Genetic Alterations in Differentiated Thyroid Cancer Patients with Acromegaly.

AIM: Acromegaly is associated with increased thyroid cancer risk. We aimed to analyze the frequency of point mutations of BRAF and RAS genes, and RET/PTC, PAX8/PPARγ gene rearrangements in patients with acromegaly having differentiated thyroid cancers (DTC) and their relation with clinical and histological features. MATERIALS AND METHODS: 14 acromegalic patients (8 male, 6 female) with DTC were included. BRAF V600E and NRAS codon 61 point mutations, RET/PTC1, RET/PTC3, and PAX8/PPARγ gene rearrangements were analyzed in thyroidectomy specimens. We selected 14 non-acromegalic patients with DTC as a control group. RESULTS: 2 patients (14.3%) were detected to have positive BRAF V600E and 3 patients (21.4%) were detected to have NRAS codon 61 mutation. NRAS codon 61 was the most frequent genetic alteration. Patients with positive mutation had aggressive histologic features more frequently than patients without mutations. Comparison of the acromegalic and non-acromegalic patients with DTC revealed that BRAF V600E mutation was more frequent in non-acromegalic patients with DTC (14.2% vs. 64.3%, p=0.02). RET/PTC 1/ 3, PAX8/PPARγ gene rearrangements were not detected in any patient. None of the patients including the patients with positive point mutations had recurrence, and local and/or distant metastasis. CONCLUSION: NRAS codon 61 is the most frequent genetic alteration in this acromegaly series with DTC. Since acromegalic patients have lower prevalance of BRAF V600E mutation, BRAF V600E mutation may not be a causative factor in development of DTC in acromegaly. Despite the relation of BRAF V600E and NRAS codon 61 mutations with aggresive histopathologic features, their impact on tumor prognosis remains to be defined in acromegaly in further studies.

The role of apoptosis in blepharoptosis.

PURPOSE: The purpose of this study is to evaluate the role of apoptosis in the pathogenesis of blepharoptosis. PATIENTS AND METHODS: Forty-five eyelids of 43 consecutive patients (16 female, 27 males) that underwent levator resection surgery for ptosis correction were included in the study. Twenty-six of the eyelids had congenital myogenic ptosis and 19 had aponeurotic ptosis. Levator palpebrae superioris function and height of the vertical palpebral fissure were measured in all patients. After levator resection surgery, the distal part of the levator aponeurosis was fixed and sent for evaluation. Apoptotic cells were detected using Apop Tag Plus Peroxidase In Situ Apoptosis Detection Kit. RESULTS: The mean levator palpebrae superioris function was 8.4 mm (range 5-10 mm) in congenital ptosis group and 12.1 mm (range 10-17 mm) in the aponeurotic ptosis group. The mean height of the vertical palpebral fissure in patients with congenital ptosis and aponeurotic ptosis were 6.5 mm (range 5-9 mm) and 6.1 mm (3-9 mm), respectively. The mean apoptotic index of congenital ptosis and aponeurotic ptosis were 27.3 (16-39) and 29.8 (18-41), respectively. There was no statistically significant difference between congenital and aponeurotic ptosis groups in a mean apoptotic index (P<0.05). Apoptotic index was not correlated with age, levator palpebrae superioris function, palpebral fissure height, and lid crease height in two groups. CONCLUSION: We found no statistically significant difference between two subtypes of blepharoptosis regarding apoptosis. According to this study, apoptosis seems to have no significant role in the development of aponeurotic blepharoptosis.

Chemotherapy for transient myeloproliferative disorder in a premature infant with Down syndrome.

WHAT IS KNOWN AND OBJECTIVE: Congenital leukaemia is the most common leukaemia in newborns with Down syndrome, but it must be differentiated from transient myeloproliferative disorder. The majority of transient myeloproliferative disorders regresses spontaneously during the first few months of life. Data on the treatment outcomes of transient myeloproliferative disorder in premature infants are very rare. We present a case of a very-low-birthweight (1350 g) premature newborn with Down syndrome, diagnosed as having transient myeloproliferative disorder and treated with chemotherapy due to recurrent hyperleucocytosis (WBC: 148 000/mm³) after repeated exchange transfusions. CASE SUMMARY: The patient's WBC count regressed to 24 000/mm(3) without treatment. During the follow-up period, the WBC increased on consecutive days and reached 95 000/mm(3) on the 16th day of the hospitalization. Therefore, chemotherapy was started. Single-agent cytarabine infusion was administered over five days. After the therapy, the WBC count stayed stable and remained steady in the range 4600-13600/mm(3) in the second month. WHAT IS NEW AND CONCLUSION: A very-low-birthweight infant with Down syndrome and recurrent transient myeloproliferative disorder was successfully treated with cytarabine.

The association of molybdenum cofactor deficiency and pyloric stenosis.

Molybdenum cofactor deficiency (MoCD) is a rare autosomal recessive disorder that may present during the neonatal period with intractable seizures. Co-existence of MoCD and pyloric stenosis is previously reported as a coincidence or common etiology. The etiology of the two conditions is unclear; however, reports demonstrate neuronal deficiency in both. We report a neonate who was diagnosed with MoCD and hypertrophic pyloric stenosis.

Challenging diagnosis: oligodendroglioma versus extraventricular neurocytoma.

Diagnosis of oligodendroglioma from other clear cell neoplasms of central nervous system (CNS) is still challenging despite advances in neuroradiology and molecular diagnostic tools. Herein, we present a 44-year-old male patient who had a diagnosis of right parietal oligodendroglioma grade II in 1994 which recurred in 2002. He presented with intratumoral hemorrhage and he underwent radical resection of tumor in 2003. Histopathological examination of the recurrent tumor showed anaplastic progression with confusing immunohistochemical (IHC) results; the tumor was positive for NeuN and synaptophysin staining. The question arisen was whether the recurrent tumor was an oligodendroglioma with neuronal differentiation or an extraventricular neurocytoma initially misdiagnosed as oligodendroglioma. Repeated IHC staining showed negative results for NeuN and synaptophysin. Chromosomal analysis revealed 1p/19q deletion, which led to the diagnosis ofanaplastic oligodendroglioma grade III. Accurate diagnosis of oligodendroglioma is crucial due to recent advances and promises in its treatment. Current diagnostic methods of oligodendroglial tumors are discussed in context of differentiating oligodendrogliomas from other clear cell neoplasms of CNS, especially from extraventricular neurocytomas.

A glioma with an arteriovenous malformation: an association or a different entity?

A 58-year-old male was admitted with headache to our neurosurgery clinic. His neurological examination revealed slight left hemiparesis. The radiological evaluation with contrast administred magnetic resonance imaging (MRI) scan demonstrated a right temporo-parietal ring enhancing mass lesion surrounded by edema which was resembling a typical glioma (Fig. 1). The patient was operated on via a temporo-parietal craniotomy and an arteriovenous malformation surrounded by abnormal glial tissue was observed during the exposure. A nidus supplied by several branches arising from the middle cerebral artery (MCA) was obvious. The venous drainage of the malformation was to the superficial venous system. The observed arterial feeders and the draining vein were coagulated and the nidus was macroscopically totally excised. The frozen examination from surrounding glial tissue revealed a high grade glioma. The tumor was also macroscopically totally excised. Postoperatively, the cerebral angiogram demonstrated a right temporal arteriovenous malformation with a centrally excised nidus. The remaining major feeders involved the angular gyrus and the posterior temporal arteries. The venous drainage was to the straight and sigmoid sinuses (Fig. 2). The final histopathological examination of the specimen revealed an arteriovenous malformation surrounded by a high grade glioma (Fig. 3). The patient refused a second operation for total removal of the AVM. Postoperatively, he is doing well with improvement of his left hemiparesis.

Alterations in the morphology of lamina cribrosa pores in glaucomatous eyes.

AIMS: To determine alterations which occur in the size and shape of lamina cribrosa (LC) pores in glaucomatous eyes over a period of time. METHODS: Baseline and follow up optic disc photographs were retrospectively studied in 39 eyes of 39 patients with glaucoma. Only eyes with a vertical cup to disc ratio equal to or greater than 0.6 were included in the study. In addition, all selected eyes had to have serial optic disc photographs obtained at least 3 years apart allowing clear visualisation of LC surface. The association of the alterations in LC surface morphology with patient specific and eye specific characteristics was statistically analysed. RESULTS: During a mean study period of 3.90 (SD 0.7) years, individual pore size (mean pore area to disc area ratio) exhibited a significant decrease between baseline and follow up measurements of each eye (p<0.0001). However, during the study period, total pore area to disc area ratio did not change (p>0.05), and the change in pore shape in some eyes (from circular to more oval and elongated) was statistically insignificant (p = 0.12). Although a relation was detectable between the optic disc and lamina cribrosa parameters at a given time, which reflects cumulative effects, during the study period, there was no significant association between the changes of the LC parameters and neural tissue damage. The rate and the magnitude of the changes in individual pore size during the study period were not significantly different among the eyes exhibiting progressive neural rim damage and those staying stable (p>0.05). CONCLUSION: These findings demonstrate that the LC surface morphology exhibits changes along with the glaucomatous optic disc damage. However, the clinical appearance of LC surface in glaucomatous eyes may continue to change, even when the neural rim damage is clinically stable. These findings are probably associated with the chronic cellular events of tissue remodelling that occur in the glaucomatous optic nerve head.

Cranial infantile myofibromatosis: report of three cases.

BACKGROUND: Infantile myofibromatosis is a proliferative disorder of infancy and early childhood characterized by the development of single or multiple nodular lesions arising from cutaneous or subcutaneous tissue, muscle, bone or visceral organs. In approximately one-third of cases, this myofibroblastic proliferation involves the head and neck region. CASE REPORT: In this paper we report on three cases of cranial infantile myofibromatosis in infants. The clinical presentation and the deceptive histopathological features can make diagnosis difficult. CONCLUSION: The significance of recognizing this entity is stressed, since its indolent clinical behavior might prevent diagnosis.

TNF-alpha and TNF-alpha receptor-1 in the retina of normal and glaucomatous eyes.

PURPOSE: To determine the expression and localization of tumor necrosis factor (TNF)-alpha and TNF-alpha receptor-1 in the retina of normal and glaucomatous eyes. METHODS: Using immunohistochemistry and in situ hybridization, retinal expression and localization of TNF-alpha and TNF-alpha receptor-1 were studied in retina sections from 20 eyes of donors with glaucoma, and 20 eyes of age-matched normal donors. RESULTS: According to immunohistochemistry, the intensity of the immunostaining and the number of labeled cells for TNF-alpha or its receptor were greater in retina sections of glaucomatous eyes than in control eyes of age-matched normal donors. In situ hybridization showed that mRNA signals for TNF-alpha or TNF-alpha receptor-1 were similarly more intense in glaucomatous eyes than in age-matched control eyes. Both protein and mRNA of TNF-alpha or TNF-alpha receptor-1 were predominantly localized to the inner retinal layers. Double-immunofluorescence labeling demonstrated that retinal immunostaining for TNF-alpha was predominantly positive in the glial cells, whereas immunostaining for TNF-alpha receptor-1 was mainly positive in the retinal ganglion cells. CONCLUSIONS: Upregulation of TNF-alpha and its receptor-1 in glaucomatous retina suggest that TNF-alpha-mediated cell death is involved in the neurodegeneration process of glaucoma.

Clinical factors associated with progression of glaucomatous optic disc damage in treated patients.

BACKGROUND: Reducing intraocular pressure (IOP) in glaucomatous eyes does not always prevent disease progression. OBJECTIVE: To determine the clinical factors associated with progressive optic disc damage in glaucomatous eyes receiving treatment to reduce IOP. METHODS: Baseline and follow-up optic disc photographs as well as demographic and clinical data were retrospectively studied in 186 eyes of 93 patients with primary open-angle glaucoma, and in 138 eyes of 69 patients with normal-pressure glaucoma. The patients with primary open-angle glaucoma were included in the study only if their treated IOPs during a follow-up period of 5 years were less than 21 mm Hg. The patients with normal-pressure glaucoma were included only if their IOPs were reduced by at least 20% during the follow-up period. The association of progressive optic disc damage with patient- and eye-specific characteristics was examined using multivariate analysis. RESULTS: During the 5-year study period, 141 (43.5%) of the 324 eyes exhibited progressive optic disc damage defined by at least a 5% decrease in the neural rim area-to-disc area ratio. Using multivariate analysis, the following were found to be strongly associated with progressive neural rim damage: a baseline smaller neural rim area-disc area ratio (P<.001); a baseline larger zone beta area-disc area ratio (P =.04); a baseline larger parapapillary atrophy length-disc circumference ratio (P =.05); a diagnosis of normal-pressure glaucoma (P =.01); and combined medical and surgical treatment prior to the study period (P =.01). CONCLUSIONS: Clinical factors other than IOP may be important indicators of subsequent progression of glaucomatous optic disc damage. Our findings suggest that eyes with advanced glaucomatous optic disc damage and normal-pressure glaucoma are more likely to progress despite receiving treatment to reduce IOP.

Serum autoantibody against glutathione S-transferase in patients with glaucoma.

PURPOSE: To identify retinal proteins that are the targets of serum autoantibodies in patients with glaucoma. METHODS: To identify retinal antigens that are recognized by the sera of patients with glaucoma, immunoreactive bands were separated, by using two-dimensional gel electrophoresis of the bovine retinal soluble fraction. A 29-kDa band was then selected for further analysis. Tryptic peptides of the 29-kDa band were analyzed using electrospray mass spectrometry to identify the protein. After protein identification, immunoreactivity against this newly identified protein was studied by Western blot analysis using sera from 65 patients with glaucoma (25 with primary open-angle glaucoma [POAG]; 40 with normal-pressure glaucoma [NPG]) and 25 age-matched healthy subjects. In addition, serum antibody titers were compared in these groups, by using a specific enzyme-linked immunosorbent assay (ELISA). RESULTS: The 29-kDa band was identified as glutathione S-transferase (GST). Western blot analysis revealed that serum antibodies against GST antigen were recognized in 34 (52%) of 65 patients with glaucoma (22 of NPG and 12 of POAG) and 5 (20%) of 25 age-matched control subjects (chi(2) test, P < 0.05). By ELISA, it was also found that patients with glaucoma had higher titers of anti-GST antibody, compared with the control group (Mann-Whitney test; NPG versus control, P = 0.013; POAG versus control, P = 0.0006). CONCLUSIONS: These findings indicate that GST is one of the retinal antigens targeted by the serum antibodies detected in some patients with glaucoma.

In vitro evaluation of reactive astrocyte migration, a component of tissue remodeling in glaucomatous optic nerve head.

In order to improve understanding of remodeling events in the glaucomatous optic nerve head, the migration of optic nerve head astrocytes was studied in vitro. Since elevated intraocular pressure is an important stress factor identified in glaucomatous eyes, optic nerve head astrocytes were incubated under physical stress created by elevated hydrostatic pressure. In addition, they were incubated in the presence of a chemical stimulus, lipolysaccharide (LPS). Migration of reactivated astrocytes in the presence of these stressors was examined using chambers in which cell migration through extracellular matrix-coated pores is only possible following proteolytic digestion of the matrix. We observed that the migratory ability of optic nerve head astrocytes was approximately 4-6 times greater following exposure to elevated hydrostatic pressure or LPS for up to 48 h. Phosphoinositide 3-kinase, protein kinase C, and tyrosine kinase were found to be involved in the signal transduction for activated migration of optic nerve head astrocytes in response to elevated hydrostatic pressure or LPS. In addition, we observed that the stress-induced migration of optic nerve head astrocytes, which is accompanied by proteolytic degradation, resulted in the formation of culture cavities containing mucopolysaccharides. These in vitro findings provide a clearer understanding of the pathophysiologic mechanisms of characteristic tissue remodeling events that occur, in vivo, in the glaucomatous optic nerve head.

In situ detection of apoptosis in normal pressure glaucoma. a preliminary examination.

Retinal ganglion cell (RGC) neurons are believed to die via apoptosis in human primary and secondary open-angle glaucoma. Previous studies have relied solely on the TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate [UTP]-biotin nick end-labeling) method of detecting DNA fragmentation to identify apoptotic nuclei. However, it is now clear that the TUNEL method cannot distinguish between the single- and double-strand DNA breaks that can be a feature of both apoptosis and necrosis. We have developed a double fluorescent labeling method that simultaneously combines in situ end-labeling (ISEL) to detect DNA fragmentation followed by staining with a cyanine dye, YOYO-1, to visualize apoptotic chromatin condensation. This allows for the unequivocal identification of an apoptotic nucleus. Our preliminary data obtained from one case of normal pressure glaucoma suggests that RGC neurons may die via apoptosis when intraocular pressure is not elevated.

Induction of HLA-DR expression in human lamina cribrosa astrocytes by cytokines and simulated ischemia.

PURPOSE: Recent evidence strongly suggests that activated immunity occurs during the neurodegenerative process of glaucomatous optic neuropathy. Although activation of lamina cribrosa astrocytes has been identified in glaucomatous optic nerve head, their role on the activated immune responses seen in glaucoma patients is unknown. Here, the authors aimed to study the potential role of lamina cribrosa astrocytes as a component of activated immune responses seen in glaucoma patients. METHODS: Expression of HLA-DR in optic nerve head astrocytes was studied using immunohistochemistry in postmortem eyes of patients with glaucoma and normal donors. Serum cytokine levels of patients with glaucoma and control subjects were measured using enzyme-linked, immunosorbent assay. In addition, in vitro experiments were performed using astrocyte cultures derived from human optic nerve head or fetal human brain. The cultured astrocytes were incubated under selected stress conditions such as exposure to cytokines, IFN-gamma and IL-10, or simulated ischemia for up to 48 hours. The expression of HLA-DR was studied in these cells using flow cytometry and immunocytochemistry. RESULTS: Immunohistochemistry demonstrated an upregulation of the HLA-DR expression in the optic nerve head astrocytes in glaucoma. In addition, serum levels of IL-10 was higher in the patients with normal pressure glaucoma compared to age-matched control subjects (P: = 0.001). Regarding in vitro experiments, unlike brain astrocytes, the percentage of cells expressing HLA-DR was approximately 3 times higher in the cultures of optic nerve head astrocytes exposed to simulated ischemia compared to cultures incubated under normal conditions (P: = 0.09). Incubation with IFN-gamma induced HLA-DR expression in brain and lamina cribrosa astrocytes, up to 25-fold, (P < 0.001) either in the absence or presence of simulated ischemia. Induction of HLA-DR expression by IL-10 was approximately 6 times higher in lamina cribrosa astrocytes incubated under simulated ischemia compared to that incubated under normal condition (P: = 0.004) and was not prominent in brain astrocytes. CONCLUSIONS: These findings suggest that optic nerve head astrocytes function as antigen-presenting cells and that their immunogenic capacity is more sensitive to ischemia than brain astrocytes. Taken together, these findings provide novel evidence that regulation of immunogenic capacity of optic nerve head astrocytes by cytokines or ischemic stress may have a role during the neurodegeneration process in patients with glaucoma.

Serum autoantibodies to heat shock proteins in glaucoma patients from Japan and the United States.

OBJECTIVE: To study serum titers of antibodies against heat shock proteins in glaucoma patients from two different ethnic populations and to examine the relationship between serum antibody titers and glaucomatous damage. STUDY DESIGN: Comparative, cross-sectional study. PARTICIPANTS: Twenty-seven age-matched patients with primary open-angle glaucoma, 28 patients with normal pressure glaucoma, and a control group of 26 healthy subjects from Japan; and 21 age-matched patients with primary open-angle glaucoma, 40 patients with normal pressure glaucoma, and a control group of 20 healthy subjects from the United States. MAIN OUTCOME MEASURES: Measurement of serum antibody titers and examination of optic disc and visual field parameters. METHODS: Serum immunoreactivity against heat shock proteins, including hsp27, alphaB-crystallin, and human and bacterial hsp60, was studied by enzyme-linked immunosorbent assay (ELISA). The relationship of serum antibody titers to glaucoma parameters, including mean deviation, neural rim area-to-disc area ratio, and peripapillary atrophy area-to-disc area ratio was examined. RESULTS: The serum ELISA titers of antibodies, including hsp27, alphaB-crystallin, human hsp60, and bacterial hsp60 antibodies, were higher in glaucoma patients compared with control subjects in both the Japanese and American groups (P: < 0.05). There was no association between the serum antibody titers and optic disc parameters in either group from Japan or the United States (P: > 0.05). CONCLUSIONS: These findings suggest that increased titers of circulating antibodies against heat shock proteins occur in both Japanese and American patients with glaucoma. The lack of a relationship between the level of serum antibody titers and the degree of glaucomatous damage in either ethnic group suggests that increased antibodies to heat shock proteins do not occur as an epiphenomenon of the glaucomatous neurodegeneration process.

Concordance of parapapillary chorioretinal atrophy in ocular hypertension with visual field defects that accompany glaucoma development.

OBJECTIVE: To determine whether the extent and location of progressive parapapillary chorioretinal atrophy noted in some patients with ocular hypertension are correlated with the extent and location of visual field defects that occur with progression to glaucoma. STUDY DESIGN: Retrospective cohort study. PARTICIPANTS: Thirty patients with ocular hypertension who had progressive changes of parapapillary atrophy develop before clinically detectable optic disc or visual field damage. MAIN OUTCOME MEASURES: Assessment of changes in the parapapillary atrophy and visual field parameters. METHODS: Baseline and follow-up optic disc photographs and visual field test results were retrospectively analyzed. The relationship between the extent of parapapillary atrophy observed during the ocular hypertension period and initial visual field abnormalities detected after glaucoma development, as well as their spatial relationship, was statistically analyzed. RESULTS: The extent of progressive changes of the parapapillary atrophy detected during the ocular hypertension period was correlated with the extent of changes in the visual field parameters, including corrected pattern standard deviation and mean deviation measured after glaucoma development (Mantel-Haenszel chi-square test, P = 0.026, P = 0.037, respectively). In addition, the visual field abnormalities occurred in the corresponding quadrants of the progressive parapapillary atrophy. Analysis of the spatial relationship revealed that the location of progressive changes of the parapapillary atrophy was concordant with the location of visual field abnormalities in 78% of the quadrants (94 of 120 quadrants) (chi-square test, P = 0.001). CONCLUSIONS: The extent and location of visual field abnormalities that develop in ocular hypertensive eyes with progression to glaucoma exhibit a concordance with the extent and location of progressive parapapillary atrophy noted in the ocular hypertension period. This suggests the importance of detailed examination of the parapapillary area in ocular hypertensive eyes.

Matrix metalloproteinases and tumor necrosis factor alpha in glaucomatous optic nerve head.

OBJECTIVE: To study expression and location of matrix metalloproteinases (MMPs) and tumor necrosis factor alpha (TNF-alpha) in glaucomatous optic nerve heads, which are known to be secreted in response to a variety of neuronal injury. METHODS: Four postmortem eyes from patients with primary open-angle glaucoma, 7 eyes from patients with normal-pressure glaucoma, and 4 eyes from age-matched normal donors were studied by immunohistochemistry. The sections of the optic nerve heads were examined after immunostaining with antibodies to MMPs (MMP-1, MMP-2, and MMP-3), TNF-alpha, or TNF-alpha receptor 1. RESULTS: The intensity of the immunostaining and the number of stained cells for MMPs, TNF-alpha, or TNF-alpha receptor 1 were greater in the glaucomatous optic nerve heads, particularly in eyes with normal-pressure glaucoma compared with age-matched controls. Positive immunostaining was observed in all regions of the glaucomatous optic nerve heads, but most prominently in the postlaminar region. Immunostaining was observed mainly in glial cells and their processes around the axons and blood vessels and in pial septae. CONCLUSION: There is increased immunostaining for MMPs, TNF-alpha and TNF-alpha receptor 1 in the glaucomatous optic nerve head, which suggests increased expression of these proteins in glaucoma and thereby implies a role in the tissue remodeling and degenerative changes seen in glaucomatous optic nerve heads. CLINICAL RELEVANCE: The MMPs and TNF-alpha may be components of astroglial activation that occurs in glaucomatous optic nerve heads. The biological alterations in the expression of these proteins may play a role in the progression of glaucomatous optic neuropathy.

The mechanisms of hsp27 antibody-mediated apoptosis in retinal neuronal cells.

Although elevated titers of serum antibodies to hsp27 accompany human diseases such as cancer and glaucoma, evidence of their pathogenic effects is lacking. Here we present novel evidence that exogenously applied hsp27 antibody enters neuronal cells in human retina by an endocytic mechanism. Subsequent to internalization, hsp27 antibody facilitates apoptotic cell death as characterized by morphological assessment, DNA fragmentation, and the activation of cysteine aspartic acid proteases. In addition, we demonstrate that after internalization, hsp27 antibody is detected in discrete cytoplasmic and nuclear structures and colocalizes to actin cytoskeleton. Hsp27 antibody binding to actin results in depolymerization and proteolytic cleavage of actin in a dose-dependent manner. These results suggest that exogenous hsp27 antibody may induce neuronal apoptosis by inactivating or attenuating the ability of native hsp27 to stabilize actin cytoskeleton, thereby providing a novel mechanism by which autoantibodies to hsp27 may impair cell survival in selective human diseases.

Immunostaining of heat shock proteins in the retina and optic nerve head of normal and glaucomatous eyes.

PURPOSE: To examine immunostaining of 60-kd and 27-kd heat shock proteins (HSP 60 and HSP 27), which are known to increase cell survival in response to stress, in glaucomatous retina and optic nerve head. METHODS: Six postmortem eyes from patients with primary open-angle glaucoma, 6 eyes from patients with normal-pressure glaucoma, and 6 eyes from age-matched normal subjects were studied by immunohistochemistry. The sections of the retina and optic nerve head were examined after immunostaining with antibodies to HSP 60 and HSP 27. RESULTS: The intensity of the immunostaining and the number of labeled cells for heat shock proteins (HSPs) were greater in retina sections from glaucomatous eyes than in sections from normal eyes from age-matched donors. Retinal immunostaining of HSP 60 was prominent in the retinal ganglion cells and photoreceptors, whereas immunostaining of HSP 27 was prominent in the nerve fiber layer and ganglion cells as well as in the retinal vessels. In addition, retinal immunostaining of these HSPs exhibited regional and cellular differences. Optic nerve heads of glaucomatous eyes exhibited increased immunostaining of HSP 27, but not HSP 60, which was mostly associated with astroglial cells in the lamina cribrosa. CONCLUSION: The increased immunostaining of HSP 60 and HSP 27 in the glaucomatous eyes may reflect a role of these proteins as a cellular defense mechanism in response to stress or injury in glaucoma. CLINICAL RELEVANCE: These findings suggest that immunoregulation is an important component of glaucomatous optic neuropathy.