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.

Tacrolimus-Induced Apoptosis is Mediated by Endoplasmic Reticulum-derived Calcium-dependent Caspases-3,-12 in Jurkat Cells.

Apoptotic signal pathways are delivered to caspase-3, caspase-9, or both in different cells via the death receptor pathway, mitochondrial pathway, or by the endoplasmic reticulum (ER) pathway through initiators of caspase-3, -8, -9, or -12. Tacrolimus (Tac)-induced apoptosis was characterized by nuclear fragmentation and caspase-3 activation. We examined the effect of tacrolimus on ER-derived calcium and caspase-3,-12-mediated apoptosis on Jurkat human T lymphocyte. Tac decreased the viability of Jurkat cells in a dose-dependent manner. Tac also increased continuously intracellular concentration of calcium from 24 hours to 72 hours. We did not find intracellular calcium changes on the treatment of calcium ionorpore (A23187) regardless of 1 nmol/L Tac concentration level. However, calcium adenosine triphosphatase inhibitor (thapsigargin) increased intracellular calcium accumulation and co-treating 1 nmol/L Tac further induced intracellular calcium accumulation. Interestingly, we found that 1 nmol/L Tac treatment induced activation of caspase-12 protease as well as the catalytic activity of caspase-3 but not catalytic activation of caspase-6, -8, and -9 proteases in Jurkat cells. These data advance our understanding of Tac-induced apoptosis is ER-derived calcium and caspases-3,-12- mediated apoptosis in human Jurkat cell line.

Expression of Endoplasmic Reticulum-Mediated Stress Proteins in FK506-Treated T-Lymphocytes.

BACKGROUND: FK506-induced apoptotic endoplasmic reticulum (ER)-mediated stress protein expression was investigated in Jurkat human T-lymphocytes. METHODS: The effect of FK506 on apoptosis and cell viability were examined. FK506-induced apoptosis was confirmed by nuclear fragmentation after DAPI staining. Expression of apoptotic ER-mediated stress proteins was examined by means of Western blotting of Grp78/BiP, Grp94, double-stranded RNA-dependent protein kinase (PKR)-like ER kinase (PERK), phosphor-PERK, CHOP/GADD153, and Bak. A flow cytometry analysis was performed after DAF-DA or DCF-DA staining. FK506-induced apoptosis was dose-dependent (10 nmol/L) and time-dependent (72 hours). RESULTS: Grp78/BiP and Grp94 expressions were increased 36 hours after FK506 treatment. Increased phospho-PERK expression was observed 6 hours after FK506 treatment and peak activation of phospho-PERK was observed at 36 hours. CHOP/GADD153 expression was increased 48 hours after FK506 treatment. Expression of iNOS after FK506 treatment began to increase at 12 hours, peaked at 24 hours, and decreased after 36 hours. CONCLUSIONS: From these results, we confirmed that FK506 induces apoptosis and acts dose- and time-dependently to decrease the viability of Jurkat cells through activation of apoptosis signaling and expression of apoptotic ER-mediated stress proteins.

Transcriptional activation of nuclear-related factor 2 by FK506 in Jurkat T cells.

BACKGROUND: We investigated the effect of FK506 in transcriptional activation of nuclear factor (erythroid-derived 2)-like2 (Nrf2) in human Jurkat T cells. METHODS: FK506 treatment increased the generation of reactive oxygen species and reactive nitrogen species in Jurkat cells in a dose-dependent manner. Generation of nitric oxide was also increased after treatment with FK506 in Jurkat cells. Peak levels of endothelial nitricoxide synthase expression occurred at 24 hours and then decreased after 48 hours. RESULTS: We found that a marked dissociation of Nrf 2 from Kelch-like ECH-associated protein-1 and subsequently Nrf 2 nuclear translocation occurred in Jurkat cells treated with FK506 during 48 hours. Immunohistochemistry and Western blot analysis data revealed that the FK506 treatment increased expression of heme oxygenase-1 (HO-1) in Jurkat cells in a dose-dependent manner. HO-1 expression was induced after 6 hours of treatment of FK506 to Jurkat cells, peaked at 24 hours, and then decreased after 48 hours. CONCLUSIONS: These results suggest that FK506 induces Nrf 2-driven transcriptional activation of the antioxidant response element by activating HO-1 and free radicals such as reactive oxygen species and nitric oxide.

Molecular characterization of photosensitizer-mediated photodynamic therapy by gene expression profiling.

Photodynamic therapy (PDT) is a novel cancer treatment based on the tumor-specific accumulation of a photosensitizer followed by irradiation with visible light, which induces selective tumor cell death via production of reactive oxygen species. To elucidate the underlying mechanisms, microarray analysis was used to analyze the changes in gene expression patterns during PDT induced by various photosensitizers. Cancer cells were subjected to four different photosensitizer-mediated PDT and the resulting gene expression profiles were compared. We identified many differentially expressed genes reported previously as well as new genes for which the functionfunctions in PDT are still unclear. Our current results not only advance the general understanding of PDT but also suggest that distinct molecular mechanisms are involved in different photosensitizer-mediated PDT. Elucidating the signaling mechanisms in PDT will provide information to modulate the antitumor effectiveness of PDT using various photosensitizers.

Nestin expression as an indicator of cervical cancer initiation.

Nestin is an intermediate filament protein expressed in proliferating cells during embryonic development of the central nervous system (CNS) and considered to be a neuronal stem cell/progenitor cell marker. This study investigated the difference of nestin expression between pre-cancer (carcinoma in situ - CIS) and cancer of cervix in 129 tissues (49 normal cervix, 41 CIS, and 39 invasive cervical cancer) through the use of a paraffin-embedded tissue array. Immunostaining was evaluated by intensity, proportion of stained cells, and pattern of expression. The expression of nestin was positive in 63.4% (26/41) for CIS and 43.6% (17/39) for invasive cervical cancer, but only 26.5% (13/49) for normal tissues (p = 0.002). Strong positive staining/large proportion staining were 53.7% (22/41) / 36.6% (15/41), 15.4% (6/39) / 61.5% (24/39) in the CIS and invasive cervical cancer tissues, respectively (p = 0.043, p < 0.001). The diffuse stain with basal layer was positive in 90.2% (37/41) for CIS, but only 24.5% (12/49) of the samples were positive in normal tissues (p < 0.001). Based on these results, the authors suggest that nestin expression seems to participate in the step of cancer initiation and could potentially be a useful marker in the early detection of cervical cancer.

CFTR suppresses tumor progression through miR-193b targeting urokinase plasminogen activator (uPA) in prostate cancer.

Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is expressed in the epithelial cells of a wide range of organs/tissues from which most cancers are derived. Although accumulating reports have indicated the association of cancer incidence with genetic variations in CFTR gene, the exact role of CFTR in cancer development and the possible underlying mechanism have not been elucidated. Here, we report that CFTR expression is significantly decreased in both prostate cancer cell lines and human prostate cancer tissue samples. Overexpression of CFTR in prostate cancer cell lines suppresses tumor progression (cell growth, adhesion and migration), whereas knockdown of CFTR leads to enhanced malignancies both in vitro and in vivo. In addition, we demonstrate that CFTR knockdown-enhanced cell proliferation, cell invasion and migration are significantly reversed by antibodies against either urokinase plasminogen activator (uPA) or uPA receptor (uPAR), which are known to be involved in various malignant traits of cancer development. More interestingly, overexpression of CFTR suppresses uPA by upregulating the recently described tumor suppressor microRNA-193b (miR-193b), and overexpression of pre-miR-193b significantly reverses CFTR knockdown-enhanced malignant phenotype and abrogates elevated uPA activity in prostate cancer cell line. Finally, we show that CFTR gene transfer results in significant tumor repression in prostate cancer xenografts in vivo. Taken together, the present study has demonstrated a previously undefined tumor-suppressing role of CFTR and its involvement in regulation of miR-193b in prostate cancer development.

Synthetic colourings of some snack foods consumed by primary school children aged 8-9 years in Hong Kong.

An HPLC method with photodiode array detection was used for the quantification of 11 synthetic dyes in 87 snack food products commonly consumed by children in Hong Kong, China. Dietary exposure to synthetic colours was estimated using food-frequency questionnaire data obtained from 142 primary school children aged 8-9 years in three districts of Hong Kong. Dietary exposure to synthetic colours for an average primary school student was considerably lower than the threshold for acceptable daily intake (ADI) for their ages, except for sunset yellow FCF. Data obtained showed that the average daily intake of sunset yellow FCF (E110) was 51% over the ADI threshold in 9-year-old boys. The higher intakes of sunset yellow FCF were mainly due to the high consumption of soft drinks and desserts such as jellies, which have high concentrations of this synthetic colour additive.

A sperm GPI-anchored protein elicits sperm-cumulus cross-talk leading to the acrosome reaction.

The acrosome reaction has long been thought to be induced by the zona pellucida. Here we report the identification and function of a novel human sperm glycosylphosphatidylinositol (GPI)-anchored membrane protein, NYD-SP8. The release of the protein during sperm-egg interaction and its binding to the cumulus, the first layer of egg investment, elicits cross-talk between the gametes and produces calcium dependant release of progesterone, which lead to the acrosome reaction. An in vivo mouse model of NYD-SP8 immunization is also established showing a reduced fertility rate. Thus, contrary to accepted dogma, our study demonstrates for the first time that, prior to reaching the zona pellucida, sperm may release a surface protein that acts on the cumulus cells leading to the acrosome reaction, which may be important for determining the outcome of fertilization.

Lactobacillus casei prevents the development of dextran sulphate sodium-induced colitis in Toll-like receptor 4 mutant mice.

Probiotics, defined as live or attenuated bacteria or bacterial products, confer a significant health benefit to the host. Recently, they have been shown to be useful in the treatment of chronic inflammatory bowel disease and infectious colitis. In this study, we investigated the effect of probiotics on the development of experimental colitis using Toll-like receptor 4 (TLR-4) mutant (lps-/lps-) mice. TLR-4(lps-/lps-) and wild-type (WT) mice were given 2.5% dextran sulphate sodium (DSS) in drinking water to induce colitis with or without Lactobacillus casei pretreatment. Clinical and histological activity of DSS-colitis was attenuated markedly both in TLR-4(lps-/lps-) and WT mice pretreated with L. casei. Interestingly, histological activity was less severe in TLR-4(lps-/lps-) mice than in WT mice. The levels of myeloperoxidase activity and interleukin (IL)-12p40 were attenuated in pretreated TLR-4(lps-/lps-) mice after DSS administration. By contrast, transforming growth factor (TGF)-beta and IL-10 mRNA and protein expressions were increased markedly in pretreated TLR-4(lps-/lps-) mice. The current results suggest that L. casei has a preventive effect in the development of acute DSS-induced colitis and its action depends largely upon TLR-4 status. L. casei modulates the expression of inflammatory cytokines and down-regulates neutrophilic infiltration in the case of incomplete TLR-4 complex signalling.

Patient factors predictive of pain and difficulty during sedation-free colonoscopy: a prospective study in Korea.

BACKGROUND: Successful colonoscopy depends on insertion of the instrument to the cecum, precise observation, and minimal patient discomfort during the procedure. This prospective study was designed to identify factors, apart from the endoscopist's skill, that predict patient pain and technical difficulty during sedation-free colonoscopy. METHODS: A total of 426 sedation-free colonoscopies performed by one experienced endoscopist were evaluated in a prospective manner. Factors were recorded, including patient pain level, intubation time, demographic data, history of abdominal surgery, bowel preparation status, diverticular disease, bowel habits, anxiety level, and number of previous colonoscopies. These factors were analysed to determine their association with difficulty and pain during the procedure. RESULTS: Four hundred six colonoscopies were completed to the cecum (95.3%). Mean insertion time for complete colonoscopy was 6.5+/-3.5 min. Multivariate logistic regression analyses revealed that older age, lower body mass index, previous hysterectomy, diarrhoea, 1st time colonoscopy and anxiety were predictors of patient pain. Older age, lower body mass index and previous hysterectomy were predictors of difficulty of intubation. CONCLUSIONS: This prospective study identified several factors that may predict patient pain and technical difficulty associated with the procedure. These findings have implications for the practice and teaching of colonoscopy.

Smoking and tuberculosis among silicotic patients.

The aim of the present study was to investigate the relationship between smoking and tuberculosis (TB) among high-risk silicotic patients in Hong Kong. A cohort of 435 silicotic patients tuberculin tested from 1995-2002 was prospectively followed-up until the end of 2005. Baseline characteristics were analysed with respect to positive tuberculin reaction (> or =10 mm) at baseline and subsequent development of TB. Smoking, alcohol use and body mass index were independent predictors of positive tuberculin reaction at baseline in multiple logistic regression analysis. Total cigarette pack-yrs did not demonstrate any significant effect. The annual incidences of TB were 1,841, 2,294 and 4,181 per 100,000 for never-, ex- and current smokers, respectively. On Cox proportional hazard analysis, current smokers have a significantly higher risk of TB than other silicotic patients (adjusted hazard ratio (95% confidence interval (CI)): 1.96 (1.14-3.35)) after controlling for age, alcohol use, tuberculin status, treatment for latent TB infection and other relevant background/disease factors. A significant dose-response relationship was also observed with the daily number of cigarettes currently smoked. Smoking cessation may reduce 32.4% (95% CI: 6.5-54.0) of the risk. Smoking increases the risk of both tuberculosis infection and subsequent development of the disease among silicotic patients.

Evidence for an age-related attenuation of cerebral microvascular antioxidant response to oxidative stress.

Effects of aging and oxidative stress were studied in cerebral microvessels and microvessel-depleted brain from 6-, 18-, and 24-month-old C57Bl/6J mice exposed to normoxia, 24 or 48 h hyperoxia, or 24 h hyperoxia followed by 24 h normoxia. Microvessels lacked smooth muscle and consisted predominantly of endothelium. Following exposure and isolation of microvessel and parenchymal proteins, Western blot analysis was performed for detection of cytosolic thioredoxin 1 (TRx 1) and mitochondrial thioredoxin 2 (TRx 2), protein carbonyl, and mitochondrial superoxide dismutase (MnSOD). Both microvessel and parenchymal TRx 1 levels were increased by hyperoxia; however, the microvascular response was limited and delayed in comparison to that of the parenchymal fraction. Whereas TRx 2 levels in microvessels were increased in older mice, irrespective of exposure condition, hyperoxia per se had little or no apparent effect. Parenchymal cells showed no age-related increase in TRx 2 level under normoxic conditions, but showed increased levels following hyperoxia. Microvessel MnSOD was lower than that in parenchymal cells, but increased with age under normoxia, and also was correlated with the duration of hyperoxia. Although hyperoxia augmented MnSOD levels in young (6 months) and middle-aged (18 months) animals, the response was less pronounced in microvessels from senescent, 24-month-old mice. Unlike microvessels, which showed a sustained age-related increase in MnSOD level under each exposure condition, parenchymal cells from normoxic mice showed no increase, and hyperoxia-induced elevations declined with prolonged 48 h exposure. These results indicate that the microvessel endothelium is (1) subjected to a more intense oxidative environment than neurons and glia and (2) is limited by aging in its ability to respond to oxidative insult.

Association of obesity, serum glucose and lipids with the risk of advanced colorectal adenoma and cancer: a case-control study in Korea.

BACKGROUND: Previous studies on colorectal cancer risk suggest that obesity, serum lipids and glucose might be related to colorectal carcinogenesis. This case-control study was conducted to investigate the association between obesity, serum lipids and glucose, and the risk of advanced colorectal adenoma and cancer. METHODS: Patients with histologically confirmed colorectal cancers (n=105), same number of patients with advanced colorectal adenomas matched by age and sex, and the same number of controls matched by age and sex were selected in Hanyang University Guri Hospital between January 2002 and June 2004. RESULTS: Adenoma and cancer group showed significantly higher levels of mean body mass index and serum glucose. Cancer group also showed significantly lower mean serum lipids levels than controls. We used an unordered polytomous logistic model to calculate multivariate odds ratios for advanced adenoma and cancer relative to controls. Higher serum glucose level was more strongly associated with increased risk of cancer relative to controls (odds ratio, 3.0; 95% confidence interval, 0.9-9.8) than with increased risk of advanced adenoma (odds ratio, 2.1; 95% confidence interval, 0.9-5.4). Higher body mass index was strongly associated with increased risk of advanced adenoma (odds ratio, 10.8; 95% confidence interval, 4.6-25.3), but associated with attenuated risk of cancer (odds ratio, 2.3; 95% confidence interval, 0.9-5.8). Serum triglycerides and cholesterol levels were strongly associated with reduced risk of cancer (odds ratio, 0.3; 95% confidence interval, 0.1-0.8 and odds ratio, 0.2; 95% confidence interval, 0.1-0.6, respectively). CONCLUSIONS: Obesity and hyperglycaemia are positively related to advanced colorectal adenoma formation. Furthermore, hyperglycaemia plays an important role in progression to cancer. Findings on an inverse relationship between serum triglyceride and cholesterol levels and the risk of colorectal cancer may be the secondary results from metabolic or nutritional changes in advanced colorectal cancer patients and should be clarified in further studies.

Huge gastric diospyrobezoars successfully treated by oral intake and endoscopic injection of Coca-Cola.

A diospyrobezoar is a type of phytobezoar that is considered to be harder than any other types of phytobezoars. Here, we describe a new treatment modality, which effectively and easily disrupted huge gastric diospyrobezoars. A 41-year-old man with a history of diabetes mellitus was admitted with lower abdominal pain and vomiting. Upper gastrointestinal endoscopy revealed three huge, round diospyrobezoars in the stomach. He was made to drink two cans of Coca-Cola every 6 h. At endoscopy the next day, the bezoars were partially dissolved and turned to be softened. We performed direct endoscopic injection of Coca-Cola into each bezoar. At repeated endoscopy the next day, the bezoars were completely dissolved.

The proximity of the lesion to cell bodies determines the free radical risk induced in rat rubrospinal neurons subjected to axonal injury.

To find out whether close axonal injury resulted in greater free radical risk to cord-projection central neurons than distant ones, we studied the expressions of nitric oxide synthase, calcineurin, and superoxide dismutase in rat rubrospinal neurons following brainstem, C2 and T10 axotomies using immunohistochemical methods. We found that nitric oxide synthase expression was upregulated more following brainstem than C2 lesion while T10 lesion triggered no detectable changes. This response peaked at 1 week and returned to control level by 8-week-post-injury. At the same time, calcineurin, which activated nitric oxide synthase, was increased 1 week following brainstem and C2 axotomies. These suggest that close, but not distant, axotomy enhanced NO production, which appeared to be cytotoxic since blocking NO synthesis with N-nitro- l-arginine methyl ester reduced brainstem axotomy-induced rubrospinal cell loss. On the other hand, the mitochondrial Mn-superoxide dismutase, which competes with NO to prevent the formation of the cytotoxic free radical peroxynitrite, was notably reduced after brainstem but almost unaltered following C2 axotomy. Meanwhile, the cytosolic Cu/Zn-superoxide dismutase was not altered following C2 but increased after brainstem axotomy. Ultrastructurally, in rubrospinal neurons more mitochondria became swollen following brainstem than C2 axotomy. Based on these, we proposed that besides the NO-overproduction-induced toxicity, superoxide-loading-induced mitochondrial damage also added to hampering the survival of the closely axotomized neurons.

Dynamic evaluation of absorbed dose to the bladder wall with a balloon-bladder phantom during a study using [(18)F]fluorodeoxyglucose positron emission imaging.

An accurate evaluation of the absorbed dose to the bladder wall from 2-[(18)F]fluoro-2-deoxy-d-glucose (FDG) is clinically important because the bladder is considered as a critical organ in most positron emission tomography (PET) studies that cumulate about 20% of the total activity injection during image procedures. In the MIRD calculation, no allowance is made for the inclusion of all the dynamic parameters that affect the actual dose to the bladder wall to be taken in the dose assessment. The goal of the study is to propose a dose evaluation model by using a dynamic bladder phantom and time-activity curves from the bladder PET imaging. The proposed model takes all dynamic parameters into account and provides a much more accurate dose estimation to the bladder. In this study, the lowest dose to the bladder wall was obtained at the conditions of having a larger initial volume for the bladder contents and a higher production rate for urine. It is then advised patients to drink a bulk amount of water before the FDG injection or after urine voiding to facilitate urine production and to enlarge the bladder surface area, which are the most crucial steps in reducing the dose to the bladder wall. In our study, the voiding schedule in dose calculation plays certain roles although it is much more critical in the conventional MIRD calculation. The model estimated that the lowest dose to the bladder would occur at an initial void about 40 min after the FDG injection and the urine voiding was as complete as possible.

Androgen dependent expression of AT1 receptor and its regulation of anion secretion in rat epididymis.

Our previous studies have provided solid evidence for the presence of an intrinsic angiotensin-generating system in the rat epididymis, which plays an important role in the regulation of the anion and thus fluid secretion by the epididymal epithelium. In the present study, the effect of androgen on the expression of AT(1)receptor and its subsequent regulation of anion secretion by the epididymis were investigated using Western blotting, semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) and in vitro electrophysiological approaches. Results from Western blotting analysis showed that the expression of AT(1)receptor protein was almost abolished by castration whereas its expression was completely restored to the control level when the castrated rats were hormonally replaced with testosterone. Efferent duct ligation, however, appeared not to affect the expression of AT(1)receptor protein by the epididymis. Results from RT-PCR showed that mRNA expression of AT(1)receptor was consistent with that observed in protein expression. Results from short-circuit current (I(SC)) showed that castration almost abolished the angiotensin II-induced I(SC). However, efferent duct ligation did not affect the angiotensin II-induced I(SC), which was completely blocked in the presence of losartan, a specific antagonist of the AT(1)receptor. These data indicate that the expression of epididymal AT(1)receptor is predominantly influenced by testicular androgens but not by testicular factors. This androgen-dependent expression of AT(1)receptor could have a role in the control of AT(1)receptor-mediated anion secretion and thus fluid secretion by the rat epididymis.

Effects of neonatal polychlorinated biphenyl exposure on female sexual behavior.

The effects of polychlorinated biphenyls (PCBs) on development and reproduction are well documented. However, very little is known about the effects of PCBs on sexual behavior. In this study, we examined the effects of two commercial PCB mixtures, Aroclor 1221 (A1221) and Aroclor 1254 (A1254), on the development of female sexual behavior and of the incertohypothalamic dopaminergic cells (A11 and A13) in Long-Evans rats. Neonatal exposure to A1254 significantly reduced sexual receptivity and reduced the female's latency to approach a male after an intromission. Neonatal treatment with A1221 did not affect female sexual behavior nor did treatment of adult females with A1221 or A1254. Since sexual behavior is affected by dopamine and since PCBs have been reported to alter dopamine content in the brain, we examined the effects of A1221 or A1254 on dopaminergic cells in the incertohypothalamic region of neonatally exposed rats. None of the treatments significantly affected the number of A11 or A13 neurons that were immunoreactive for tyrosine hydroxylase (TH) or the expression of Fos (i.e., the product of the immediate early gene c-fos) in these dopaminergic neurons. Therefore, the disruption of behavior induced by neonatal treatment with A1254 does not appear to be mediated by toxic effects of the mixture on incertohypothalamic dopaminergic systems.