Evaluation of Skeletal Muscle Dysfunction Associated With Acute Inflammation by Electrical Impedance Myography: A Case Report on Skeletal Muscle Dysfunction After Cardiac Surgery and Literature Review.

Electrical impedance myography (EIM) is an evaluation technique for skeletal muscles that uses electrical impedance technology. Recent reviews have shown that EIM is useful as a method to assess changes in skeletal muscle quality and quantity with aging. These may be utilized for functional changes in inflammatory skeletal muscles, such as disease and operation. In this report, the impedance parameters using EIM present perioperative skeletal muscle changes in patients after cardiac surgery. In addition, we will describe the efficacy of EIM in skeletal muscle dysfunction due to inflammation or disease. This study aimed to elucidate the efficacy of EIM in acute inflammation-associated skeletal muscle dysfunction.

Clinical Features of Systemic Metastatic Retinal Lymphoma in Japanese Patients.

PURPOSE: Systemic metastatic retinal lymphoma (SMRL) originates in systemic organs. It has been reported to exhibit clinical features similar to those of primary vitreoretinal lymphoma (PVRL). We report six cases of SMRL in a single-center survey in Japan. METHODS: The clinical and pathologic features in SMRL at the Kyushu University Hospital were retrospectively studied. RESULTS: The mean patient age at the onset of ocular involvement was 75.3 years. Four patients had brain involvement. The primary sites were: breast (2); chest (1); testis (1); intestinal tract (1); and nasal sinus (1). In all patients, the cytology of vitreous samples indicated diffuse large B-cell lymphoma (DLBCL). CONCLUSIONS: DLBCL is the most common subtype in our study. The prevalence of CNS involvement in patients with SMRL is similar to that with PVRL. The testis and breast may be common sites of origin for SMRL.

[A Case of Primary Dural Lymphoma of Jugular Tubercle Mimicking Lower Clival Meningioma].

Primary dural lymphoma (PDL) is a rare type of primary central nervous system lymphoma (PCNSL); however, its clinical etiology and appearance on magnetic resonance images (MRI) are similar to those of meningioma. We report a case of PDL mimicking a meningioma in the jugular tubercle, with hemiparesis and double vision, and review the published PDL case reports. A 41-year-old woman experienced numbness on her right side, and reported right hemiparesis and double vision 2 days thereafter. Her cranial computed tomography (CT) scan showed a mass lesion in the posterior fossa, and contrasted MRI revealed homogenous tumor with a dural tail sign in the left jugular tubercle. The patient was diagnosed as having jugular tubercle meningioma. However, her symptoms disappeared promptly with the injection of dexamethasone, and follow-up MRI showed that the tumor had diminished. After 9 months, her double vision recurred and MRI results indicated tumor regrowth. She underwent sub-total resection of the tumor via the left trans-condylar fossa approach. A histological diagnosis was PDL. She was treated with 3 courses of high-dose methotrexate, and subsequent MRI results showed a partial reduction of the residual tumor. PDL is histologically associated with marginal zone lymphoma (MZL), and is sensitive to radiation and chemotherapy. This patient responded well to high-dose methotrexate alone. PDL is one of the important differential diagnoses of meningioma.

Life-Threatening Intracranial Hypotension after Skull Base Surgery with Lumbar Drainage.

Although lumbar drainage (LD) is widely used in skull base surgery (SBS), no cases with intracranial hypotension (IH) following LD-assisted SBS have been reported, and skull base surgeons lack awareness of this potentially life-threatening condition. We report two cases of IH after LD-assisted SBS, a spheno-orbital meningioma and an osteosarcoma in the orbit. Despite a minimal amount of cerebrospinal fluid (CSF) drainage and early LD removal, severe postural headache and even a deteriorating consciousness level were observed in the early postoperative course. Neuroimages demonstrated epidural fluid collections, severe midline shift, and tonsillar sag compatible with IH. Epidural blood patch (EBP) immediately and completely reversed the clinical and radiologic findings in both patients. IH should be included in the differential diagnosis of postural headache after LD-assisted SBS that can be managed successfully with EBP. Persistent leakage of CSF at the LD-inserted site leads to IH. Broad dural dissection and wide removal of bony structure may be involved in the midline shift. EBP should be performed soon after conservative management fails. Further reports will determine the risk factors for IH development following LD-assisted SBS.

Black soybean extract reduces fatty acid contents in subcutaneous, but not in visceral adipose triglyceride in high-fat fed rats.

It is known that black soybean (BS) extract, rich in polyphenols, has beneficial effects against obesity, inflammation and insulin resistance. However, detailed effects of BS on lipid metabolism have not been documented well. In the present study, we compared fatty acid composition in visceral and subcutaneous adipose tissues of high-fat fed (HFF) rats and BS administered HFF rats. Black soybean administration for 6 weeks influenced neither body nor adipose tissue weights, blood glucose, plasma insulin levels, or insulin sensitivity. However, BS reduced several saturated (C14:0 and C16:0), monounsaturated (C14:1n-5 and C18:1n-9) and n-6 polyunsaturated (C18:2n-6, C20:3n-6, C20:4n-6 and C22:4n-6) fatty acid contents in subcutaneous fat without any change in n-3 polyunsaturated fatty acid contents. No such effect was observed in fatty acid composition in visceral fat. Long-chain fatty acids are involved in regulation of inflammation. Therefore, those reduced fatty acids may be linked to the effects on suppressing inflammation.

Black soybean extract improves lipid profiles in fenofibrate-treated type 2 diabetics with postprandial hyperlipidemia.

Black soybeans (Glycine max (L.) Merr.) are known to be rich in polyphenols, including anthocyanins, and they have been consumed since ancient times for their beneficial effects on health. In addition, it has been reported that black soybean (BS) seed coat may ameliorate obesity and insulin resistance. In the present study, we administered BS extract to type 2 diabetics for 2 months to investigate the effects of BS on glycemic control and lipid metabolism parameters. In addition, we administered BS and antihyperlipidemic agent, fenofibrate, to patients with type 2 diabetes complicated by postprandial hyperlipidemia for 2 months and assessed the combined effects of fenofibrate and BS on serum lipid profile. The results showed that administration of the BS alone had no effect on the blood glucose or lipid levels, but that administration of fenofibrate alone and fenofibrate in combination with the BS significantly lowered their serum triglyceride (TG) level at fasting state, and the percent decrease in the serum TG level after combined administration was significantly higher than in the subjects who received fenofibrate alone. Furthermore, the serum LDL cholesterol concentration, which did not decrease when fenofibrate was administered alone, decreased significantly when the BS and fenofibrate were administered in combination. These results suggest that combined administration of the BS with fenofibrate enhanced the antihyperlipidemic action of fenofibrate, and the results of this study demonstrated the usefulness of the BS in clinical practice.

[A case of acute intracranial epidural hematoma caused by chronic nasal sinusitis].

Non-traumatic intracranial acute epidural hematoma(EDH)is rare. It is mostly caused by coagulation disorders, dural metastasis, or vascular malformations of the dura. We report a case of non-traumatic acute EDH caused by chronic nasal sinusitis and review the literature comprising 10 cases of acute EDH caused by chronic nasal sinusitis. A 16-year-old boy visited our outpatient clinic with a 2-day history of severe headache. He did not have fever or neurological abnormalities and showed no evidence of head trauma. Cranial computed tomography(CT)revealed sphenoid sinusitis and a small amount of epidural air in the middle fossa, but no other intracranial abnormalities. After eight days with no subsequent history of trauma, radiological exams showed a massive acute epidural hematoma in the left middle fossa and temporal convexity without any vascular lesion or skull fracture. The patient underwent a hematoma evacuation that revealed neither a skull fracture nor a vascular abnormality. In this adolescent, chronic nasal sinusitis caused fragility of the meningeal artery wall, an air collection in the epidural space, and the detachment of the dura mater from the inner surface of the skull, thereby resulting in a non-traumatic acute EDH.

Continuous intraoperative monitoring of abnormal muscle response in microvascular decompression for hemifacial spasm; a real-time navigator for complete relief.

Intermittent monitoring of abnormal muscle response (iAMR) has been reported to be useful for improving the surgical outcome of microvascular decompression (MVD) for hemifacial spasm (HFS). However, iAMR has not elucidated the relationship between AMR change and the corresponding surgical procedure, or the pathogenesis of AMR and HFS. The purpose of this study is to clarify the usefulness of continuous AMR monitoring (cAMR) for improving the surgical results of MVD and for understanding the relationship between AMR change and corresponding surgical procedure, and the pathogenesis of AMR and HFS. Fifty consecutive patients with HFS treated by MVD under cAMR monitoring, which continuously records AMR every minute throughout the surgical period, were retrospectively analyzed. The patients were assessed for the presence of HFS 1 week after the surgery and at final follow-up. Forty-six patients showed the complete disappearance of HFS. In 32, AMR disappeared abruptly and simultaneously with decompression of an offending vessel. AMR showed dynamic and various changes including temporary disappearance, or sudden, gradual, or componential disappearance before and during the decompression procedure, and even during the dural and skin closure after the initial decompression procedure. Facial spasm remained in four patients despite permanent AMR disappearance. cAMR monitoring improves the outcome of MVD. Although the main cause of HFS and AMR is vascular compression at the facial nerve, hyperexcitability of the facial nucleus is also involved in the pathogenesis of HFS and AMR. The proportional involvement of these causes differs between patients.

Inverse correlation between stroke and urinary 3-hydroxypropyl mercapturic acid, an acrolein-glutathione metabolite.

BACKGROUND: We found previously that increases in plasma levels of protein-conjugated acrolein and polyamine oxidases, enzymes that produce acrolein, are good biomarkers for stroke. The aim of this study was to test whether 3-hydroxypropyl mercapturic acid (3-HPMA), an acrolein-glutathione metabolite, was increased in the urine of stroke patients. METHODS: The level of 3-HPMA in urine was measured by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Stroke (78 subjects) was divided into 52 cerebral infarction (CI) and 26 cerebral hemorrhage (CH) on the basis of clinical information including brain imaging. RESULTS: A major acrolein derivative in urine is 3-HPMA. Being different from the results of PC-Acro in plasma, 3-HPMA in urine decreased following stroke. The median value of µmol 3-HPMA/g creatinine (Cre) for 90 control subjects was 2.83, while that for 78 stroke patients was 1.56. The degree of the decrease in 3-HPMA was similar in both CI and CH patients. Furthermore, the median value of µmol 3-HPMA/g Cre in 56 patients with lesions ≥ 1cm in diameter (1.39) was significantly lower than that in 20 patients with lesion <1cm in diameter (2.16). CONCLUSION: Inverse correlation between stroke and urinary 3-HPMA was observed. The results suggest that stroke is aggravated when nervous system tissues have a reduced level of glutathione.

A superoxide anion-scavenger, 1,3-selenazolidin-4-one suppresses serum deprivation-induced apoptosis in PC12 cells by activating MAP kinase.

Synthetic organic selenium compounds, such as ebselen, may show glutathione peroxidase-like antioxidant activity and have a neurotrophic effect. We synthesized 1,3-selenazolidin-4-ones, new types of synthetic organic selenium compounds (five-member ring compounds), to study their possible applications as antioxidants or neurotrophic-like molecules. Their superoxide radical scavenging effects were assessed using the quantitative, highly sensitive method of real-time kinetic chemiluminescence. At 166µM, the O(2)(-) scavenging activity of 1,3-selenazolidin-4-ones ranged from 0 to 66.2%. 2-[3-(4-Methoxyphenyl)-4-oxo-1,3-selenazolidin-2-ylidene]malononitrile (compound b) showed the strongest superoxide anion-scavenging activity among the 6 kinds of 2-methylene-1,3-selenazolidin-4-ones examined. Compound b had a 50% inhibitory concentration (IC(50)) at 92.4µM and acted as an effective and potentially useful O(2)(-) scavenger in vitro. The effect of compound b on rat pheochromocytome cell line PC12 cells was compared with that of ebselen or nerve growth factor (NGF) by use of the MTT [3-(4, 5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] assay. When ebselen was added at 100µM or more, toxicity toward PC12 cells was evident. On the contrary, compound b suppressed serum deprivation-induced apoptosis in PC12 cells more effectively at a concentration of 100µM. The activity of compound b to phosphorylate mitogen-activated protein kinase/extracellular signal-regulated protein kinase (ERK) 1/2 (MAP kinase) in PC12 cells was higher than that of ebselen, and the former at 100µM induced the phosphorylation of MAP kinase to a degree similar to that induced by NGF. From these results, we conclude that this superoxide anion-scavenger, compound b, suppressed serum deprivation-induced apoptosis by promoting the phosphorylation of MAP kinase.

Relationship between metabolic disorders and relative risk values of brain infarction estimated by protein-conjugated acrolein, IL-6 and CRP together with age.

BACKGROUND: We have recently found that the median relative risk value (RRV) (0-1) of brain infarction estimated by protein-conjugated acrolein (PC-Acro), IL-6 and CRP together with age was in the order silent brain infarction (SBI) (0.80)>carotid atherosclerosis (CA) (0.76)>white matter hyperintensity (WMH) (0.46)>control (0.14). We clarified how metabolic disorders [hypertension (HT), hyperlipidemia (HL) and hyperglycemia (HG)] are correlated with RRV. METHODS: The levels of PC-Acro, IL-6 and CRP in plasma were measured by ELISA. SBI and WMH were evaluated by MRI, and CA was evaluated by duplex carotid ultrasonography. RESULTS: The median RRV of metabolic disorders was in the order HT+HG (0.84)>HT+HL (0.73)>HT (0.65)≈HG (0.65)>HL (0.61)>HL+HG (0.48)>no metabolic disorder (0.24)>normal (0.11). Correlation with SBI was in the order HT+HG (52%)>HT+HL (42%)>HT (40%)>HG (34%)≈HL(33%)>HL+HG (14%)≈no metabolic disorder (14%). CONCLUSION: The results indicate that HT is the most strongly associated factor with SBI among metabolic disorders and that the seriousness of metabolic disorder estimated by RRV was well correlated with SBI.

Efficacy of amniotic membrane-assisted bleb revision for elevated intraocular pressure after filtering surgery.

PURPOSE: To compare the effectiveness of standard revision surgery using mitomycin C (MMC) with revision using amniotic membrane transplantation and MMC for elevated intraocular pressure (IOP) after trabeculectomy. PATIENTS AND METHODS: A retrospective, nonrandomized comparative study of 36 eyes of 36 patients with a failed trabeculectomy. Patients were divided into two groups, ie, a nonamnion-transplanted group and an amnion-transplanted group. The amniotic membrane was placed on the scleral flap under the conjunctiva in the amnion-transplanted group. Both groups recovered filtration of aqueous humor from the surgical site with the adjunctive use of MMC. The changes in IOP and cumulative survival rate were compared for the two groups. Success was defined as a 30% reduction in IOP from the preoperative IOP and maintenance below 21 mmHg with or without the use of antiglaucomatous agents. RESULTS: The mean preoperative IOP was not significantly different in the two groups. The mean postoperative IOP in the nonamnion group, 12.1 +/- 5.5 mmHg, was significantly lower than the IOP in the amnion group, 16.0 +/- 3.7 mmHg. Survival curves in the two groups did not reach significantly different levels. CONCLUSIONS: Conventional surgical bleb revision with MMC can significantly reduce the elevated IOP associated with a failed filtration bleb. The use of an amniotic membrane transplant did not improve the surgical outcome in our cases.

Phacoemulsification and trabeculotomy combined with goniosynechialysis for uncontrollable chronic angle-closure glaucoma.

BACKGROUND AND OBJECTIVE: To assess and explore the effectiveness of phacoemulsification and trabeculotomy combined with goniosynechialysis in lowering intraocular pressure in eyes with uncontrollable chronic angle-closure glaucoma. PATIENTS AND METHODS: The medical charts of 24 eyes of 22 patients with chronic angle-closure glaucoma were reviewed retrospectively. The probability of successful treatment in 12 eyes that had earlier glaucoma attacks and 12 that did not have an attack were evaluated with Kaplan-Meier life-table analysis with the target pressure set at 15 mm Hg. RESULTS: Mean preoperative intraocular pressure for all eyes was 33.3 +/- 12.0 mm Hg and decreased to 11.8 +/- 2.3 mm Hg. The success rate was 86.6% at 1 year after surgery. Life-table analysis showed that there was no significant difference in the two groups. CONCLUSION: Phacoemulsification and trabeculotomy combined with goniosynechialysis is an effective surgical treatment for chronic angle-closure glaucoma in eyes with or without a previous glaucoma attack.

Correlation between images of silent brain infarction, carotid atherosclerosis and white matter hyperintensity, and plasma levels of acrolein, IL-6 and CRP.

OBJECTIVE: We found previously that the measurement of plasma levels of protein-conjugated acrolein (PC-Acro) together with IL-6 and CRP can be used to identify silent brain infarction (SBI) with high sensitivity and specificity. The aim of this study was to clarify how three biochemical markers are correlated to SBI, carotid atherosclerosis (CA) and white matter hyperintensity (WMH). METHODS: The levels of PC-Acro, IL-6 and CRP in plasma were measured by ELISA. SBI and WMH were evaluated by MRI, and CA was evaluated by duplex carotid ultrasonography. RESULTS: A total of 790 apparently healthy volunteers were classified into 260 control, 214 SBI, 263 CA and 245 WMH subjects, which included 187 subjects with two or three pathologies. When the combined measurements of PC-Acro, IL-6 and CRP were evaluated together with age, using a receiver operating characteristic curve and artificial neural networks, the relative risk value (RRV), an indicator of tissue damage, was in the order SBI with CA (0.90)>SBI (0.80)>CA (0.76)>WMH with CA (0.65)>WMH (0.46)>control (0.14). RRV was also correlated with severity in each group of SBI, CA and WMH. CONCLUSION: The RRV supports the idea that the degree of risk to develop a stroke is in the order SBI>CA>WMH.

Selective laser trabeculoplasty for glaucoma after penetrating keratoplasty.

PURPOSE: Postoperative intraocular pressure elevation is the most common complication to occur after penetrating keratoplasty (PKP). When topical antiglaucoma drops or oral systemic medication cannot lower this pressure, surgical intervention is necessary. However, surgery cannot yet be performed that does not adversely affect the graft, and better surgical treatments are required. METHODS: A 62-year-old man had undergone PKP to treat bullous keratopathy in the left eye. Secondary glaucoma occurred early postoperation and was controlled through topical antiglaucoma eye drops, medication, and the decreasing use of topical steroids. However, 7 months postsurgery, intraocular pressure (IOP) in the eye re-elevated to 42 mm Hg (Goldmann applanation tonometer). Selective laser trabeculoplasty was performed inferiorly for 6 h and then added selective laser trabeculoplasty performed superiorly for 6 h, 1 week later. Complete slit lamp biomicroscopy, visual acuity, IOP, gonioscopy, and mydriatic funduscopy were performed pre- and posttreatment for 6 months. RESULTS: IOP decreased from 42 to 27 mm Hg 1 week after selective laser trabeculoplasty (SLT) (inferior 180 degrees). After an additional superior 180 degrees SLT performed 2 weeks after this, IOP decreased to 15 mm Hg. Six months later, IOP was stable at 18 mm Hg, and graft rejection, new peripheral anterior synechiae, and visual acuity disturbance were not observed. CONCLUSIONS: IOP elevation after PKP was successfully treated with SLT. SLT will become a valuable therapeutic method that limits invasive surgery for treatment of secondary glaucoma after PKP.

Metabolic impact of overexpression of liver glycogen synthase with serine-to-alanine substitutions in rat primary hepatocytes.

To investigate the effect of elevation of liver glycogen synthase (GYS2) activity on glucose and glycogen metabolism, we performed adenoviral overexpression of the mutant GYS2 with six serine-to-alanine substitutions in rat primary hepatocytes. Cell-free assays demonstrated that the serine-to-alanine substitutions caused constitutive activity and electrophoretic mobility shift. In rat primary hepatocytes, overexpression of the mutant GYS2 significantly reduced glucose production by 40% and dramatically induced glycogen synthesis via the indirect pathway rather than the direct pathway. Thus, we conclude that elevation of glycogen synthase activity has an inhibitory effect on glucose production in hepatocytes by shunting gluconeogenic precursors into glycogen. In addition, although intracellular compartmentation of glucose-6-phosphate (G6P) remains unclear in hepatocytes, our results imply that there are at least two G6P pools via gluconeogenesis and due to glucose phosphorylation, and that G6P via gluconeogenesis is preferentially used for glycogen synthesis in hepatocytes.

Cellular migration associated with macular hole: a new method for comprehensive bird's-eye analysis of the internal limiting membrane.

OBJECTIVE: To elucidate the pathogenesis of macular hole formation, focusing in particular on the possible role of cellular migration on the cortical vitreous and internal limiting membrane (ILM) around the macular hole. METHODS: To gain a comprehensive overview of the ILM excised in macular hole surgery (n = 36), the ILMs were carefully unfolded and spread out onto glass slides as continuous flat sheets that each contained a macular hole. The specimens were observed by light microscopy and transmission electron microscopy (n = 9), and the cellular distribution was analyzed by scanning electron microscopy in a quantitative manner (n = 27). Immunohistochemistry for glial fibrillary acidic protein and cytokeratin 18 was carried out for cellular characterization. Cellular proliferation was assessed by immunohistochemistry for proliferating cell nuclear antigen and Ki-67. RESULTS: Cellular migration was not apparent around the macular hole in the early stage of development of the macular hole (stage 2, 0 microm). As the macular hole passed through the later stages of development, cellular migration developed around the macular hole (stage 3, 84 microm) and the area of cellular migration gradually enlarged (stage 4, 420 microm). The immunophenotypic analysis showed that these cells were mainly glial fibrillary acidic protein-positive glial cells and cytokeratin 18-positive retinal pigment epithelial cells. The proliferating cell nuclear antigen and Ki-67 immunohistochemistry showed that some of these cells were proliferating on the ILM. CONCLUSIONS: Cellular migration on the ILM is not necessary for the initial formation of a macular break. Cellular migration developed after the macular break occurred, and the migration and proliferation increased gradually from the macular hole. CLINICAL RELEVANCE: This study provides a new method for understanding the ultrastructural analysis of the pathogenesis of the macular hole.

A new method for comprehensive bird's-eye analysis of the surgically excised internal limiting membrane.

PURPOSE: To investigate the role of cells and extracellular matrix on the internal limiting membrane (ILM), we demonstrated a new method for a comprehensive bird's-eye analysis of surgically excised ILM. DESIGN: Laboratory investigation. METHODS: The ILM of an idiopathic epiretinal membrane was fixed and spread out onto a glass slide, using fine needles under a biomicroscope. The expanded ILM was analyzed by light microscopy, immunohistochemistry, and scanning electron microscopy. RESULTS: The excised ILM could be unfolded and spread out as a flat sheet onto the glass slide. Immunohistochemistry revealed that most migrating cells were glial cells. Scanning electronmicroscopy revealed that the vitreous surface of the ILM was smooth, in contrast to the rough retinal surface. The ILM showed abundant cellular migration as a continuous stratified cellular sheet. CONCLUSIONS: This new bird's-eye-view observation of excised ILM enables us to carry out comprehensive analysis of cellular distribution from a temporal and spatial perspective.

Pigment epithelium-derived factor inhibits fibroblast-growth-factor-2-induced capillary morphogenesis of endothelial cells through Fyn.

Pigment epithelium-derived factor (PEDF) exerts anti-angiogenic actions. However, the signal-transduction pathways regulated by PEDF remain to be elucidated. We show here that PEDF inhibited fibroblast growth factor 2 (FGF-2) induced capillary morphogenesis of a murine brain capillary endothelial cell line (IBE cells) and of human umbilical-vein endothelial cells (HUVECs) cultured on growth-factor-reduced Matrigel. We previously showed that FGF-2-mediated capillary morphogenesis was blocked by the Src-kinase inhibitor PP2 and that expression of dominant negative Fyn in IBE cells inhibited capillary morphogenesis. We examined the effect of PEDF on kinase activity of Fyn and found that PEDF downregulated FGF-2-promoted Fyn activity by tyrosine phosphorylation at the C-terminus in a Fes-dependent manner. In a stable IBE cell line expressing kinase-inactive Fes (KE5-15 Fes cells), PEDF failed to inhibit FGF-2-induced capillary morphogenesis or Fyn activity. PEDF induced the colocalization of Fyn and Fes in IBE cells expressing wild-type Fes, but not in KE5-15 Fes cells. In addition, wild-type Fes increased the tyrosine phosphorylation of Fyn in vitro, suggesting that Fes might directly phosphorylate Fyn. Expression of constitutively active Fyn (Y531F) in IBE cells exhibited capillary morphogenesis in the absence of FGF-2 and was resistant for PEDF treatment. Our results suggest that PEDF downregulates Fyn through Fes, resulting in inhibition of FGF-2-induced capillary morphogenesis of endothelial cells.

Macrophage inflammatory protein-1alpha as a costimulatory signal for mast cell-mediated immediate hypersensitivity reactions.

Regulation of the immune response requires the cooperation of multiple signals in the activation of effector cells. For example, T cells require signals emanating from both the TCR for antigen (upon recognition of MHC/antigenic peptide) and receptors for costimulatory molecules (e.g., CD80 and CD60) for full activation. Here we show that IgE-mediated reactions in the conjunctiva also require multiple signals. Immediate hypersensitivity reactions in the conjunctiva were inhibited in mice deficient in macrophage inflammatory protein-1alpha (MIP-1alpha) despite normal numbers of tissue mast cells and no decrease in the levels of allergen-specific IgE. Treatment of sensitized animals with neutralizing antibodies with specificity for MIP-1alpha also inhibited hypersensitivity in the conjunctiva. In both cases (MIP-1alpha deficiency and antibody treatment), the degranulation of mast cells in situ was affected. In vitro sensitization assays showed that MIP-1alpha is indeed required for optimal mast cell degranulation, along with cross-linking of the high-affinity IgE receptor, FcepsilonRI. The data indicate that MIP-1alpha constitutes an important second signal for mast cell degranulation in the conjunctiva in vivo and consequently for acute-phase disease. Antagonizing the interaction of MIP-1alpha with its receptor CC chemokine receptor 1 (CCR1) or signal transduction from CCR1 may therefore prove to be effective as an antiinflammatory therapy on the ocular surface.