Über die Diffusion des Jodions ins Kammerwasser des Kaninchenauges

Ohne Zusammenfassung     

Expression of the hepatic endothelin system in human cirrhotic livers

It is considered that endothelin-1 participates in the development of liver cirrhosis and it has been recognized that every component of the endothelin system is upregulated in cirrhotic livers. However, the expression pattern of this system, including interaction between its components, is not fully understood in human livers. In this study, the expression pattern of the endothelin system was examined. Immunohistochemical analysis for endothelin-1, endothelin receptors and endothelin-converting enzyme was performed in 16 cirrhotic and 17 normal human liver tissues. Peptides, proteins, and RNAs extracted from the livers were also investigated using quantitative assays for the components of the hepatic endothelin system. Hepatic endothelin-1 levels were significantly higher in cirrhotic livers (0.084 +/- 0.052 pg/mg wet liver) than in normal livers (0.041 +/- 0.032 pg/mg; p < 0.01), and were closely related to the severity of liver fibrosis and portal hypertension. Immunoreactivity for endothelin-1, endothelin receptors, and endothelin-converting enzyme was detected mainly in fibrous areas and in the hepatic vasculature, and was enhanced in cirrhosis. Although there was a negative correlation between the expression of receptor mRNA and the hepatic endothelin-1 level, the amounts of the mRNAs were greater in cirrhotic livers than in normal livers. However, expression of endothelin-converting enzyme in cirrhotic livers was increased at the protein level but was relatively reduced at the mRNA level. These findings suggest that the hepatic endothelin system is activated in human cirrhotic livers in association with worsening of the disease, but that the regulation of the components of this system in this disorder is complex.     

Voltage-dependent gating and block by internal spermine of the murine inwardly rectifying K+ channel, Kir2.1

The mechanism of inward rectification was investigated by recording single-channel currents through an inwardly rectifying  K⁺  channel (Kir2.1). cDNA encoding a wild-type (WT) channel, a mutant replacing Asp 172 with Asn (D172N), and a tandem tetramer WT-(D172N)2-WT, was transfected into COS-1 cells using the liposome method, and after 48–72 h single-channel currents were recorded in the inside-out configuration at 150 m m internal and external  K⁺  . Steady-state open probability of outward currents decreased with larger depolarizations. The activation curve was fitted with a single Boltzmann equation. The voltages of half-activation in the absence of spermine were +35.9 mV (WT), +55.0 mV (WT-(D172N)2-WT) and +76.7 mV (D172N). Open-time and zero-current-time histograms were constructed. The open-time histogram was fitted with a single exponential function. Two exponential functions were necessary to fit the closed-time histogram. In each channel, internal spermine at a concentration of 1–100 n m reduced the open time of the outward currents in a concentration-dependent manner and produced one blocked state without affecting the inward currents, suggesting that spermine acts as an open channel blocker. The normalized steady-state open probability-spermine concentration curve was fitted by saturation kinetics with a Hill coefficient of 1. On the assumption of the linear sequential state model, the unblock and blocking rates were estimated in each channel. Unblock rates depended on the number of D172N mutant subunits, but blocking rates did not. The results suggest that closing gates work independently of the spermine block and D172 is involved in both intrinsic gating and the spermine block.     

Inhibition by ginsenoside Rg3 of bombesin-enhanced peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane in Wistar rats

The effects of concomitant use of bombesin and ginsenoside Rg3 on the incidence of peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane were investigated in male inbred Wistar rats. From the start of the experiment, rats were given weekly s.c. injections of azoxymethane (7.4mg/kg body weight) for 10 weeks and s.c. injection of bombesin (40g/kg body weight) every other day, and from week 20, s.c. injections of ginsenoside Rg3 (2.5 or 5.0mg/kg body weight) every other day until the end of the experiment in week 45. Bombesin significantly increased the incidence of intestinal tumors and cancer metastasis to the peritoneum in week 45. It also significantly increased the labeling index of intestinal cancers. Although administration of a higher dose of ginsenoside Rg3 with bombesin had little or no effect on the enhancement of intestinal carcinogenesis by bombesin, the location, histologic type, depth of involvement, infiltrating growth pattern, labeling and apoptotic indices and tumor vascularity of intestinal cancers, it significantly decreased the incidence of cancer metastasis. These findings indicate that ginsenoside Rg3 inhibits cancer metastasis through activities that do not affect the growth or vascularity of intestinal cancers.     

Inducible expression of endothelial PAS domain protein-1 by hypoxia in human lung adenocarcinoma A549 cells. Role of Src family kinases-dependent pathway.

Hypoxia is a potent inducer of tumor angiogenesis, the process of which is mostly mediated by induction of vascular endothelial growth factor (VEGF). In this study, we investigated the effect of hypoxia on the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and endothelial PAS domain protein-1 (EPAS1). These two similar but distinct basic helix-loop-helix-PAS proteins have been postulated to activate VEGF expression in response to hypoxia. We showed that EPAS1, but not HIF-1alpha, is abundantly expressed in human lung adenocarcinoma A549 cells. Exposure of cultured A549 cells to hypoxia increased EPAS1 mRNA and protein levels. A specific inhibitor for Src family kinases, PP1, abolished the hypoxia-induced expression of EPAS1. Transient transfection assays revealed that forced expression of EPAS1 increased the reporter gene activity driven by EPAS1 promoter as well as by VEGF promoter. Finally, overexpression of EPAS1 by infection of adenoviral vector expressing EPAS1 cDNA evidently induced the endogenous EPAS1 gene expression. Together, these data demonstrate Src family kinases mediate the hypoxia-mediated EPAS1 gene expression, which in turn positively autoregulates its own expression. Given an EPAS1 as a potent activator of the VEGF gene, these findings will provide a novel insight into the mechanisms underlying the enhancement of growth property of EPAS1-expressing tumor cells under the hypoxic environment.     

Additive effect of intravenous prednisolone for acute severe asthma in infants and toddlers: a randomized controlled clinical trial]

BACKGROUND: The efficacy of systemic corticosteroids for infants and toddlers with acute severe asthma has been inadequately evaluated. OBJECTIVE: The purpose of this study was to evaluate the additive efficacy of intravenous prednisolone in a randomized controlled study in the management of infants and toddlers with acute severe asthma. METHODS: Sixty-two patients (aged 8 to 70 months) hospitalized with status asthmaticus were studied. They were randomized into two groups. One group received intravenous prednisolone treatment (1 approximately 3 mg/kg/day, 3 days); the other group served as a control. Each group received continuous aminophylline infusion and low-dose continuous isoproterenol inhalation by an Inspiron nebulizer. They were monitored their heart rate, respiratory rate and symptoms (Wood's clinical score). RESULTS: Each group showed rapid improvement in heart rate, respiratory rate and clinical score by low-dose continuous isoproterenol inhalation. There were no significant differences in the time course of these clinical indexes or the duration of aminophylline infusion, continuous isoproterenol inhalation and hospital stay. CONCLUSION: This study failed to confirm the additive benefit of intravenous prednisolone in the management of infants and toddlers with acute severe asthma.     

Niravoline, a selective kappa-opioid receptor agonist effectively reduces elevated intracranial pressure

To ascertain the effects of niravoline (RU 51599, a selective kappa-opioid receptor agonist) on elevated intracranial pressure with mass lesion, the authors experimentally induced intracranial hypertension in cats by progressive inflation of an extradural balloon with physiological saline at the constant rate of 0.5 ml/h for 2.5 h. After 2.5 h, inflation was discontinued, but the balloon remained inflated for an additional 3 h. Immediately after cessation of balloon inflation and while the balloon remained expanded, the control group (n = 8) received ringer's lactate solution only. In the treatment group (n = 8), each cat was treated with an intravenous administration of niravoline at a dose of 1.0 mg/kg immediately after the cessation of balloon inflation and every hour for 3 h in post-inflation period (three injections total). Changes in intracranial pressure (ICP), mean arterial blood pressure (MAP), cerebral perfusion pressure (CPP), electroencephalogram (EEG), pupil size, blood gasses and pH, plasma osmolality and electrolytes, and brain water content were studied in both groups. Compared with the untreated group, niravoline treatment produced significant decreases in ICP and significant increases in CPP at 1, 2, and 3 h post-inflation in the presence of an extradural mass lesion. Brain water content was significantly reduced both in the compressed and contralateral hemispheres following niravoline treatment. No significant changes were observed in plasma osmolality and systemic arterial blood pressure following niravoline administration. The results from this present study provide further evidence that niravoline is effective in reducing elevated intracranial pressure, brain water content, and maintaining an adequate cerebral perfusion pressure even in the presence of an extradural mass lesion. Niravoline may offer a new therapeutic modality in head-injury patients with an acute intracranial, expanding mass lesion by providing a safer extended time-period until the mass can be surgically evacuated.     

Abnormality of vascular elastic fibers in the macular mouse and a patient with Menkes'' disease: ultrastructural and immunohistochemical study

The macular mouse is a mutant mouse with the same gene abnormality as that of Menkes' disease, and it exhibits symptoms and abnormalities similar to those of Menkes' disease. In an electron microscopic study, we examined morphological changes in the internal elastic lamina (IEL) of the elastic arteries (EA) and the muscular arteries (MA) in a patient with Menkes' disease and in the macular mouse, an animal model of this disease. The IEL of the EA was significantly thinner in the macular mouse than that in controls, but the IEL of the MA in the macular mouse was significantly thicker than that of the controls. These contrary results for the thickness of the IEL in the MA and the EA in this animal model of Menkes' disease may reflect differences in the anatomical and pathophysiological properties of the two types of vessels.     

Diagnostic strategy for inherited hypomagnesemia

Background

Hereditary hypomagnesemia is difficult to diagnose accurately because of its rarity and the variety of causative genes. We established a flowchart for identifying responsible genes for hypomagnesemia, and we confirmed its diagnostic efficacy in patients with suspected inherited hypomagnesemia.

Methods

We established a flowchart and applied it to five index cases with suspected inherited hypomagnesemia. Direct sequence analysis was used to detect the causative gene variants in four cases, and targeted sequencing analysis using next-generation sequencing (NGS) of all causative genes for hypomagnesemia was used in one.

Results

Expected pathogenic variants were detected in the HNF1B, TRPM6, CLDN16, CASR, or SLC12A3 gene in all five cases. The results of all genetic analyses were consistent with the clinical diagnostic results using the flowchart.

Conclusions

Accurate genetic diagnosis is crucial for estimating the prognosis, detecting complications in organs other than the kidneys, and for directing genetic counseling. The developed flowchart for identifying responsible genes for hypomagnesemia was useful for diagnosing inherited hypomagnesemia. In addition, NGS analysis will help to resolve clinical difficulties in making an accurate diagnosis and thus improve the diagnostic strategy for inherited hypomagnesemia.