An extended fatty liver index to predict non-alcoholic fatty liver disease.

BACKGROUND: In clinical practice, there is a strong interest in non-invasive markers of non-alcoholic fatty liver disease (NAFLD). Our hypothesis was that the fold-change in plasma triglycerides (TG) during a 2-h oral glucose tolerance test (fold-change TGOGTT) in concert with blood glucose and lipid parameters, and the rs738409 C>G single nucleotide polymorphism (SNP) in PNPLA3 might improve the power of the widely used fatty liver index (FLI) to predict NAFLD. METHODS: The liver fat content of 330 subjects was quantified by 1H-magnetic resonance spectroscopy. Blood parameters were measured during fasting and after a 2-h OGTT. A subgroup of 213 subjects underwent these measurements before and after 9 months of a lifestyle intervention. RESULTS: The fold-change TGOGTT was closely associated with liver fat content (r=0.51, P<0.0001), but had less power to predict NAFLD (AUROC=0.75) than the FLI (AUROC=0.79). Not only was the fold-change TGOGTT independently associated with liver fat content and NAFLD, but so also were the 2-h blood glucose level and rs738409 C>G SNP in PNPLA3. In fact, a novel index (extended FLI) generated from these and the usual FLI parameters considerably increased its power to predict NAFLD (AUROC=0.79-0.86). The extended FLI also increased the power to predict changes in liver fat content with a lifestyle intervention (n=213; standardized beta coefficient: 0.23-0.29). CONCLUSION: This study has provided novel data confirming that the OGTT-derived fold-change TGOGTT and 2-h glucose level, together with the rs738409 C>G SNP in PNPLA3, allow calculation of an extended FLI that considerably improves its power to predict NAFLD.

Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation.

For differentiation-defective malignancies, compounds that modulate transcription, such as retinoic acid and histone deacetylase (HDAC) inhibitors, are of particular interest. HDAC inhibitors are currently under investigation for the treatment of a broad spectrum of cancer diseases. However, one clinical drawback is class-specific toxicity of unselective inhibitors, limiting their full anticancer potential. Selective targeting of individual HDAC isozymes in defined tumor entities may therefore be an attractive alternative treatment approach. We have previously identified HDAC family member 8 (HDAC8) as a novel target in childhood neuroblastoma. Using small-molecule inhibitors, we now demonstrate that selective inhibition of HDAC8 exhibits antineuroblastoma activity without toxicity in two xenograft mouse models of MYCN oncogene-amplified neuroblastoma. In contrast, the unselective HDAC inhibitor vorinostat was more toxic in the same models. HDAC8-selective inhibition induced cell cycle arrest and differentiation in vitro and in vivo. Upon combination with retinoic acid, differentiation was significantly enhanced, as demonstrated by elongated neurofilament-positive neurites and upregulation of NTRK1. Additionally, MYCN oncogene expression was downregulated in vitro and tumor cell growth was markedly reduced in vivo. Mechanistic studies suggest that cAMP-response element-binding protein (CREB) links HDAC8- and retinoic acid-mediated gene transcription. In conclusion, HDAC-selective targeting can be effective in tumors exhibiting HDAC isozyme-dependent tumor growth in vivo and can be combined with differentiation-inducing agents.

[Hypercalcemic crisis in intensive care]. / Die hyperkalzämische Krise in der Intensivmedizin.

A hypercalcemic crisis is a life-threatening disease with multiorgan failure due to severe hypercalcemia. If left untreated, a hypercalcemic crisis is associated with a very high mortality and requires immediate diagnostic and therapeutic interventions. Especially a rapid rise to high calcium levels impairs the function of several organ systems and leads to central nervous, renal, cardiovascular and gastrointestinal symptoms. A hypercalcemic crisis is caused in more than 90 % by malignancy or primary hyperparathyreoidism and only in very rare cases by other diseases such as granulomatous diseases or other endocrinological diseases. Causal therapeutic options include an adequate treatment of malignancy and a surgical resection of the adenomatous tissue in primary hyperparathyreoidism. In addition, an adequate supportive therapy to lower calcium levels should be initiated as soon as possible. Rehydration with normal saline is the mainstay of therapy. Additional pharmacological therapies include biphosphonates, loop diuretics, calcitonin, steroids and calcimimetics. Besides classic hemodialysis continous renal replacement therapy with citrate anticoagulation is new therapeutical approach that can be used for the acute reduction of elevated serum calcium levels.

Case report: Nitazoxanide treatment failure in chronic isosporiasis.

We report a 60-year-old immunocompetent patient with chronic biliary isosporiasis who failed to respond to orally administered cotrimoxazole prophylaxis and orally administered treatment with nitazoxanide, a 5-nitrothiazole benzamide compound. Severe malabsorption was regarded as responsible for the subtherapeutic levels of nitazoxanide in plasma and bile, resulting in treatment failure. Intravenously administered cotrimoxazole stopped the shedding of Isospora belli oocysts in bile within 5 days, excluding initially suspected resistance to cotrimoxazole. Patients with malabsorption and cholangitis due to Coccidia such as Isospora belli and Cryptosporidium spp. or due to protozoa that cause microsporidiasis seem to be predisposed to fail to respond to otherwise effective treatment.

Flow cytometric detection and binding studies of human endometrial stromal cell epidermal growth factor receptor in monolayer culture: influence of progesterone.

Epidermal growth factor (EGF) has been shown to modulate endometrial differentiation in vivo and in vitro. Therefore, endometrial stromal cell EGF receptors were characterized in intact endometrial stromal cells, cultured in vitro. The methods used for characterization were flow cytometry, binding and displacement studies, and gel electrophoresis followed by autoradiography. In flow cytometry the histogram of labelled stromal cells was identical to Caski cells, which served as a positive control. EGF binding revealed the typical binding hierarchy for EGF receptors. The Scatchard analysis showed a curvilinear plot with a calculated dissociation constant of 0.36 nM for high affinity binding sites. In autoradiography a band of approximately 170 kDa was visualized corresponding to the known size of the EGF receptor. The intensity of this band was increased by pretreatment of stromal cells with 10 nM progesterone for 4 days. Furthermore, stimulation with progesterone led to an increase in specific EGF binding activity of stromal cells by 21% compared to control. These data indicate that intact stromal cells in monolayer culture maintain specific EGF receptors, which are up-regulated by progesterone.

Characterization of receptors for insulin-like growth factor type I on cultured human endometrial stromal cells: downregulation by progesterone.

Because insulin-like growth factor type I (IGF-I) is reputed to be involved in the endometrial decidualization, we analyzed the expression of IGF-I receptors in an in vitro system of human endometrial stromal cells. Competitive binding studies of both intact stromal cells and membrane preparation indicated the presence of specific components with high affinity for binding IGF-I. Half-maximum displacement was obtained with 2.3 nmol/l native IGF-I, whereas insulin was unable to achieve half-maximum displacement even at higher concentrations. This IGF-I binding component was found to be a saturable protein in respect of the radioligand [125I]IGF-I, with a dissociation constant of 0.16 nmol/l. Affinity cross-linking studies revealed a labelled band of approximate relative molecular mass 135000, corresponding to the known alpha-subunit of IGF-I receptor. This band was significantly inhibited dose-dependently by the IGF-I receptor monoclonal antibody alpha-IR3 or native IGF-I, suggesting that the IGF-I binding component in the membrane of stromal cells has the identity of the alpha-subunit of IGF-I receptor. Cell proliferation in vitro was stimulated by progesterone. Furthermore, progesterone downregulated the [125I]IGF-I binding activity by downregulation of the IGF-I membrane receptor of human endometrial stromal cells. These data show that the IGF-I receptor is a functionally integral component of the stromal cell membrane structure, and its expression might be directly modulated by progesterone and, therefore, might play an important role in the preparation of the stroma for successful embryo implantation.