticism in ferrets. This condition may be defined as a disease resulting from the expression of LH-R on sex steroid-producing adrenocortical cells.

17-alpha-Hydroxyprogesterone↗

Molecular pathogenesis of bilateral breast cancer.

Bilateral breast cancer (biBC) offers intriguing possibilities for molecular genetic investigations, however it is disproportionally less studied than its unilateral counterpart. By now, genetic research has succeeded to resolve at least two important aspects of biBC pathogenesis. First, it has been confirmed, that the vast majority if not all biBC arise due to clonally independent events but not due to contralateral metastatic spread. Second, unselected biBC cases have been shown to have a modest prevalence of BRCA germ-line mutations (approximately 5%), although a considerable frequency of BRCA defects (up to 20%) has been observed in early-onset and/or familial forms of the disease. Other data related to biBC appear to be at suggestive stage. Recent reports demonstrate, that the tumors forming biBC pair may show similarities of their molecular portraits, especially if they develop synchronously. This observations imply that the host factors may determine not only the level of breast cancer susceptibility, but also the molecular variant of the disease development. Apart from this, biBC may serve as a very demonstrative case group in the studies of breast cancer predisposing low-penetrance gene polymorphisms, because it is more likely to accumulate unfavorable allele combinations than the unilateral patients. The utility of this approach has been already exemplified by several scientific publications. Further research on the biBC molecular pathogenesis may significantly contribute to the general understanding of the process of malignant transformation.

Allelic Imbalance↗

Serial experimental and clinical studies on the pathogenesis of multiple organ dysfunction syndrome (MODS) in severe burns.

These serial clinical and experimental studies were designed to clarify the pathogenesis of postburn MODS. Both animal and clinical studies were performed. In animal experiments, 46 male cross-bred dogs were cannulated with Swan-Ganz catheters and 39 of them were inflicted with 50% TBSA third degree burns (7 were used as controls). The burned dogs were randomly divided into 4 groups: immediate infusion, delayed infusion, delayed fast infusion and delayed fast infusion combined with ginsenosides. All dogs were kept under constant barbiturate sedation during the whole study period. Hemodynamics, visceral MDA, mitochondrial respiratory control rate (RCR) and ADP/O ratio, ATP, succinic dehydrogenase (SDH), organ water content as well as light and electron microscopy of visceral tissues were determined. In the clinical study, 61 patients with extensive deep burns were chosen, of which 16 sustained MODS. Plasma TXB2/6-keto-PGF1alpha ratio, TNF, SOD, MDA, circulatory platelet aggregate ratio (CPAR), PGE2, interleukin-1, total organ water content and pathological observations of visceral tissues from patients who died of MODS were carried out. Results demonstrated that ischemic-reperfusion damage due to severe shock, sepsis and inhalation injury are three main causes of postburn death. All inflammatory mediators increased markedly in both animals and patients who sustained organ damage or MODS. SDH, RCR, ADP/O and ATP decreased significantly. These findings suggested that ischemic damage and systemic inflammatory response syndrome (SIRS) initiated by mediators or cytokines might be important in the pathogenesis of postburn MODS.

6-Ketoprostaglandin F1 alpha↗

Hypophosphatemic osteomalacia in neurofibromatosis 1: hypotheses for pathogenesis and higher incidence of spinal deformity.

Osteomalacia is rarely encountered in association with neurofibromatosis 1, characterized by phosphate loss in the urine and its pathogenesis is still unknown. Incidence of spinal deformities in cases of neurofibromatosis 1 associated with osteomalacia seems to be high. Spinal deformities are unlikely to be due to osteomalacia itself. Melatonin deficiency was proposed to be present in cases of neurofibromatosis 1 and to be an operating factor in progression of spinal deformities. We might hypothesize that putative melatonin deficiency in cases of neurofibromatosis 1 might play a role in the pathogenesis of hyperphosphaturea by decreasing sodium-phosphate cotransport, increasing the level of cAMP, the un-antagonized effect of dopamine on phosphate reabsorption and increasing glucocorticoid levels. Parathyroid overactivity that may occur secondary to osteomalacia might have synergistic effects with dopamine and further exaggerate phosphate loss in urine. On the other hand, excess corticosteroid secretion would decrease nocturnal melatonin level. Moreover, in the presence of hypophosphatemia, hypercortisolism might further inhibit melatonin secretion that might lead to progression of spinal deformities in these cases.

Hypophosphatemia, Familial↗