Clinical characteristics and management of orbital apex syndrome: a 10-year multicentre experience.

BACKGROUND: Orbital apex syndrome (OAS) is a condition characterised by lesions within the orbital apex, leading to various ophthalmologic symptoms. This study aimed to analyse the clinical characteristics and treatment strategies of OAS with respect to aetiology. METHODS: This retrospective analysis utilised data from 5 medical institutions between 2013 and 2022. Patients who were diagnosed with OAS were initially enrolled, but patients who failed to follow up at least 1 month were excluded. The prevalence of initial ophthalmologic symptoms and visual improvement after treatment was compared according to aetiology. Factors related to visual improvement were analysed. RESULTS: Among 73 enrolled patients, the leading aetiology was tumours, followed by fungal infections and inflammation. Visual impairment and proptosis were prevalent in tumour-related OAS cases. Inflammation-related OAS exhibited a higher likelihood of painful eye movements and ophthalmoplegia. Ptosis was most frequently observed in fungal infection-related OAS. Notably, fungal infections emerged as the sole significant factor negatively impacting vision progression. In inflammation-related OAS, the time interval between symptom onset and the administration of steroids was longer in patients without visual improvement, even though there was no statistically significant difference. CONCLUSIONS: Tumours were the predominant cause of OAS. Visual impairment was a common manifestation in tumour-related OAS, while fungal infections were strongly associated with a poor visual prognosis. The timely administration of steroids might be helpful for improving vision in patients with inflammation-related OAS. However, further studies are needed to enhance understanding and management of OAS.

RAC-LATS1/2 signaling regulates YAP activity by switching between the YAP-binding partners TEAD4 and RUNX3.

The tumor-suppressor RUNX3 has a critical role in a lineage determination, cell cycle arrest and apoptosis. Lozenge (Lz), a Drosophila homolog of mammalian RUNX family members, has integral roles in these processes and specifically in eye cell fate determination. To elucidate the genetic modifiers of Lz/RUNX3, we performed a large-scale functional screen in a fly mutant library. The screen revealed genetic interactions between the Lz, Rac and Hippo pathways. Analysis of interactions among these genes revealed that the defective phenotype resulting from activation of Yki, an end point effector of the Hippo pathway, was suppressed by Lz and enhanced by Rac-Trio. Molecular biological analysis using mammalian homologs reveled that LATS1/2-mediated YAP phosphorylation-facilitated dissociation of the YAP-TEAD4 complex and association of the YAP-RUNX3 complex. When cells were stimulated to proliferate, activated RAC-TRIO signaling inhibited LATS1/2-mediated YAP phosphorylation; consequently, YAP dissociated from RUNX3 and associated with TEAD, thereby replacing the YAP-RUNX3 complex with YAP-TEAD. RUNX3 contributed to both association and dissociation of YAP-TEAD complex, most likely through the formation of the YAP-TEAD-RUNX3 ternary complex. Ectopic expression of RUNX3 in MKN28 gastric cancer cells reduced tumorigenicity, and the tumor-suppressive activity of RUNX3 was associated with its ability to interact with YAP. These results identify a novel regulatory mechanism, mediated by the Hippo and RAC-TRIO pathways, that changes the binding partner of YAP.

Chronic stress-induced memory deficits are reversed by regular exercise via AMPK-mediated BDNF induction.

Chronic stress has a detrimental effect on neurological insults, psychiatric deficits, and cognitive impairment. In the current study, chronic stress was shown to impair learning and memory functions, in addition to reducing in hippocampal Adenosine monophosphate-activated protein kinase (AMPK) activity. Similar reductions were also observed for brain-derived neurotrophic factor (BDNF), synaptophysin, and post-synaptic density-95 (PSD-95) levels, all of which was counter-regulated by a regime of regular and prolonged exercise. A 21-day restraint stress regimen (6 h/day) produced learning and memory deficits, including reduced alternation in the Y-maze and decreased memory retention in the water maze test. These effects were reversed post-administration by a 3-week regime of treadmill running (19 m/min, 1 h/day, 6 days/week). In hippocampal primary culture, phosphorylated-AMPK (phospho-AMPK) and BDNF levels were enhanced in a dose-dependent manner by 5-amimoimidazole-4-carboxamide riboside (AICAR) treatment, and AICAR-treated increase was blocked by Compound C. A 7-day period of AICAR intraperitoneal injections enhanced alternation in the Y-maze test and reduced escape latency in water maze test, along with enhanced phospho-AMPK and BDNF levels in the hippocampus. The intraperitoneal injection of Compound C every 4 days during exercise intervention diminished exercise-induced enhancement of memory improvement during the water maze test in chronically stressed mice. Also, chronic stress reduced hippocampal neurogenesis (lower Ki-67- and doublecortin-positive cells) and mRNA levels of BDNF, synaptophysin, and PSD-95. Our results suggest that regular and prolonged exercise can alleviate chronic stress-induced hippocampal-dependent memory deficits. Hippocampal AMPK-engaged BDNF induction is at least in part required for exercise-induced protection against chronic stress.

RUNX family members are covalently modified and regulated by PIAS1-mediated sumoylation.

Transcription factors of the RUNX family (RUNXs), which play pivotal roles in normal development and neoplasia, are regulated by various post-translational modifications. To understand the molecular mechanisms underlying the regulation of RUNXs, we performed a large-scale functional genetic screen of a fly mutant library. The screen identified dPias (the fly ortholog of mammalian PIASs), an E3 ligase for the SUMO (small ubiquitin-like modifier) modification, as a novel genetic modifier of lz (the fly ortholog of mammalian RUNX3). Molecular biological analysis revealed that lz/RUNXs are sumoylated by dPias/PIAS1 at an evolutionarily conserved lysine residue (K372 of lz, K144 of RUNX1, K181 of RUNX2 and K148 of RUNX3). PIAS1-mediated sumoylation inhibited RUNX3 transactivation activity, and this modification was promoted by the AKT1 kinase. Importantly, PIAS1 failed to sumoylate some RUNX1 mutants associated with breast cancer. In nude mice, tumorigenicity was promoted by RUNX3 bearing a mutation in the sumoylation site, but suppressed by wild-type RUNX3. Our results suggest that RUNXs are sumoylated by PIAS1, and that this modification could play a critical role in the regulation of the tumor-suppressive activity of these proteins.

In vitro time-kill activities of ciprofloxacin alone and in combination with the iron chelator deferasirox against Vibrio vulnificus.

Iron plays a major role in the growth and virulence of ferrophilic organisms like Vibrio vulnificus. People who reside in the coastal areas with raw fish eating habits have a high risk of Vibrio infection and aggressive therapy can only reduce their mortality. We investigated the in vitro efficacy of ciprofloxacin, a bactericidal drug used in V. vulnificus patients, and the orally active iron chelator deferasirox against V. vulnificus infection. We performed in vitro time-kill studies on two ATCC strains and one clinical isolate of V. vulnificus collected from a patient admitted to Chosun University Hospital with either ciprofloxacin or iron chelator deferasirox alone and the two drugs in combination. The combination of an iron chelator plus an antibiotic creates a novel form of synergism at 24 h. The antimicrobial effect of deferasirox may be ascribed to its ability to deplete iron that would otherwise be used for bacterial growth. Combination therapy with ciprofloxacin plus deferasirox has potential clinical application by lowering the iron availability against a ferrophilic organism like V. vulnificus infections.

Risk factors associated with optic disc haemorrhage in patients with normal tension glaucoma.

PURPOSE: To evaluate the risk factors associated with optic disc haemorrhage in patients with normal tension glaucoma (NTG). PATIENTS AND METHODS: Two hundred and eighty-one eyes of 281 patients with NTG (113 eyes with optic disc haemorrhage and 168 eyes without haemorrhage) were included in this study. Associations between optic disc haemorrhage and various patient-related variables (diabetes; hypertension; hypotension; cardiac disease; stroke; cold hand; migraine; constipation; use of steroids, aspirin, anticoagulant, or gingko extract; smoking history; and glaucoma family history) and eye-related variables (baseline intraocular pressure (IOP); maximum, minimum, and range of IOP; vertical and horizontal cup/disc ratio; mean deviation and pattern standard deviation of the visual field; corneal thickness; and average retinal nerve fibre layer (RNFL) thickness measured by optical coherence tomography) were investigated by univariate and multivariate logistic regression analyses. Differences in risk factors between patients with single optic disc haemorrhages and recurrent haemorrhages were also analysed. RESULTS: Optic disc haemorrhage was associated with systemic hypertension (odds ratio, 1.998; 95% confidence interval, 1.094-3.651; P=0.001). IOP range (P=0.080), diabetes (P=0.056), and use of aspirin (P=0.079) also tended to be associated with optic disc haemorrhage. No risk factor was significantly different between the single haemorrhage group and the recurrent haemorrhage group. CONCLUSION: Optic disc haemorrhage was associated with systemic hypertension in patients with NTG.

New p53 target, phosphatase of regenerating liver 1 (PRL-1) downregulates p53.

Most of the p53 target genes, all except MDM2, COP1 and PIRH2, perform functions in apoptosis, differentiation and cell cycle arrest. The aforementioned oncogenes downregulate p53 through a negative feedback mechanism, and thus contribute to tumor development. In this study, we report a new p53 target, PRL-1, which is believed to be a significant regulator in the development and metastasis of a variety of cancer types. Phosphatase of regenerating liver 1 (PRL-1) overexpression reduced the levels of endogenous and exogenous p53 proteins, and inhibited p53-mediated apoptosis. On the other hand, the ablation of PRL-1 by small interfering RNA (siRNA) increased p53 protein levels. The p53 downregulation was mediated by p53 ubiquitination and subsequent proteasomal degradation. Furthermore, p53 ubiquitination by PRL-1 was achieved through two independent pathways, by inducing PIRH2 transcription and by inducing MDM2 phosphorylation through Akt signaling. In addition, we showed that the PRL-1 gene harbors a p53 response element in the first intron, and its transcription is regulated by the p53 protein. These findings imply that the new oncogenic p53 target, PRL-1, may contribute to tumor development by the downregulation of p53 by a negative feedback mechanism.

Ectopic Cushing's syndrome due to concurrent corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) secreted by malignant gastrinoma.

Ectopic Cushing's syndrome due to various malignancies is not uncommon. However, a few cases of ectopic Cushing's syndrome caused by corticotropin-releasing hormone (CRH), or CRH with adrenocorticotropic hormone (ACTH) have been reported. A 28-year-old woman presented with acute upper gastrointestinal bleeding caused by an active ulcer, located atypically in the 2nd portion of duodenum. Further work-up revealed high gastrin levels and abdominal computed tomography (CT) scans showed a large pancreatic head mass with multiple liver metastases. The serum cortisol and ACTH levels were checked due to hypokalemia with metabolic alkalosis and recent amenorrhea. Cortisol and ACTH were both highly elevated with pituitary hyperplasia and elevated CRH. The existence of ectopic ACTH and CRH in the liver biopsy was also demonstrated immunohistochemically. Since an operation was not feasible, chemotherapy was conducted using paclitaxel and etoposide. These two drugs were chosen according to the IN VITRO chemotherapy response assay to maximize the treatment. This report demonstrates concurrent ACTH- and CRH-related ectopic Cushing's syndrome caused by malignant gastrinoma with multiple liver metastases that was treated with marginal success using a multidisciplinary medical approach.

The shooty callus induced by suppression of tobacco CHRK1 receptor-like kinase is a phenocopy of the tobacco genetic tumor.

CHRK1 encodes a tobacco receptor-like kinase that contains a chitinase-like sequence in the extracellular domain. In a previous study, CHRK1-suppressed transgenic tobacco plants exhibited pleiotropic developmental abnormalities including spontaneous growth of shooty callus from emerging embryos in the absence of any exogenous hormones. In this study, we show that the CHRK1 shooty callus mimics tobacco genetic tumors in its morphology, physiology, and gene expression profiles. Similar to CHRK1 shooty callus, tobacco genetic tumors exhibit shooty callus morphology and hormone-independent shoot organogenesis. Both the CHRK1 callus and genetic tumors constitutively expressed KNOTTED1-type homeobox genes at the high levels, consistent with their vigorous shoot formation. These two types of calli exhibited cell death phenotypes, accompanied by high H2O2 production, increased ion leakage, and callose accumulation. Consistently, both types of calli constitutively expressed high levels of defense genes induced during pathogen-mediated HR cell death. These results, together with previous reports that both the CHRK1 shooty callus and tobacco genetic tumor contained high levels of cytokinin, indicate that CHRK1 shooty callus is a phenocopy of tobacco genetic tumor. CHRK1-mediated signal transduction may play a role in the formation of the genetic tumor in tobacco.

Regeneration of adenosine triphosphate from glycolytic intermediates for cell-free protein synthesis.

A new approach for adenosine triphosphate (ATP) regeneration in a cell-free protein synthesis system is described. We first show that pyruvate can be used as a secondary energy source to replace or supplement the conventional secondary energy source, phosphoenol pyruvate (PEP). We also report that glucose-6-phosphate, an earlier intermediate of the glycolytic pathway, can be used for ATP regeneration. These new methods provide more stable maintenance of ATP concentration during protein synthesis. Because pyruvate and glucose-6-phosphate are the first and last intermediates of the glycolytic pathway, respectively, the results also suggest the possibility of using any glycolytic intermediate, or even glucose, for ATP regeneration in a cell-free protein synthesis system. As a result, the methods described provide cell-free protein synthesis with greater flexibility and cost efficiency.

Prolonging cell-free protein synthesis by selective reagent additions.

Factors causing the early cessation of protein synthesis have been studied in a cell-free system from Escherichia coli. We discovered that phosphoenol pyruvate (PEP), the secondary energy source for ATP regeneration, and several amino acids are rapidly degraded during the cell-free protein synthesis reaction. The degradation of such compounds takes place even in the absence of protein synthesis. This degradation severely reduces the capacity for protein synthesis. The lost potency was completely recovered when the reaction mixture was supplied with additional PEP and amino acids. Of the 20 amino acids, only arginine, cysteine, and tryptophan were required to restore system activity. Through repeated additions of PEP, arginine, cysteine,and tryptophan, the duration of protein synthesis was greatly extended. In this fed-batch reaction, after a 2 h incubation, the level of cell-free synthesized chloramphenicol acetyl transferase (CAT) reached 350 microg/mL, which is 3.5 times the yield of the batch reaction. Addition of fresh magnesium further extended the protein synthesis. As a result, through coordinated additions of PEP, arginine, cysteine, tryptophan, and magnesium, the final concentration of cell-free synthesized CAT increased more than 4-fold compared to a batch reaction. SDS-PAGE analysis of such a fed-batch reaction produced an obvious band of CAT upon Coomassie Blue staining.

Platelet adhesion onto segmented polyurethane film surfaces modified by addition and crosslinking of PEO-containing block copolymers.

Polyethylene oxide (PEO) surfaces were prepared by the addition of PEO-containing amphiphilic block copolymers as surface modifying additives and of dicumyl peroxide (DCP) as a crosslinking agent in segmented polyurethane (PU). PEO-polypropylene oxide-PEO triblock copolymers (Pluronics) with different PEO chain length (from 0 to 98) were used as the surface modifying additives. The PEO additives in the PU film were then crosslinked to be stably entrapped in the PU matrix. The crosslinking was done by free radicals produced from the decomposition of DCP in the film through heating (120 degrees C) or ultraviolet irradiation (254 nm). The surface properties of the PEO additive-entrapped PU films were investigated by the measurement of water contact angles and electron spectroscopy for chemical analysis. The bulk properties such as water absorption, long-term film stability, and tensile strength and elongation at break, were also investigated. It was observed that addition of a small amount (5 wt% based on PU) of the PEO additives resulted in a considerable change of surface characteristics. The PEO additives were stably entrapped in the PU films by crosslinking of them, without significant changes of bulk properties of the films. From the platelet adhesion test on the prepared PEO additive-containing film surfaces, it was observed that the platelet adhesion on the surfaces decreases with increase in PEO chain length of PEO additives. The film surface containing additive with long PEO chains (chain length of 98) was particularly effective in preventing platelet adhesion. The crosslinking of the PEO additives in PU films did not affect the behavior of platelet adhesion on the surfaces; the films with crosslinked PEO additives showed similar platelet adhesion on the surfaces to the films with uncrosslinked ones.

Enhancement of secretion and extracellular stability of staphylokinase in Bacillus subtilis by wprA gene disruption.

Staphylokinase (SAK), a polypeptide secreted by Staphylococcus aureus, is a plasminogen activator with a therapeutic potential in thrombosis diseases. A Bacillus subtilis strain which is multiply deficient in exoproteases was transformed by an expression plasmid carrying a promoter and a signal sequence of subtilisin fused in frame with the sak open reading frame. However, the amount of SAK secretion was marginal (45 mg/liter). In contrast, disruption of the wprA gene, which encodes a subtilisin-type protease, strongly promoted the production of SAK in the stationary phase (181 mg/liter). In addition, the extracellular stability of mature SAK was dramatically enhanced. These data indicate a significant role of the wprA gene product in degrading foreign proteins, both during secretion and in the extracellular milieu.

Prolonging cell-free protein synthesis with a novel ATP regeneration system.

A new approach for the regeneration of adenosine triphosphate (ATP) during cell-free protein synthesis was developed to prolong the synthesis and also to avoid the accumulation of inorganic phosphate. This approach was demonstrated in a batch system derived from Escherichia coli. Contrary to the conventional methods in which exogenous energy sources contain high-energy phosphate bonds, the new system was designed to generate continuously the required high-energy phosphate bonds within the reaction mixture, thereby recycling the phosphate released during protein synthesis. If allowed to accumulate, phosphate inhibits protein synthesis, most likely by reducing the concentration of free magnesium ion. Pediococcus sp. pyruvate oxidase, when introduced in the reaction mixture along with thiamine pyrophosphate (TPP) and flavin adenine dinucleotide (FAD), catalyzed the generation of acetyl phosphate from pyruvate and inorganic phosphate. Acetyl kinase, already present with sufficient activity in Escherichia coli S30 extract, then catalyzed the regeneration of ATP. Oxygen is required for the generation of acetyl phosphate and the H(2)O(2) produced as a byproduct is sufficiently degraded by endogenous catalase activity. Through the continuous supply of chemical energy, and also through the prevention of inorganic phosphate accumulation, the duration of protein synthesis is extended up to 2 h. Protein accumulation levels also increase. The synthesis of human lymphotoxin receives greater benefit than than that of chloramphenicol acetyl transferase, because the former is more sensitive to phosphate inhibition. Finally, through repeated addition of pyruvate and amino acids during the reaction period, protein synthesis continued for 6 h in the new system, resulting in a final yield of 0.7 mg/mL.

Indirect modulation of dopamine D2 receptors as potential pharmacotherapy for schizophrenia: I. Adenosine agonists.

OBJECTIVE: To review preclinical and clinical information related to pharmacologic modulation of dopamine D2 receptors as potential novel antipsychotic therapy. Specifically, to summarize the data that suggest a modulatory action of adenosine A2A receptors on dopamine D2 receptors and, therefore, a possible rational role of adenosine A2A agonists as novel antipsychotic agents. DATA SOURCES: Primary and review articles were identified by MEDLINE search (from 1966 to May 1998) and through secondary sources. STUDY SELECTION AND DATA EXTRACTION: All of the articles identified from the data sources were evaluated and all information deemed relevant was included in this review. DATA SYNTHESIS: For all of the older and many of the newer antipsychotic agents, there is a strong correlation between clinical antipsychotic activity and affinity for dopamine D2 receptors. Unfortunately, dopamine D2 receptors are believed to also be involved in the adverse effect profile of these agents. The indirect modulation of dopamine D2 receptors, rather than direct block, might produce antipsychotic effects without the usual adverse reactions. Several lines of evidence from animal studies suggest that the use of selective A2A agonists might represent a novel approach to the treatment of psychoses. CONCLUSIONS: Dopamine receptor modulation might represent a novel antipsychotic approach or adjunct therapy. The data regarding adenosine agonists (particularly selective A2A receptor agonists) are inconclusive at the present time. Direct clinical demonstration of effectiveness is required.

Effect of diode laser trans-scleral cyclophotocoagulation in the management of glaucoma after intravitreal silicone oil injection for complicated retinal detachments.

AIMS: To evaluate the effect of trans scleral cyclophotocoagulation (TSCPC) on intraocular pressure (IOP) in the eyes retaining intravitreal silicone oil with medically uncontrolled secondary glaucoma following intravitreal silicone oil injection. METHODS: Medical records of 11 eyes of 11 patients who underwent TSCPC for medically uncontrolled glaucoma without pupillary block following intravitreal silicone oil injection for complicated retinal detachment were reviewed retrospectively. In all cases, intravitreal silicone oil was not removed for fear of retinal redetachment. Diode laser contact TSCPC was performed at a power of 1.5-2.5 W, for a duration of 2 seconds, and with 20-27 applications. IOP, number of glaucoma medications, and success rate were evaluated. RESULTS: After a mean follow up period of 52.5 (SD 8.2) (range 42-68) weeks, the mean pretreatment level of IOP, 43.0 (14.4) (26-67) mmHg, had fallen to 14.5 (4.3) (7-20) mm Hg (p=0.003). The number of glaucoma medications was reduced from 2.6 (0.8) to 0.6 (1.0) (p= 0.005). Qualified success was achieved in nine eyes (81.8%) and complete success in six (54.5%). After TSCPC, patients' retinal status had not changed. CONCLUSION: Patients with medically uncontrolled glaucoma secondary to intravitreal silicone oil injection can be treated with TSCPC in spite of the retained intravitreal silicone oil.

Hydroxyapatite implantation with scleral quadrisection after evisceration.

BACKGROUND AND OBJECTIVES: In contrast to the literature on enucleation, reports of hydroxyapatite (HA) implantation during evisceration are limited; however, those that have been published mention the high HA exposure rate. The authors examined the scleral quadrisection procedure to evaluate its effect on cosmetic appearance and the prevention of HA exposure after evisceration. PATIENTS AND METHODS: The authors analyzed the surgical outcomes of 17 patients who had undergone an HA implantation with scleral quadrisection after evisceration between November 1994 and November 1995. RESULTS: In each case, the authors were able to use HA implants of 18 mm or more. During follow-up (average 10.7 months), there were no cases of conjunctival erosion, HA exposure, implant migration, significant enophthalmos, or superior sulcus deformity. All of the patients, 7 of whom had a ball- and-socket prosthesis, were satisfied with their cosmetic appearance and prosthetic motility. More than 11 weeks after evisceration, all 10 studied patients had complete, round uptakes with orbital bone SPECT (single photon emission computed tomography). CONCLUSION: For good cosmetic appearance and for the prevention of implant exposure, scleral quadrisection is a safe and effective procedure for HA implantation after evisceration.

Topical cyclosporine and glaucoma drainage implant surgery in rabbits.

BACKGROUND AND OBJECTIVE: To assess the effect of topical cyclosporine on the function of filtering blebs and fibroblast proliferation after glaucoma drainage implant surgery in rabbits. MATERIALS AND METHODS: Intraocular pressure, flow resistance through the implant capsule, and fibroblast density in the capsule were compared between 12 eyes that received implant surgery only (group A) and 11 eyes treated with topical 2% cyclosporine twice a day for 2 weeks after implant surgery (group B). RESULTS: There were significantly larger decreases in intraocular pressure at 1,2,4, and 8 weeks postoperatively in group B than in group A (n = 12, P < .05). Flow resistance was significantly lower in group B than in group A (n = 5, P < .05) at 8 weeks postoperatively. Fibroblast density was not significantly different between the two groups (n = 3, P > .05). CONCLUSION: These results suggest that topical 2% cyclosporine may enhance the effectiveness of glaucoma drainage implant surgery.