Use of the complement inhibitor Coversin to treat HSCT-associated TMA.

Finding an inherited complement abnormality in HSCT-associated TMA provides a rationale for the use of a complement inhibitor.Alternative complement inhibitors such as Coversin should be considered in patients who are resistant to eculizumab.

FTY720 inhibits germ cell apoptosis in testicular torsion/detorsion.

BACKGROUND: Testicular torsion/detorsion (T/D) can induce germ cells apoptosis, which may lead to impairment of spermatogenesis. FTY720, an agonist of the sphingosine-1-phosphate receptor 1 (S1PR1), inhibits apoptosis in ischemic stroke. We examined whether FTY720 could mitigate germ cell apoptosis in testicular T/D rats. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were allocated to receive testicular T/D (the T/D group), T/D plus FTY720 (the T/D-FTY group), or T/D plus FTY720 plus the potent S1PR1 antagonist VPC23019 (the T/D-FTY-VPC group; n = 6 in each group). Sham control groups were run simultaneously. At 24 h after detorsion, rats were euthanized. RESULTS: Our data revealed that, in the ipsilateral twisted testes, sperm counts and expression of the S1PR1 of the T/D and the T/D-FTY-VPC groups were significantly lower than those of the T/D-FTY group (all P < 0.001). In contrast, signals of apoptotic cells stained by terminal deoxynucleotidyl transferase dUTP nick end labeling and the proapoptotic protein cleaved caspase-3 of the T/D, and the T/D-FTY-VPC groups were significantly stronger than those of the T/D-FTY group. Moreover, the terminal deoxynucleotidyl transferase dUTP nick end labeling signals mainly localized to germ cells. CONCLUSIONS: FTY720 could mitigate testicular T/D-induced germ cell apoptosis, and the mechanisms may involve the S1PR1.

Cutaneous adnexal carcinoma with apocrine differentiation.

Primary cutaneous apocrine carcinomas are uncommon malignant neoplasms that can be difficult, if not impossible, to distinguish histologically from metastatic breast carcinomas. We present the case of a 71-year-old man with a 5-year history of extensive ulcerated plaques on the posterior neck and posterior scalp. Biopsy revealed a poorly differentiated infiltrating adenocarcinoma consistent with either primary cutaneous apocrine carcinoma or occult metastatic breast carcinoma. Immunohistochemical analysis demonstrated positive staining for cytokeratin (CK) 7, estrogen receptor, and progesterone receptor, and negative staining for p63, podoplanin, CK20, and thyroid transcription factor 1. Extensive radiologic imaging studies showed no evidence of occult breast or other internal malignancies. Based on the indolent clinical course, lack of evidence for an internal primary site, and immunohistochemical staining, the lesion was determined to be consistent with a cutaneous neoplasm with features of apocrine differentiation. This case highlights the distinction between apocrine carcinoma and other primary adnexal carcinomas for which p63 and D2-40 have been reported to be sensitive and specific markers but are negative in apocrine carcinomas.

Regulation of Intermittent Hypoxia on Brain Dopamine in Amphetaminized Rats.

We investigated intermittent hypoxia (IH) on dopamine (DA) release in rat brain treated with or without amphetamine (AMPH). Rats were divided into four groups including normoxia, IH, AMPH, and AMPH + IH treatments. The cerebrospinal fluid (CSF) was collected and the DA levels were detected by high performance liquid chromatography (HPLC). The plasma prolactin (PRL) concentration was measured by radioimmunoassay (RIA). We found that IH reduced basal DA concentration in media prefrontal cortex (mPFC), but increased that in striatum, where DA level was also increased in rats treated with AMPH or AMPH + IH. Angiotensin II (Ang II) increased the DA release in mPFC and striatum and this effect was enhanced in AMPH + IH group. The stimulatory effect of IH on plasma PRL was attenuated in presence of AMPH. Tyrosine hydroxylase (TH) expression was decreased by IH, but increased by AMPH + IH in mPFC. IH or AMPH treatment decreased the expression of vesicular monoamine transporter-2 (VMAT-2) in rat brain. These data suggested that IH altered the DA release and changed the protein expression levels in different parts of rat brain treated with AMPH. IH may play a role in regulating DA metabolism in AMPH addiction.

FTY720 mitigates torsion/detorsion-induced testicular injury in rats.

BACKGROUND: FTY720, a sphingosine-1-phosphate (S1P) receptor agonist, possesses potent anti-inflammation capacity. We evaluated the therapeutic potentials of FTY720 against testicular injury induced by testicular torsion and/or detorsion (T/D). MATERIALS AND METHODS: Young adult male Sprague-Dawley rats were allocated to receive T/D (the T/D group) and T/D plus FTY720 (4 mg/kg, the T/D-FTY group, n = 6 in each group). To investigate the possible roles of the S1P receptors, another group of rats received T/D plus FTY720 plus the potent S1P receptor antagonist VPC23019 (1 mg/kg, the T/D-FTY-VPC group, n = 6). FTY720 was administered immediately before testicular detorsion, and VPC23019 was administered 30 min before FTY720. Another set of rats that received sham operation, immediately followed by injection of normal saline, FTY720, or FTY720 plus VPC23019, served as control groups. Sham control groups were run simultaneously. After euthanization, levels of testicular injury were measured. RESULTS: Histologic findings revealed severe testicular injury changes in both the T/D and T/D-FTY-VPC groups and moderate testicular injury changes in the T/D-FTY group. In addition, malondialdehyde activity (oxidative status), concentration of interleukin-1ß (inflammation index), myeloperoxidase activity (neutrophil infiltration index), and wet-to-dry weight ratio (tissue edema index) of both the T/D and T/D-FTY-VPC groups were significantly higher than those of the T/D-FTY group. These data confirmed the protective effects of FTY720 against testicular T/D. Moreover, antagonizing the S1P receptors could reverse the protective effects of FTY720. CONCLUSIONS: FTY720 significantly mitigated testicular injury induced by testicular T/D. The mechanisms may involve activating the S1P receptors.

Exploration of approaches to adjusting brand-name drug prices in Mainland of China: based on comparison and analysis of some brand-name drug prices of Mainland and Taiwan, China.

BACKGROUND: Under the circumstance of the New Medical Reform in Mainland of China, lowering drug prices has become an approach to relieving increase of medical expenses, and lowering brand-name medication price is a key strategy. This study, by comparing and analyzing brand-name medication prices between Mainland of China and Taiwan, explores how to adjust brand-name medication prices in Mainland of China in the consideration of the drug administrative strategies in Taiwan. METHODS: By selecting brand-name drug with generic name and dose types matched in Mainland and Taiwan, calculate the average unit price and standard deviation and test it with the paired t-test. In the mean time, drug administrative strategies between Mainland and Taiwan are also compared systematically. RESULTS: Among the 70 brand-name medications with generic names and matched dose types, 54 are at higher prices in Mainland of China than Taiwan, which is statistically significant in t-test. Also, among the 47 medications with all of matched generic names, dose types, and manufacturing enterprises, 38 are at higher prices in Mainland than Taiwan, and the gap is also statistically significant in t-test. In Mainland of China, brand-name medication took cost-plus pricing and price-based price adjustment, while in Taiwan, brand-name medication took internal and external reference pricing and market-based price adjustment. CONCLUSIONS: Brand-name drug prices were higher in Mainland of China than in Taiwan. The adjustment strategies of drug prices are scientific in Taiwan and are worth reference by Mainland of China.

Exploration of approaches to adjusting brand-name drug prices in Mainland of China: based on comparison and analysis of some brand-name drug prices of Mainland and Taiwan, China / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Under the circumstance of the New Medical Reform in Mainland of China, lowering drug prices has become an approach to relieving increase of medical expenses, and lowering brand-name medication price is a key strategy. This study, by comparing and analyzing brand-name medication prices between Mainland of China and Taiwan, explores how to adjust brand-name medication prices in Mainland of China in the consideration of the drug administrative strategies in Taiwan.</p><p><b>METHODS</b>By selecting brand-name drug with generic name and dose types matched in Mainland and Taiwan, calculate the average unit price and standard deviation and test it with the paired t-test. In the mean time, drug administrative strategies between Mainland and Taiwan are also compared systematically.</p><p><b>RESULTS</b>Among the 70 brand-name medications with generic names and matched dose types, 54 are at higher prices in Mainland of China than Taiwan, which is statistically significant in t-test. Also, among the 47 medications with all of matched generic names, dose types, and manufacturing enterprises, 38 are at higher prices in Mainland than Taiwan, and the gap is also statistically significant in t-test. In Mainland of China, brand-name medication took cost-plus pricing and price-based price adjustment, while in Taiwan, brand-name medication took internal and external reference pricing and market-based price adjustment.</p><p><b>CONCLUSIONS</b>Brand-name drug prices were higher in Mainland of China than in Taiwan. The adjustment strategies of drug prices are scientific in Taiwan and are worth reference by Mainland of China.</p>

Integrated wireless fast-scan cyclic voltammetry recording and electrical stimulation for reward-predictive learning in awake, freely moving rats.

OBJECTIVE: Fast-scan cyclic voltammetry (FSCV) is commonly used to monitor phasic dopamine release, which is usually performed using tethered recording and for limited types of animal behavior. It is necessary to design a wireless dopamine sensing system for animal behavior experiments. APPROACH: This study integrates a wireless FSCV system for monitoring the dopamine signal in the ventral striatum with an electrical stimulator that induces biphasic current to excite dopaminergic neurons in awake freely moving rats. The measured dopamine signals are unidirectionally transmitted from the wireless FSCV module to the host unit. To reduce electrical artifacts, an optocoupler and a separate power are applied to isolate the FSCV system and electrical stimulator, which can be activated by an infrared controller. MAIN RESULTS: In the validation test, the wireless backpack system has similar performance in comparison with a conventional wired system and it does not significantly affect the locomotor activity of the rat. In the cocaine administration test, the maximum electrically elicited dopamine signals increased to around 230% of the initial value 20 min after the injection of 10 mg kg(-1) cocaine. In a classical conditioning test, the dopamine signal in response to a cue increased to around 60 nM over 50 successive trials while the electrically evoked dopamine concentration decreased from about 90 to 50 nM in the maintenance phase. In contrast, the cue-evoked dopamine concentration progressively decreased and the electrically evoked dopamine was eliminated during the extinction phase. In the histological evaluation, there was little damage to brain tissue after five months chronic implantation of the stimulating electrode. SIGNIFICANCE: We have developed an integrated wireless voltammetry system for measuring dopamine concentration and providing electrical stimulation. The developed wireless FSCV system is proven to be a useful experimental tool for the continuous monitoring of dopamine levels during animal learning behavior studies of freely moving rats.

Temporal dynamics of antibiotics in wastewater treatment plant influent.

A yearlong field experimental campaign was conducted to reveal time scales over which antibiotic fluxes vary in the influent of a wastewater treatment plant (WTP). In particular, sampling was carried out to ascertain the amplitudes of monthly, daily and hourly fluctuations of several antibiotics. A total of 180 samples was collected at the entrance of a WTP in Lausanne, Switzerland. Sample concentrations were multiplied by flow rate to obtain monthly, daily and hourly mass fluxes of six antibiotics (trimethoprim, norfloxacin, ciprofloxacin, ofloxacin, clindamycin and metronidazole). Seasonality in mass fluxes was observed for all substances, with maximum values in winter being up to an order of magnitude higher than in summer. The hourly measurements of the mass flux of antibiotics were found to have a period of 12h. This was due to peaks in toilet use in the morning and early evening. In particular, the morning peak in flushing coincided with high concentrations (and hence high mass fluxes) due to overnight accumulation of substances in urine. However, little variation was observed in the average daily flux. Consequently, fluctuations in mass fluxes of antibiotics were mainly evident at the monthly and hourly time scales, with little variation on the day-week time scale. These results can aid in optimizing removal strategies and future sampling campaigns focused on antibiotics in wastewater.

Baicalein protects against retinal ischemia by antioxidation, antiapoptosis, downregulation of HIF-1α, VEGF, and MMP-9 and upregulation of HO-1.

PURPOSE: Retinal ischemia-associated ocular disorders are vision threatening. This study examined whether the flavonoid baicalein is able to protect against retinal ischemia/reperfusion. METHODS: Using rats, the intraocular pressure was raised to 120 mmHg for 60 min to induce retinal ischemia. In vitro, an ischemic-like insult, namely oxidative stress, was established by incubating dissociated retinal cells with 100 µM ascorbate and 5 µM FeSO4 (iron) for 1 h. The rats or the dissociated cells had been pretreated with baicalein (in vivo: 0.05 or 0.5 nmol; in vitro: 100 µM), vehicle (1% ethanol), or trolox (in vivo: 5 nmol; in vitro: 100 µM or 1 mM). The effects of these treatments on the retina or the retinal cells were evaluated by electrophysiology, immunohistochemistry, terminal deoxynucleotidyl-transferase-mediated dUTP nick end-labeling (TUNEL) staining, Western blotting, or in vitro dichlorofluorescein assay. In addition, real-time-polymerase chain reaction was used to assess the retinal expression of hypoxia-inducible factor-1α (HIF-1α), matrix metalloproteinase-9 (MMP-9), vascular endothelium growth factor (VEGF), and heme oxygenase-1 (HO-1). RESULTS: The retinal changes after ischemia included a decrease in the electroretinogram b-wave amplitude, a loss of choline acetyltransferase immunolabeling amacrine cell bodies/neuronal processes, an increase in vimentin immunoreactivity, which is a marker for Müller cells, an increase in apoptotic cells in the retinal ganglion cell layer linked to a decrease in the Bcl-2 protein, and changes in the mRNA levels of HIF-1α, VEGF, MMP-9, and HO-1. Of clinical importance, the ischemic detrimental effects were concentration dependently and/or significantly (0.05 nmol and/or 0.5 nmol) altered when baicalein was applied 15 min before retinal ischemia. Most of all, 0.5 nmol baicalein significantly reduced the upregulation of MMP-9; in contrast, 5 nmol trolox only had a weak attenuating effect. In dissociated retinal cells subjected to ascorbate/iron, there was an increase in the levels of reactive oxygen species, which had been significantly attenuated by 100 µM baicalein and trolox (100 µM or 1 mM; a stronger antioxidative effect at 1 mM). CONCLUSIONS: Baicalein would seem to protect against retinal ischemia via antioxidation, antiapoptosis, upregulation of HO-1, and downregulation of HIF-1α, VEGF, and MMP-9. The antioxidative effect of baicalein would appear to play a minor role in downregulation of MMP-9.

Resveratrol mitigates rat retinal ischemic injury: the roles of matrix metalloproteinase-9, inducible nitric oxide, and heme oxygenase-1.

PURPOSE: Retinal ischemia-associated ocular disorders, such as retinal occlusive disorders, neovascular age-related macular degeneration, proliferative diabetic retinopathy, and glaucoma are vision-threatening. In this study, we examined whether and by what mechanisms resveratrol, a polyphenol found in red wine, is able to protect against retinal ischemia/reperfusion injury. METHODS: In vivo rat retinal ischemia was induced by high intraocular pressure (HIOP), namely, 120 mmHg for 60 min. The mechanism and management was evaluated by electroretinogram (ERG) b-wave amplitudes measurement, immunohistochemistry, and real-time polymerase chain reaction. RESULTS: The HIOP-induced retinal ischemic changes were characterized by a decrease in ERG b-wave amplitudes, a loss of choline acetyltransferase immunolabeling of amacrine cell bodies/neuronal processes, and increased vimentin immunoreactivity, which is a marker of Müller cells, together with upregulation of matrix metalloproteinase-9 (MMP-9), heme oxygenase-1 (HO-1), and inducible nitric oxide (iNOS), and downregulation of Thy-1, both at the mRNA level. The detrimental effects due to the ischemia were concentration-dependent (weaker effect at 0.05 nmole) and/or significantly (at 0.5 nmole) altered when resveratrol was applied 15 min before or after retina ischemia. CONCLUSION: This study supports the hypothesis that resveratrol may be able to protect the retina against ischemia by downregulation of MMP-9 and iNOS, and upregulation of HO-1.

The effects and underlying mechanisms of S-allyl l-cysteine treatment of the retina after ischemia/reperfusion.

PURPOSE: Retinal ischemia-associated ocular disorders are vision-threatening. The aim of the present study was to examine whether S-allyl l-cysteine (SAC) is able to protect against retina ischemia/reperfusion injury. METHODS: In vivo, retinal ischemia in the rat was induced by raising intraocular pressure (IOP) to 120 mmHg for 60 min. In vitro, an ischemic-like insult, namely oxidative stress, was established by incubating retinal ganglion cell-5 (RGC-5) with 500 µM H(2)O(2) for 24 h. The mechanisms involved in these processes were evaluated by electrophysiology, immunohistochemistry, and molecular biological approaches. RESULTS: The retinal changes caused by the high IOP were characterized by a decrease in electroretinogram b-wave amplitudes, a loss of choline acetyltransferase immunolabeling amacrine cell bodies/neuronal processes, and an upregulation of the mRNA levels of hypoxia-inducible factor-1α (HIF-1α), vascular endothelium growth factor (VEGF), and matrix metalloproteinase-9 (MMP-9). The increased protein levels of HIF-1α, VEGF, and MMP-9 were also seen in RGC-5 cells subjected to defined oxidative stress. Of clinical importance, the ischemic/ischemic-like detrimental effects were concentration-dependently (least effect at 25 µM) and/or significantly (50 and/or 100 µM) blunted when SAC was applied 15 min before retinal ischemia or ischemic-like insult, respectively. CONCLUSION: SAC would seem to protect against retinal ischemia by acting as an antioxidant and inhibiting the upregulation of HIF-1α, VEGF, and MMP-9.

Baicalein significantly protects human retinal pigment epithelium cells against H2O2-induced oxidative stress by scavenging reactive oxygen species and downregulating the expression of matrix metalloproteinase-9 and vascular endothelial growth factor.

PURPOSE: Age-related macular degeneration is a leading cause of blindness in the elderly. At a later stage, neovascular or exudative age-related macular degeneration can lead to severe central vision loss that is related to aging-associated cumulative oxidative stress of the human retinal pigment epithelium (hRPE) cells. Early prevention with antioxidants is mandatory. The aim of this study was to determine whether and how baicalein can act as an antioxidant. METHODS: The methods used included lactate dehydrogenase, 2',7'-dichloro-fluorescein diacetate, or enzyme-linked immunosorbent assay to measure cell viability, oxygen free radical levels, or the levels of vascular endothelial growth factor (VEGF)/matrix metalloproteinase-9 (MMP-9), respectively. RESULTS: H2O2 dose-dependently reduced the cell viability of hRPE cells. This negative effect was dose-dependently (with a lower effect at 20µM) and significantly counteracted by pretreatment with baicalein (50µM). Treatment with H2O2 significantly stimulated the formation of oxygen free radicals. This increase was dose-dependently and significantly blunted by baicalein. Further, treatment with a sublethal dose of H2O2 was associated with an upregulation in the levels of VEGF and MMP-9. The increases in these proteins were also dose-dependently (with a lower effect at 20µM) and significantly (50µM) blunted by pretreatment with baicalein. CONCLUSION: This study supports an antioxidative role for baicalein whereby it protects hRPE cells against H2O2-induced oxidative stress by downregulating the levels of VEGF and MMP-9, which are increased by H2O2.