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Tumor hypoxia is a common feature in colorectal cancer (CRC), and is associated with resistance to radiotherapy and chemotherapy. Thus, a specifically targeted probe for the detection of hypoxic CRC cells is urgently needed. Carbonic anhydrase 9 (CA9) is considered to be a specific marker for hypoxic CRC diagnosis. Here, a nuclear imaging Indium-111 (111In)-labeled dual CA9-targeted probe was synthesized and evaluated for CA9 detection in in vitro, in vivo, and in human samples. The CA9-targeted peptide (CA9tp) and CA9 inhibitor acetazolamide (AAZ) were combined to form a dual CA9-targeted probe (AAZ-CA9tp) using an automatic microwave peptide synthesizer, which then was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for radioisotope (111In) labeling (111In-DOTA-AAZ-CA9tp). The assays for cell binding, stability, and toxicity were conducted in hypoxic CRC HCT15 cells. The analyses for imaging and biodistribution were performed in an HCT15 xenograft mouse model. The binding and distribution of 111In-DOTA-AAZ-CA9tp were detected in human CRC samples using microautoradiography. AAZ-CA9tp possessed good CA9-targeting ability in hypoxic HCT15 cells. The dual CA9-targeted radiotracer showed high serum stability, high surface binding, and high affinity in vitro. After exposure of 111In-DOTA-AAZ-CA9tp to the HCT15-bearing xenograft mice, the levels of 111In-DOTA-AAZ-CA9tp were markedly and specifically increased in the hypoxic tumor tissues compared to control mice. 111In-DOTA-AAZ-CA9tp also targeted the areas of CA9 overexpression in human colorectal tumor tissue sections. The results of this study suggest that the novel 111In-DOTA-AAZ-CA9tp nuclear imaging agent may be a useful tool for the detection of hypoxic CRC cells in clinical practice.

Bromelain, a cysteine protease found in pineapple, has beneficial effects in the treatment of inflammatory diseases; however, its effects in cardiovascular pathophysiology are not fully understood. We investigated the effect of bromelain on atherosclerosis and its regulatory mechanisms in hyperlipidemia and atheroprone apolipoprotein E-null (apoe−/−) mice. Bromelain was orally administered to 16-week-old male apoe−/− mice for four weeks. Daily bromelain administration decreased hyperlipidemia and aortic inflammation, leading to atherosclerosis retardation in apoe−/− mice. Moreover, hepatic lipid accumulation was decreased by the promotion of cholesteryl ester hydrolysis and autophagy through the AMP-activated protein kinase (AMPK)/transcription factor EB (TFEB)-mediated upregulation of autophagy- and antioxidant-related proteins. Moreover, bromelain decreased oxidative stress by increasing the antioxidant capacity and protein expression of antioxidant proteins while downregulating the protein expression of NADPH oxidases and decreasing the production of reactive oxygen species. Therefore, AMPK/TFEB signaling may be crucial in bromelain-mediated anti-hyperlipidemia, antioxidant, and anti-inflammatory effects, effecting the amelioration of atherosclerosis.

The awareness on ischemic heart disease (IHD) in women with dysmenorrhea is insufficient. We utilized the National Health Insurance Research Database (NHIRD) of Taiwan to evaluate this relationship. From the claims data, we established a cohort of women aged 15–50 years with primary dysmenorrhea diagnosed from 2000 to 2008 (n = 18,455) and a comparison cohort (n = 36,910) without dysmenorrhea, frequency matched by age and diagnosis date. Both cohorts were followed until the end of 2013 to assess IHD events. With 75% of study population aged 15–29 years, the incidence of IHD was greater in the dysmenorrheal cohort than in the comparison cohort (1.93 versus 1.18 per 10,000 person-years), with an adjusted hazard ratio of 1.60 (95% confidence interval [CI] = 1.38–1.85). The incidence increased with age and the rate of increase was greater in the dysmenorrheal cohort than the comparison cohort. Nested case-control analysis in the dysmenorrhea cohort showed that IHD risk was also associated with hypertension and arrhythmia, with adjusted odds ratios of 2.50 (95% CI = 1.64–3.81) and 3.30 (95% CI = 2.25–4.86), respectively. Women with dysmenorrhea are at a higher risk of developing IHD, particularly for older patients and patients with comorbidity.

Background C-X-C motif chemokine receptor 4 (CXCR4) plays a prominent role in inflammation, atherosclerosis, and cancer biology. Therefore, CXCR4 represents a promising target for molecular imaging in cardiovascular diseases such as atherosclerosis and arterial wall injury. CXCR4 and its cognate ligand, stromal cell–derived factor 1α (SDF-1α), induced monocyte recruitment to the injured endothelium and subsequent plaque formation is the crucial progression of atherosclerosis. CXCR4 was been proved to be intensively expressed on monocytes/macrophage. [68Ga]-APD, based on the structure of CXCR4 antagonists TIQ-15, had designed by computer simulation as a PET tracer for imaging activated macrophages within the atherosclerotic lesions. The aim of this study was to evaluate the biological characteristics of [68Ga]-APD, and compared with the PET tracers targeting atherosclerotic lesion such as [18F]-FDG, [18F]-NaF, and [68Ga]-Pentixafor in apolipoprotein-E-deficient (ApoE−/−) mice. Results The specification and quality of APD was identified by Mass, NMR and HPLC. After being labeled with Ga-68 under acetate buffer (pH≒5.5), radiochemical purity was over 90% and stable for more than 4 hours in 37℃human serum. After being injected from tail vein on ApoE−/− atherosclerotic mice model, hydrophilic [68Ga]-APD was quickly eliminate from the kidney and bladder. [68Ga]-APD could accumulate in the atherosclerotic aorta site and CXCR4 expression organs. The highest target/background ratio (TBR) on atherosclerotic sites were 17.68 ± 0.71 (n = 3) on high-fat diet ApoE−/− mice for 12 weeks after [68Ga]-APD injection within 1 hour. However, [68Ga]-Pentixafor was only 2.06 ± 0.67 (n = 3) on the same mice model. Competitive study represented that CXCR4 antagonist AMD3465 could effectively block the uptake of [68Ga]-APD on the atherosclerotic site and CXCR4 expression organs. Comparing with [18F]-FDG and [18F]-NaF, [68Ga]-APD represented relatively better TBR and specificity on the imaging of atherosclerotic lesions. Conclusion In vivo evaluation of CXCR4 expression in ApoE−/− mice revealed the uptake of [68Ga]-APD mainly accumulated in the atherosclerotic aorta site. Moreover, the TBR of [68Ga]-APD was 8 times higher than [68Ga]-Pentixafor, a radiotracer targeting CXCR4 and under phase II clinical trial, indicating this novel tracer [68Ga]-APD is more feasible as a surrogate marker for inflammatory atherosclerosis.

Background: Studies on strokes associated with dysmenorrhea are limited. We conducted a propensity-score-matched retrospective cohort study to assess the risk of stroke in women with primary dysmenorrhea (PD). Methods: From the claims data of one million people in Taiwan’s insurance program, we identified 18,783 women aged 15–40 years, newly diagnosed with PD in 2000–2010, without a history of stroke. We randomly selected a comparison cohort without stroke history and dysmenorrhea, with the same sample size matched by age, index date, and propensity score. We began a follow-up with individuals one year after cohort entry to the end of 2013 to capture stroke events. Results: The two study cohorts were well-matched for age and comorbidities, with 54% of women aged 15–24. Stroke incidence was 1.5-fold higher in the PD cohort than in the comparison cohort (6.05 vs. 4.01 per 10,000 person-years, or 99 vs. 65 cases), with an adjusted hazard ratio (aHR) of 1.51 (95%CI 1.11–2.06) after adjustment for matched pairs. Nearly 70% of strokes were ischemic strokes, which occurred 1.6 times more frequently in the PD cohort than in the comparison cohort (4.40 vs. 2.71 per 10,000 person-years, or 72 vs. 44 cases), aHR = 1.61 (95% CI 1.11–2.33), after adjustment for matched pairs. The incidence of hemorrhagic stroke was also higher in the PD cohort than in the comparison cohort (1.65 vs. 1.29 per 10,000 person-years, or 27 versus 21 cases), but the difference was not significant. Conclusion: Women of reproductive age with PD are at increased risk for ischemic stroke.

Tumor hypoxia is a common feature in colorectal cancer (CRC), and is associated with resistance to radiotherapy and chemotherapy. Thus, a specifically targeted probe for the detection of hypoxic CRC cells is urgently needed. Carbonic anhydrase 9 (CA9) is considered to be a specific marker for hypoxic CRC diagnosis. Here, a nuclear imaging Indium-111 (

Postherpetic neuralgia (PHN) is a common, painful, and long-term complication of herpes zoster (HZ). PHN increases the demand for healthcare services and, previous studies showed that patients who received antiviral agents were less likely to develop PHN. The objective of this study was to compare the efficacy of prodrugs and acyclovir in treating PHN among patients with HZ. The search included the PubMed, Medline, Embase, and Cochrane Center of Register of Controlled Trails databases through February 2022. Clinical trials and randomized controlled trials (RCTs) involving antiviral agent intervention for HZ patients diagnosed with PHN were eligible for inclusion. A meta-analysis was conducted to calculate pooled risk ratios (RRs) with 95% confidence intervals (CIs) with a fix-effect model. Five RCTs with 1147 HZ patients met our eligibility criteria. Our meta-analysis found that there was a significantly lower risk of PHN for members of the prodrugs group (famciclovir and valaciclovir) compared with those who received acyclovir (RR = 0.86, 95%, CI: 0.75 to 0.98, p = 0.03). The review of studies indicated that the efficacy of prodrugs was better than acyclovir for reliving PHN.

Safrole is a natural compound categorized as a group 2B carcinogen extracted from betel quid chewing, which is a common practice of psychoactive habits integrated into social and cultural ceremonies among serveral million people, especially in Southern or Southeastern Asia. Safrole is one of the major risk compunds for development of oral squamous cell carcinoma and hepatocellular carcinoma via DNA adduction. In innate immunity, macrophages are the predominant cells for non-specific first line defense against pathogens in oral tissue. Up to now, there is no evidence to implicate the potential toxicological effect of safrole on macrophages. In this study, we found safrole induced the generation of reactive oxygen species (ROS) and myeloperoxidase (MPO) in RAW264.7 macrophages in a concentration-dependent manner. Furthermore, cytotoxicity, DNA damage, and apoptosis were caused by safrole in a concentration-dependent manner. While the activation of antioxidative enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx) was reduced, the phosphorylation of Akt was induced by safrole in a concentration-dependent manner. These results indicated that the induction of cytotoxicity, DNA damage, and apoptosis in macrophages by safrole was through generation of ROS and inhibition of antioxidative enzymes possibly via Akt phosphorylation.

BackgroundDysmenorrhea and stroke are health problems affecting women worldwide in their day-to-day lives; however, there is limited knowledge of the stroke risk in women with dysmenorrhea, and there have been no studies assessing the specific distribution of stroke subtypes. This case-control study assessed stroke subtypes by age and the role of comorbidities in women with dysmenorrhea.Methods and findingsData obtained between 1997 and 2013 from Taiwan's health insurance database identified 514 stroke cases and 31,201 non-stroke controls in women with dysmenorrhea aged 15-49 years. Proportional distributions of subtypes and odds ratios (ORs) of stroke associated with comorbidities by age and subtype were measured. We found that the stroke risk in dysmenorrheal patients increased with age, and that hypertension was nine-fold more prevalent in the stroke cases than in the controls and was associated with an adjusted OR of 4.53 (95% confidence interval (CI) = 3.46-5.92) for all stroke cases. Moreover, the proportion of hemorrhagic stroke was greater than that of ischemic stroke in younger dysmenorrheal patients between 15-24 years old (50.5% vs. 11.4%), whereas this was reversed in those aged 30-49 years old (16.1% vs. 21.0%). Overall, 25.3% of the stroke cases consisted of transient cerebral ischemia and 31.3% were other acute but ill-defined cerebrovascular diseases, in which the prevalence increased with age for both types of strokes. Hypertension was the comorbidity with the highest OR associated with each subtype stroke; diabetes, hyperlipidemia, arrhythmia, and thyroid disease were also comorbidities that were significantly associated with ill-defined cerebrovascular diseases.ConclusionsThe stroke type varies by age in dysmenorrheal patients, and hypertension is the most important comorbidity associated with all types of stroke; therefore, more attention for stroke prevention must be paid to women with dysmenorrhea, particularly when combined with comorbidities.

Male infertility is observed in approximately 50% of all couples with infertility. Intracytoplasmic sperm injection (ICSI), a conventional artificial reproductive technique for treating male infertility, may fail because of a severe low sperm count, immotile sperm, immature sperm, and sperm with structural defects and DNA damage. Our previous studies have revealed that mutations in the septin (SEPT)-coding gene SEPT12 cause teratozoospermia and severe oligozoospermia. These spermatozoa exhibit morphological defects in the head and tail, premature chromosomal condensation, and nuclear damage. Sperm from Sept12 knockout mice also cause the developmental arrest of preimplantation embryos generated through in vitro fertilization and ICSI. Furthermore, we found that SEPT12 interacts with SPAG4, a spermatid nuclear membrane protein that is also named SUN4. Loss of the Spag4 allele in mice also disrupts the integration nuclear envelope and reveals sperm head defects. However, whether SEPT12 affects SPAG4 during mammalian spermiogenesis remains unclear. We thus conducted this study to explore this question. First, we found that SPAG4 and SEPT12 exhibited similar localizations in the postacrosomal region of elongating spermatids and at the neck of mature sperm through isolated murine male germ cells. Second, SEPT12 expression altered the nuclear membrane localization of SPAG4, as observed through confocal microscopy, in a human testicular cancer cell line. Third, SEPT12 expression also altered the localizations of nuclear membrane proteins: LAMINA/C in the cells. This effect was specifically due to the expression of SEPT12 and not that of SEPT1, SEPT6, SEPT7, or SEPT11. Based on these results, we suggest that SEPT12 is among the moderators of SPAG4/LAMIN complexes and is involved in the morphological formation of sperm during mammalian spermiogenesis.

This study aimed to determine the mechanism of ketamine-induced cystitis without metabolism. A total of 24 adult male Sprague-Dawley rats were separated into control, ketamine, and norketamine groups. To induce cystitis, rats in the ketamine and norketamine groups were treated with intravesical instillation of ketamine and norketamine by mini-osmotic pump, which was placed in subcutaneous space, daily for 24 h for 4 weeks. After 4 weeks, all rats were subjected to bladder functional tests. The bladders were collected for histological and pathological evaluation. Compared to control, ketamine treatment demonstrated an increase in the bladder weight, high bladder/body coefficient, contractive pressure, voiding volume, collagen deposition, reduced smooth muscle content, damaged glycosaminoglycan layer, and low bladder compliance. Compared to ketamine, norketamine treatment showed more severe collagen deposition, smooth muscle loss, damaged glycosaminoglycan layer, and increased residual urine. Intravesical administration of ketamine and norketamine induced cystitis with different urodynamic characteristics. Norketamine treatment caused more severe bladder dysfunction than ketamine treatment. Direct treatment of the bladder with norketamine induced symptoms more consistent with those of bladder outlet obstruction than ketamine cystitis. Detailed studies of cellular mechanisms are required to determine the pathogenesis of ketamine cystitis.

Microglia serve important roles in chronic pain signal transduction pathways. Glia cells, especially microglia, seem to share mechanisms that lead to chronic pain and morphine‑induced tolerance. Evidence has suggested that downregulating cytoskeleton activity in microglia provides pain relief in chronic pain and morphine tolerance. The purpose of the present study was to evaluate the effect of ethanol extracts of Hericium erinaceus (EHE) mycelium on morphine‑induced BV2 microglial cell activation. BV2 cells were starved for 4 h in DMEM before being incubated with 100 ng/ml EHE for 30 min, followed by 1 µM morphine for 2 h. Subsequently, the cells were harvested and used for migration experiments and western blotting. The results showed that 1 µM morphine enhanced BV2 cell activation and chemotactic reaction, and it increased histone deacetylase 6 (HDAC6) expression and heat shock protein 90 (HSP90) deacetylation as well as HSP90 cleavage. Pretreatment with 100 ng/ml EHE significantly inhibited the morphine‑stimulated effects on BV2 cells. The present study demonstrated that EHE inhibited morphine‑induced BV2 activations by regulating the HDAC6/HSP90 deacetylation signal transduction pathway.

Lipopolysaccharide (LPS), also called endotoxin, is the important pathogen of acute lung injury (ALI), which is a clinical syndrome that still lacks effective therapeutic medicine. Rutin belongs to vitamin P and possesses various beneficial effects. In this study, we investigate the potential protective effects and the mechanisms of rutin on LPS-induced ALI. Pre-administration with rutin inhibited LPS-induced arterial blood gas exchange and neutrophils infiltration in the lungs. LPS-induced expression of macrophage inflammatory protein (MIP)-2 and activation of matrix metalloproteinase (MMP)-9 were suppressed by rutin. In addition, the inhibitory concentration of rutin on phosphorylation of Akt was similar as MIP-2 expression and MMP-9 activation. In conclusion, rutin is a potential protective agent for ALI via suppressing the blood gas exchange and neutrophil infiltration. The mechanism of rutin is down-regulation of MIP-2 expression and MMP-9 activation through inhibition of Akt phosphorylation.

The development of radioimmunotherapy has provided an impressive alternative approach in improving trastuzumab therapy. However, the mechanisms of trastuzumab and radiation treatment combined to increase therapeutic efficacy are poorly understood. Here, we try to examine the efficacy of cytotoxicity and apoptosis induction for (188)Re-HYNIC-trastuzumab in cancer cell lines with various levels of Her2.Fluorescence flow cytometry was used to detect the alterations of apoptosis induction after (188)Re-HYNIC-trastuzumab treatment in two breast cancer cell lines with different levels of HER2 (BT-474 and MCF-7) and a colorectal carcinoma cell line (HT-29) for control.Our results indicated that (188)Re-HYNIC-trastuzumab led to cell death of breast cancer cells specifically in HER2 level-dependent and radioactivity dose-dependent fashions. In BT-474 cells, 370 kBq/ml of (188)Re-HYNIC-trastuzumab enhanced the cytotoxicity to a level nearly 100-fold that of trastuzumab-alone treatment. The results also revealed that the mitochondria-dependent pathway attenuated irradiation-induced apoptosis in HER2-expressing breast cancer cells after (188)Re-HYNIC-trastuzumab treatment. In contrast, only after 48 h of (188)Re-HYNIC-trastuzumab treatment, BT-474 cells exhibited typical apoptotic changes, including exposure of phospholipid phosphatidylserine on the cell surface, or fragmented DNA formation, in a radioactivity dose-dependent manner.Briefly, our study demonstrates that (188)Re-labeled HYNIC-trastuzumab not only enhances cell death in a radioactivity dose-dependent fashion, but may also prolong the effects of apoptosis involved with the mitochondria-dependent pathway in HER2-overexpressing breast cancer cells. It is possible that the (188)Re-HYNIC-trastuzumab treatment induced a second round of apoptosis to prolong the effects of cell kill in these cancer cells. These data revealed that (188)Re-HYNIC-trastuzumab has the potential for use as a therapeutic radiopharmaceutical agent in HER2-overexpressing breast cancer cell treatment.

Ying-Hsia Shih,1,2 Xi-Zhang Lin,3 Chung-Hsin Yeh,1 Cheng-Liang Peng,1,2 Ming-Jium Shieh,2,4 Wuu-Jyh Lin,1 Tsai-Yueh Luo1,51Isotope Application Division, Institute of Nuclear Energy Research, Longtan, 2Institute of Biomedical Engineering, National Taiwan University, Taipei, 3Department of Internal Medicine, National Cheng Kung University, Tainan, 4Department of Oncology, National Taiwan University Hospital and College of Medicine, Taipei, 5Institute of Radiological Science, Central Taiwan University of Science and Technology, Taichung, TaiwanAbstract: Radiolabeled Lipiodol® (Guerbet, Villepinte, France) is routinely used in hepatoma therapy. The temperature-sensitive hydrogel polyethylene glycol-b-poly-DL-lactic acid-co-glycolic acid-b-polyethylene glycol triblock copolymer is used as an embolic agent and sustained drug release system. This study attempted to combine the polyethylene glycol-b-poly-DL-lactic acid-co-glycolic acid-b-polyethylene glycol hydrogel and radio-labeled Lipiodol to form a new radio-thermogelling emulsion, rhenium-188–N,N’-1,2-ethanediylbis-L-cysteine diethyl-ester dihydrochloride–Lipiodol/hydrogel (188Re-ELH). The therapeutic potential of 188Re-ELH was evaluated in a rodent hepatoma model. Rhenium-188 chelated with N,N’-1,2-ethanediylbis-L-cysteine diethyl-ester dihydrochloride was extracted with Lipiodol to obtain rhenium-188–N,N’-1,2-ethanediylbis-L-cysteine diethyl-ester dihydrochloride–Lipiodol (188Re-EL), which was blended with the hydrogel in equal volumes to develop 188Re-ELH. The 188Re-ELH phase stability was evaluated at different temperatures. Biodistribution patterns and micro-single-photon emission computed tomography/computed tomography images in Sprague Dawley rats implanted with the rat hepatoma cell line N1-S1 were observed after in situ tumoral injection of ~3.7 MBq 188Re-ELH. The therapeutic potential of 188Re-EL (48.58±3.86 MBq/0.1 mL, n=12) was evaluated in a 2-month survival study using the same animal model. The therapeutic effects of 188Re-ELH (25.52±4.64 MBq/0.1 mL, n=12) were evaluated and compared with those of 188Re-EL. The responses were assessed by changes in tumor size and survival rates. The 188Re-ELH emulsion was stable in the gel form at 25°C–35°C for >52 hours. Biodistribution data and micro-single-photon emission computed tomography/computed tomography images of the 188Re-ELH group indicated that most activity was selectively observed in hepatomas. Long-term 188Re-ELH studies have demonstrated protracted reductions in tumor volumes and positive effects on the survival rates (75%) of N1-S1 hepatoma-bearing rats. Conversely, the 2-month survival rate was 13% in the control sham group. Therapeutic responses differed significantly between the two groups (P

To evaluate the accuracy of a new fluorine-18-2-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) method when applying an increased upper limit of the image threshold (IULIT) to detect bladder cancer. All patients with an unknown history of bladder tumors were retrospectively included for analysis. Applying an IULIT in PET showed a hypermetabolic focus. 18F-FDG accumulation in the bladder that was higher or lower than the urinary level of 18F-FDG was considered an abnormal focus. In 12 of the 28,767 patients with bladder cancer, applying an IULIT in PET allowed the visualization of the contrast between lesion and urinary activity. The proposed method could increase the accuracy of detection of bladder cancer.

Endotoxins exist anywhere including in water pools, dust, humidifier systems, and machining fluids. The major causal factor is endotoxins in many serious diseases, such as fever, sepsis, multi-organ failure, meningococcemia, and severe morbidities like neurologic disability, or hearing loss. Endotoxins are also called lipopolysaccharide (LPS) and are important pathogens of acute lung injury (ALI). Rutin has potential beneficial effects including anti-inflammation, antioxidation, anti-hyperlipidemia, and anti-platelet aggregation. Pre-treatment with rutin inhibited LPS-induced neutrophil infiltration in the lungs. LPS-induced

Acute lung injury (ALI) is a serious disease with unacceptably high mortality and morbidity rates. Up to now, no effective therapeutic strategy for ALI has been established. Rutin, quercetin-3-rhamnosyl glucoside, expresses a wide range of biological activities and pharmacological effects, such as anti-inflammatory, antihypertensive, anticarcinogenic, vasoprotective, and cardioprotective activities. Pretreatment with rutin inhibited not only histopathological changes in lung tissues but also infiltration of polymorphonuclear granulocytes into bronchoalveolar lavage fluid in lipopolysaccharide (LPS)-induced ALI. In addition, LPS-induced inflammatory responses, including increased secretion of proinflammatory cytokines and lipid peroxidation, were inhibited by rutin in a concentration-dependent manner. Furthermore, rutin suppressed phosphorylation of NF-κB and MAPK and degradation of IκB, an NF-κB inhibitor. Decreased activities of antioxidative enzymes such as superoxide dismutase, catalase, glutathione peroxidase, and heme oxygenase-1 caused by LPS were reversed by rutin. At the same time, we found that ALI amelioration by chelation of extracellular metal ions with rutin is more efficacious than with deferoxamine. These results indicate that the protective mechanism of rutin is through inhibition of MAPK-NF-κB activation and upregulation of antioxidative enzymes.

Summary Background/Objective Standard laparoscopic adrenalectomy requires early control of the main adrenal vein; however, the small retroperitoneal working space is challenging for beginners to perform this maneuver. We report a technical modification of retroperitoneal laparoscopic adrenalectomy (RLA) for primary hyperaldosteronism (PHA) and the clinical outcomes. Methods A total of 38 RLAs were performed for the patients with PHA. The patients were placed in true lateral position with mild bending to expand the surgical field. Instead of attempting to control the main adrenal vein initially, we adopted a technical modification that manipulating and freeing the gland first before controlling the main adrenal vein. Results The RLAs were successfully performed in all but one case, which was converted to open surgery due to pancreatic injury. Mean operative time was 124 minutes and estimated blood loss was 74 ml. Mean maximal fluctuation of systolic blood pressure was 29 mmHg. For the right-side RLA, less operative time (113.5 vs. 137.9 minutes) and estimated blood loss (59.5 vs. 91.2 ml) were noted compared with the left-side procedure. Postoperative complications included cerebrovascular accident in one patient, one surgical site hematoma, and two patients had postoperative fever. Potassium level returned to normal in all patients and 70% of the patients reduced their antihypertensives. Conclusion Technical modification RLA for PHA without initial control of the main adrenal vein is a safe and feasible procedure. No vigorous blood pressure fluctuation was intraoperatively noted. No vascular injury occurred. Moreover, the right-side procedure became easier.

Background Asians have higher frequency of intracranial arterial stenosis. The present study aimed to compare the clinical features and outcomes of ischemic stroke patients with and without middle cerebral artery (MCA) stenosis, assessed by transcranial sonography (TCS), based on the Taiwan Stroke Registry (TSR). Methods Patients with acute ischemic stroke or transient ischemic attack registered in the TSR, and received both carotid duplex and TCS assessment were categorized into those with stenosis (≥50%) and without (

Microglia are the major component of intrinsic brain immune system in neuroinflammation. Although wogonin expresses anti-inflammatory function in microglia, little is known about the molecular mechanisms of the protective effect of wogonin against microglia activation. The aim of this study was to evaluate how wogonin exerts its anti-inflammatory function in BV2 microglial cells after LPS/INFγ administration. Wogonin not only inhibited LPS/ INFγ-induced PGE2 and NO production without affecting cell viability but also exhibited parallel inhibition on LPS/INFγ-induced expression of iNOS and COX-2 in the same concentration range. While LPS/INFγ-induced expression of P-p65 and P-IκB was inhibited by wogonin—only weak inhibition on P-p38 and P-JNK were observed, whereas it significantly attenuated the P-ERK1/2 and its upstream activators P-MEK1/2 and P-Src in a parallel concentration-dependent manner. These results indicated that the blockade of PGE2 and NO production by wogonin in LPS/INFγ-stimulated BV2 cells is attributed mainly to interference in the Src-MEK1/2-ERK1/2-NFκB-signaling pathway. © 2013 Wiley Periodicals, Inc. Environ Toxicol 29: 1162–1170, 2014.

According to recent estimates, 2%–15% of couples are sterile, and approximately half of the infertility cases are attributed to male reproductive factors. However, the reasons remain undefined in approximately 25% of male infertility cases, and most infertility cases exhibit spermatogenic defects. Numerous genes involved in spermatogenesis still remain unknown. We previously identified Male Germ Cells Rab GTPase-Activating Proteins (MGCRABGAPs) through cDNA microarray analysis of human testicular tissues with spermatogenic defects. MGCRABGAP contains a conserved RABGAP catalytic domain, TBC (Tre2/Bub2/Cdc16). RABGAP family proteins regulate cellular function (e.g., cytoskeletal remodeling, vesicular trafficking, and cell migration) by inactivating RAB proteins. MGCRABGAP is a male germ cell-specific protein expressed in elongating and elongated spermatids during mammalian spermiogenesis. The purpose of this study was to identify proteins that interact with MGCRABGAP during mammalian spermiogenesis using a proteomic approach. We found that MGCRABGAP exhibited GTPase-activating bioability, and several MGCRABGAP interactors, possible substrates (e.g., RAB10, RAB5C, and RAP1), were identified using co-immunoprecipitation (co-IP) and nano liquid chromatography-mass spectrometry/mass spectrometry (nano LC-MS/MS). We confirmed the binding ability between RAB10 and MGCRABGAP via co-IP. Additionally, MGCRABGAP–RAB10 complexes were specifically colocalized in the manchette structure, a critical structure for the formation of spermatid heads, and were slightly expressed at the midpiece of mature spermatozoa. Based on these results, we propose that MGCRABGAP is involved in mammalian spermiogenesis by modulating RAB10.

To investigate the inhibitory activities of norcantharidin (NCTD), a demethylated analogue of cantharidin, on Hep3B cells (a human hepatoma cell line) with deficiency of p53.The survival rate of the Hep3B cells after treating with NCTD was measured by MTT assay. Cell cycle of treated cells was analyzed by flow cytometry, and DNA fragmentation was observed by electrophoresis. The influence of inhibitors for various caspases and anti-death receptors antibodies on the NCTD-induced apoptosis in the cells was determined.NCTD treatment resulted in growth inhibition of Hep3B cells in a dose- and time-dependent manner. Cell cycle analysis of the cells after treatment with NCTD for 48 h shows that NCTD induced G(2)M phase arrest occurs at low concentration ([Symbol: see text] 25 μmol/L) but G(0)G(1) phase arrest at high concentration (50 μmol/L). The addition of both caspase-3 and caspase-10 inhibitors completely inhibited DNA fragmentation. Addition of anti-TRAIL/DR5 antibody significantly inhibited DNA fragmentation.NCTD may inhibit the proliferation of Hep3B cells by arresting cell cycle at G(2)M or G(0)G(1) phase, and induce cells apoptosis via TRAIL/DR5 signal transduction through activation of caspase-3 and caspase-10 by a p53-independent pathway.

Cigarette smoking is a major risk factor for bladder cancer (BC). Sulfotransferase 1A1 (SULT1A1), a phase II enzyme, plays an important role in the metabolism of several carcinogens contained in cigarettes. The aim of this study was to investigate the relationship between SULT1A1 G638A polymorphism, cigarette smoking and bladder cancer risk in Taiwan. A total of 150 BC patients and 150 cancer-free controls were recruited from February 2002 to February 2009. Genotyping of the SULT1A1 G638A polymerphism was determined using the polymerase chain reaction-restricted fragment length polymorphism (PCR- RFLP) method. The odds ratio (OR) and 95% confidence interval (CI) were calculated as a measure of the combined effect of cigarette smoking and the SULT1A1 G638A polymorphism on BC risk. In the present study, we found that study subjects with the G/G genotype of the SULT1A1 gene had a significantly higher BC risk of 1.7 (95% CI = 1.3 - 3.2) compared with those carrying the combination of G/A and A/A genotypes. Moreover, ever smokers who carried the G/G genotype of the SULT1A1 gene had a significantly increased UC risk of 3.5 (95% CI = 2.5 - 10.2) compared with never smokers who carried the G/A and A/A genotypes as the reference group. In conclusion, our findings suggest that SULT1A1 G638A polymorphism is associated with the development of BC, especially among cigarette smokers.

Purpose Oxidative stress and endoplasmic reticulum (ER) stress may induce renal apoptosis and contribute to the pathogenesis of the kidney with unilateral ureteral obstruction (UUO). Materials and Methods We induced UUO the female Wistar rats by ligation of the left ureter at the ureteropelvic junction. The UUO kidney was performed from 4 hr to 7 days course. At the indicated time, we measured the arterial blood pressure and renal blood flow in each rat, renal ROS measurement in vivo by a chemiluminescence analyzer. We performed immunohistochemistry of monocyte/macrophage (ED-1) stain for leukocyte infiltration, 4-hydroxynoneal (4-HNE) stain for ROS products, and apoptosis by terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) and Western blot to analyze ER stress-associated and apoptosis-related proteins expression in the UUO kidney. Results We found that UUO decreased renal blood flow and increased renal vascular resistance and renal ROS. UUO decreased renal manganese superoxide dismutase (MnSOD) and catalase protein expression in a time-dependent manner. Increased 4-HNE stain in the renal tubules and ED-1 stain in the renal tubulointerstitial compartment occurred after 4 hr of UUO in the kidney. UUO significantly enhanced ER stress markers like ER stress-response protein 25 and glucose-regulated protein 78 and ER-associated apoptosis proteins, c-JUN NH2-terminal kinase, and caspase 12, in the kidney. Subsequently, UUO enhanced renal pro-apoptotic Bax and caspase 3 expression and decreased anti-apoptotic Bcl-2 expression, leading to renal tubular apoptosis. Conclusions Our data suggest that renal tubular apoptosis induced by oxidative stress and ER stress occurred in the UUO kidney. Neurourol. Urodynam. 30:472–479, 2011. © 2011 Wiley-Liss, Inc.

Temporal lobe epilepsy is the most common type of localization-related epilepsy and may manifest as behavior change or psychosis. Sometimes it is hard to diagnose because we are used to thinking about dementia probably. Here we reported an unusual case that a 73 years-old male patient with dementia-like symptoms previously, but finally he was diagnosed as temporal lobe epilepsy by the electrophysiological and radiological finding.

Aims We hypothesize that increased H2O2 in the urinary bladder may affect ATP and acetylcholine release and activate urothelial purinergic and muscarinic signaling consequently leading to hyperactive bladder. Materials and Methods We infused 0.3% and 1.5% H2O2 to the urinary bladder to evaluate the voiding function and frequency, pelvic afferent (PANA) and pelvic efferent nerve activity (PENA) simultaneously in the urethane anesthetized rats. We measured ATP and acetylcholine content in the rat urinary bladder under saline or H2O2 stimulation. Hyaluronic acid, muscarinic, and purinergic receptor antagonists were used to evaluate their effects and mechanisms on H2O2-induced hyperactive bladder. Results Intravesical H2O2 administration increased the frequency of voiding and the maximal amplitude of intravesical pressure (IVP) in the urethane anesthetized rats. Intravesical H2O2 decreased the threshold level of PANA and PENA for triggering micturition and increased ATP and acetylcholine contents in the H2O2-treated bladder in the rat. Hyaluronic acid in vitro directly scavenged H2O2 in a dose-dependent manner. Intravesical hyaluronic acid for 30 min attenuated H2O2-elicited excitatory effects on the frequency of voiding, amplitude of IVP and the sensitization of PANA and PENA in the rats. Hyaluronic acid treatment reduced H2O2-induced ATP and acetylcholine release in the urinary bladder. Intravesical administration of muscarinic receptor antagonist atropine methyl nitrate (50 µM) or purinergic receptor antagonist PPADS (1 mM) ameliorated H2O2-induced hyperactive bladder. Conclusions These results indicate that hyaluronic acid treatment can ameliorate H2O2-induced bladder hyperactivity possibly via the antioxidant activity and the inhibition of activating purinergic and muscarinic signaling pathway. Neurourol. Urodynam. 29:765–770, 2010. © 2010 Wiley-Liss, Inc.

Nanoliposomes are important carriers capable of packaging drugs for various delivery applications through passive targeting tumor sites by enhanced permeability and retention effect. Radiolabeled liposomes have potential applications in radiotherapy and diagnostic imaging. The purpose of this study was to investigate the biodistribution, pharmacokinetics and imaging of nanotargeted (188)Re-N,N-bis (2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposomes (RBLPL) and unencapsulated (188)Re-BMEDA after intraperitoneal (ip) injection in a C26 colon carcinoma ascites mouse model. The nanopegylated liposomes were labeled with (188)Re-BMEDA. The labeling efficiency of RBLPL was 82.3+/-4.5%. In vitro stability of RBLPL in normal saline at room temperature and in rat plasma at 37 degrees C for 72 h was 92.01+/-1.31% and 82.4+/-1.64%, respectively. The biodistribution studies indicated that the radioactivity in ascites was 69.96+/-14.08 percentage injected dose per gram (% ID/g) at 1h to 5.99+/-1.97% ID/g at 48 h after ip administration of RBLPL. The levels of radioactivity in tumor were progressive accumulation to a maximum of 6.57+/-1.7% ID/g at 24 h. The radioactivity of (188)Re-BMEDA in ascites reached the maximum level of 54.89+/-5.91% ID/g at 1 h and declined rapidly with time. Pharmacokinetic studies revealed that the terminal half-life, total body clearance and area under the curve of RBLPL were 5.3-, 9.5- and 9.4-fold higher than that of (188)Re-BMEDA in blood, respectively. These results suggested that the long circulation, bioavailability and localization of RBLPL in tumor and ascites sites, which also demonstrate that the ip administration of RBLPL is a potential multifunctional nanoradiotherapeutics and imaging agents on a C26 colon carcinoma ascites mouse model.

Male infertility affects approximately 50% of all infertile couples. The male-related causes of intracytoplasmic sperm injection failure include the absence of sperm, immotile or immature sperm, and sperm with structural defects such as those caused by premature chromosomal condensation and DNA damage. Our previous studies based on a knockout mice model indicated that SEPT12 proteins are critical for the terminal morphological formation of sperm.

Dermatologic diseases are not traditional risk factors of stroke, but recent studies show atopic dermatitis, psoriasis, and bullous skin disease may increase the risk of stroke and other cardiovascular diseases. No previous studies have focused on the association between contact dermatitis and stroke.We established a cohort comprised of 48,169 contact dermatitis patients newly diagnosed in 2000-2003 and 96,338 randomly selected subjects without the disorder, frequency matched by sex, age, and diagnosis year, as the comparison cohort. None of them had a history of stroke. Stroke incidence was assessed by the end of 2011 for both cohorts.The incidence stroke was 1.1-fold higher in the contact dermatitis cohort than in the comparison cohort (5.93 vs 5.37 per 1000 person-years, P < 0.01). The multivariable Cox method analyzed adjusted hazard ratios (aHRs) were 1.12 (95% confidence interval [CI], 1.05-1.19) for all stroke types and 1.12 (95% CI, 1.05-1.20) for ischemic stroke and 1.11 (95% CI, 0.94-1.30) for hemorrhagic stroke. The age-specific aHR of stroke for contact dermatitis cohort increased with age, from 1.14 (95% CI, 1.03-1.27) for 65 to 74 years; to 1.27 (95% CI, 1.15-1.42) for 75 years and older. The aHR of stroke were 1.16 (95% CI, 1.07-1.27) and 1.09 (95% CI, 1.00-1.18) for men and women, respectively.This study suggests that patients with contact dermatitis were at a modestly increased risk of stroke, significant for ischemic stroke but not for hemorrhagic stroke. Comorbidity, particularly hypertension, increased the hazard of stroke further.

Background Discharge disposition planning is vital for poststroke patients. We investigated clinical factors associated with discharging patients to nursing homes, using the Taiwan Stroke Registry data collected from 39 major hospitals. Methods We randomly assigned 21,575 stroke inpatients registered from 2006 to 2008 into derivation and validation groups at a 3-to-1 ratio. We used the derivation group to develop a prediction model by measuring cumulative risk scores associated with potential predictors: age, sex, hypertension, diabetes mellitus, heart diseases, stroke history, snoring, main caregivers, stroke types, and National Institutes of Health Stroke Scale (NIHSS). Probability of nursing home care and odds ratio (OR) of nursing home care relative to home care by cumulative risk scores were measured for the prediction. The area under the receiver operating characteristic curve (AUROC) was used to assess the model discrimination against the validation group. Results Except for hypertension, all remaining potential predictors were significant independent predictors associated with stroke patient disposition to nursing home care after discharge from hospitals. The risk sharply increased with age and NIHSS. Patients with a cumulative risk score of 15 or more had an OR of 86.4 for the nursing home disposition. The AUROC plots showed similar areas under curves for the derivation group (.86, 95% confidence interval [CI], .85-.87) and for the validation group (.84, 95% CI, .83-.86). Conclusions The cumulative risk score is an easy-to-estimate tool for preparing stroke patients and their family for disposition on discharge.

The relationship between low estimated glomerular filtration rate (eGFR) and the outcome of ischemic stroke remains controversial, despite the close association between kidney dysfunction and atherosclerosis.This study conducted subgroup analysis using data from the prospective Taiwan Stroke Registry to investigate the relationship between eGFR at the time of admission and 6-month functional outcomes in patients with the large artery atherosclerotic (LAA) subtype of acute ischemic stroke. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS), and outcomes were defined as modified Rankin Scale and mortality status at 6 months post stroke.Of the 8052 patients with the LAA subtype of acute ischemic stroke in this study, 3312 (41.1%) had eGFR60 mL/min/1.73 m(2). The adjusted odds ratios of worse functional outcomes following a stroke were 1.10 (95% confidence interval [CI], 0.95-1.28), 1.60 (95% CI, 1.22-2.11) and 1.60 (95% CI, 1.10-2.33) in patients with eGFR 30-59, 15-29, and15 as compared with those with eGFR 60-119 mL/min/1.73 m(2), respectively. Increased risk of mortality was closely and independently related to high NIHSS scores and low eGFR levels. Stroke severity and eGFR were also synergistically related to 6-month mortality, with an adjusted hazard ratio of 21.19 (95% CI, 9.69-46.35) in patients with NIHSS15 and eGFR15 mL/min/1.73 m(2), compared with those with NIHSS 0-5 and eGFR 60-119 mL/min/1.73 m(2).Low eGFR was significantly and independently associated with 6-month functional outcomes and mortality in patients with the LAA subtype of acute ischemic stroke. The deleterious relationship between low eGFR levels and mortality following stroke was exacerbated by its synergistic association with stroke severity.

Bisphenol-A-glycidyldimethacrylate (BisGMA) is a frequently used monomer in dental restorative resins. However, BisGMA could leach from dental restorative resins after polymerization leading to inflammation in the peripheral environment. Wogonin, a natural flavone derivative, has several benefits, such as antioxidative, anti-inflammatory and neuroprotective properties. Pretreatment of macrophage RAW264.7 cells with wogonin inhibited cytotoxicity which is induced by BisGMA in a concentration-dependent manner. BisGMA induced apoptotic responses, such as redistribution of phosphatidylserine from the internal to the external membrane and DNA fragmentation, were decreased by wogonin in a concentration-dependent manner. In addition, BisGMA-induced genotoxicity, which detected by cytokinesis-blocked micronucleus and single-cell gel electrophoresis assays, were inhibited by wogonin in a concentration-dependent manner. Furthermore, wogonin suppressed BisGMA-induced activation of intrinsic caspase pathways, such as caspases-3 and -8. Parallel trends were observed in inhibition of caspase-3 and -8 activities, apoptosis, and genotoxicity. These results indicate wogonin suppressed the BisGMA-induced apoptosis and genotoxicity mainly via intrinsic caspase pathway in macrophages.