DHEA inhibits acute microglia-mediated inflammation through activation of the TrkA-Akt1/2-CREB-Jmjd3 pathway.

Dehydroepiandrosterone (DHEA) is the most abundant circulating steroid hormone in humans, produced by the adrenals, the gonads and the brain. DHEA was previously shown to bind to the nerve growth factor receptor, tropomyosin-related kinase A (TrkA), and to thereby exert neuroprotective effects. Here we show that DHEA reduces microglia-mediated inflammation in an acute lipopolysaccharide-induced neuro-inflammation model in mice and in cultured microglia in vitro. DHEA regulates microglial inflammatory responses through phosphorylation of TrkA and subsequent activation of a pathway involving Akt1/Akt2 and cAMP response element-binding protein. The latter induces the expression of the histone 3 lysine 27 (H3K27) demethylase Jumonji d3 (Jmjd3), which thereby controls the expression of inflammation-related genes and microglial polarization. Together, our data indicate that DHEA-activated TrkA signaling is a potent regulator of microglia-mediated inflammation in a Jmjd3-dependent manner, thereby providing the platform for potential future therapeutic interventions in neuro-inflammatory pathologies.

The second window of desflurane-induced preconditioning is mediated by STAT3: role of Pim-1 kinase.

BACKGROUND: Late ischemic preconditioning is mediated via nuclear transcription factor signal transducer and activator of transcription 3 (STAT3). Pim-1 kinase reduces infarct size in cardiomyocytes and is regulated by STAT3. We tested the hypothesis that late desflurane-induced preconditioning (DES-SWOP) is mediated via STAT3 and Pim-1. METHODS: After institutional approval, pentobarbital-anesthetized male C57BL/6 mice were subjected to 45 min coronary artery occlusion (CAO) and 3 h reperfusion. Control animals received no additional intervention. Desflurane was administered 48 h before CAO either alone or in combination with the janus kinase/STAT3 inhibitor AG-490 (40 µg/g i.p., 20 min before desflurane administration) or the Pim-1 kinase inhibitor II (PIM-Inh.II, 10 µg/g i.p., 15 min before CAO). Infarct size (IS) and area at risk were determined with triphenyltetrazolium chloride and Evans blue, respectively. Additionally, cytosolic and nuclear fractions were separated at two different time points and expression of STAT3, phospho-STAT3(Ser727) , phospho-STAT3(Tyr705) , Pim-1, Bad and phospho-Bad(Ser112) were determined by Western Blot analysis. Data were analyzed with one-way or two-way ANOVA and post hoc Duncan test and are presented as mean ± SEM. RESULTS: IS was 47 ± 2% (n = 7-8 per group) in control animals (CON). DES-SWOP reduced myocardial infarct size to 23 ± 4%* (*P < 0.05 vs. CON). AG-490 alone did not affect myocardial infarct size (44 ± 7%), but abolished DES-SWOP (44 ± 4%). Blockade of Pim-1 did not affect the protection by DES-SWOP (34 ± 4%*). Desflurane reduced cytosolic content and enhanced nuclear content of phospho-STAT(S) (er727) . After 48 h, desflurane enhanced Pim-1 activity, whereas Pim-1 expression remained unchanged. CONCLUSION: These data suggest that DES-SWOP is mediated by activation and nuclear translocation of STAT3. The impact of Pim-1 in DES-SWOP signaling remains unclear.

[Fractures associated with dimonshed bone density, thypercalciuria and osteolysis. Is the diagnosis an osteoporosis or a syndrome?]. / Frakturen bei verminderter Knochendichte, Hyperkalziurie und Osteolysen - Osteoporose oder Syndrom?

At first osteomalacia was presumed clinically and radiologically in a 49-year old female patient. Radiologically there were multiple suspected neoplastic osseous infiltrations, which was not confirmed by subsequent investigations. There were no indications of osteomalacia or malabsorption in the laboratory exams. The multiple microfractures and osteolysis of the fingers, the toes, the wrist and the tarsus detected with varius imaging techniques were ascribed to an acroosteolysis. Osteoporosis of both femoral necks was also present in dual photon X-ray absorptiometry densitometry. Cheney Syndrom (HCS) was diagnosed clinically and radiologically and a treatment with bisphosphonates was introduced.

Healthy first-degree relatives of patients with type 1 diabetes exhibit significant differences in basal gene expression pattern of immunocompetent cells compared to controls: expression pattern as predeterminant of autoimmune diabetes.

Expression features of genetic landscape which predispose an individual to the type 1 diabetes are poorly understood. We addressed this question by comparing gene expression profile of freshly isolated peripheral blood mononuclear cells isolated from either patients with type 1 diabetes (T1D), or their first-degree relatives or healthy controls. Our aim was to establish whether a distinct type of 'prodiabetogenic' gene expression pattern in the group of relatives of patients with T1D could be identified. Whole-genome expression profile of nine patients with T1D, their ten first-degree relatives and ten healthy controls was analysed using the human high-density expression microarray chip. Functional aspects of candidate genes were assessed using the MetaCore software. The highest number of differentially expressed genes (547) was found between the autoantibody-negative healthy relatives and the healthy controls. Some of them represent genes critically involved in the regulation of innate immune responses such as TLR signalling and CCR3 signalling in eosinophiles, humoral immune reactions such as BCR pathway, costimulation and cytokine responses mediated by CD137, CD40 and CD28 signalling and IL-1 proinflammatory pathway. Our data demonstrate that expression profile of healthy relatives of patients with T1D is clearly distinct from the pattern found in the healthy controls. That especially concerns differential activation status of genes and signalling pathways involved in proinflammatory processes and those of innate immunity and humoral reactivity. Thus, we posit that the study of the healthy relative's gene expression pattern is instrumental for the identification of novel markers associated with the development of diabetes.

Sequencing of the CHST6 gene in Czech macular corneal dystrophy patients supports the evidence of a founder mutation.

AIMS: To characterise the role of the carbohydrate sulfotransferase gene (CHST6) in macular corneal dystrophy (MCD) in Czech patients. METHODS: The coding region of the CHST6 gene was directly sequenced in 10 affected and five unaffected members from eight apparently unrelated MCD families. The type of MCD was determined by enzyme-linked immunosorbent assay of antigenic keratan sulfate (KS) in serum and by immunohistochemical staining of corneas with monoclonal anti-KS antibody. RESULTS: The following changes in the coding sequence of the CHST6 gene were observed; homozygous mutation of c.1A>T (p.M1?); homozygous mutation c.599T>G (p.L200R); compound heterozygosity for c.599T>G and c.614G>A (p.R205Q); compound heterozygosity for c.494G>A (p.C165Y) and c.599T>G; heterozygous c.599T>G mutation and no other change in the coding sequence. One proband exhibited no changes. The pathogenic mutation c.599T>G (p.L200R) was in allelic association with the c.484C>G (p.R162G) polymorphism. Nine patients from seven families were of MCD type I including the subtype IA. CONCLUSION: Four different CHST6 missense mutations, of which p.C165Y is novel, were identified. Allelic association of the c.[484C>G; 599T>G] in six probands out of eight, as well as occurrence of this particular allele in a heterozygous state in one healthy control individual, supports a common founder effect for MCD in the Czech Republic.

Adiponectin signals in prostate cancer cells through Akt to activate the mammalian target of rapamycin pathway.

Adiponectin has received much attention due to its beneficial effects on insulin sensitivity, and epidemiologic studies have further shown an inverse association between adiponectin levels and risk for multiple tumors, which is independent of the IGF system or other risk factors. Previous studies have shown that adiponectin can activate AMP-activated protein kinase (AMPK) in myocytes, hepatocytes, and adipocytes, suggesting that adiponectin may suppress tumor development through AMPK activation and subsequent inhibition of mammalian target of rapamycin (mTOR). However, the mechanisms through which adiponectin affects cancer cells are not understood, and it remains to be determined whether adiponectin is linked to the same downstream targets in all cells types, and in particular in cancer cells. In the present study, we demonstrate that while adiponectin stimulates AMPK in phosphatase and tensin homolog deleted on chromosome ten (PTEN) deficient LNCaP prostate cancer cells, it also increases mTOR activity as assessed by phosphorylation of two downstream targets, p70 S6 kinase and ribosomal protein S6. This adiponectin stimulation of mTOR was mediated through phosphatidylinositol 3-kinase (PI3 kinase) and Akt activation. These results show that adiponectin can activate both AMPK and PI3 kinase/Akt pathways, and that cell type-specific factors such as PTEN status may determine which of these pathways will have the dominant effect on mTOR. Therefore, while it is possible that high endogenous adiponectin levels could be protective against cancer by direct mechanisms or indirect systemic mechanisms, our results indicate that adiponectin may also directly stimulate signaling pathways that enhance the growth of some tumors.

Grading of internal carotid artery stenosis: validation of Doppler/duplex ultrasound criteria and angiography against endarterectomy specimen.

OBJECTIVES: duplex ultrasound has replaced angiography prior to carotid endarterectomy (CEA) in many institutions. However, the indications for CEA are based on angiographically controlled studies and widely accepted ultrasound criteria do not exist. Consequently, the reliability of Doppler and/or duplex ultrasound to predict a high-grade ICA stenosis has to be proven. DESIGN: prospective validation study. MATERIALS: one hundred and fifty carotid bifurcations assessed by ultrasound and selective angiography and 68 acrylat outcasts of carotid specimen after eversion CEA. METHODS: ICA stenosis was measured angiographically according to the ECST criteria. Combined Doppler acoustic standard criteria (CDASC), peak systolic frequency (PSF), peak systolic velocity (PSV) and end-diastolic velocity (EDV) served as criteria for the ultrasound assessment. These criteria and the results of angiography were compared to the degree of ICA stenosis determined by specimen measurements. RESULTS: the median degree of ICA stenosis as assessed by angiography (82%, range 56-97%) and CDASC (83%, range 50-99%) corresponded well to the specimen measurements (80%, range 50-95%). The sensitivity of angiography and CDASC to predict a 70-90% ICA stenosis (ECST criteria) compared to the specimen measurements was 88% and 95%, respectively. The positive predictive value (PPV) reached 92% and 96%, respectively. CDASC were equivalent to angiography and were superior to the best single frequency or velocity parameters. If CDASC do not indicate a >/=70% ICA stenosis in spite of a PSV >/=180 cm/s and/or an EDV >/=50 cm/s, angiography may detect patients with a >70% ICA stenosis. CONCLUSIONS: CDASC are valid in the quantification of high-grade ICA stenosis. They are more reliable than single velocity and/or frequency measurements. However, if velocity criteria and CDASC do not agree, angiography should be performed.

[Necrotizing sialometaplasia (salivary gland infarct) of the submandibular gland. A case report]. / Nekrotisierende Sialometaplasie (Speicheldrüseninfarkt) der Glandula submandibularis. Ein Fallbericht.

Necrotizing sialometaplasia, being a rare, nonspecific reaction to ischaemic injury in salivary gland tissues of the head, is discussed in connection with a case of our own. In contrast to former reports concerning such lesions above all in minor salivary glands the following report concentrates on a case of necrotizing sialometaplasia in the submaxillary salivary gland of a 57-year old woman who noticed after exstirpation of a pleomorphic adenoma in the submaxillary gland a swelling that presented histologically as necrotizing sialometaplasia. Emphasis is placed on a detailed morphological knowledge of this innocuous, self-repairing process, since the extensive squamous cell metaplasia of minor excretory ducts as the essential finding could be easily misdiagnosed as a squamous cell carcinoma and, therefore deserves special consideration in differential diagnosis of salivary gland tumours.

[Acid-base equilibrium of fetuses delivered by breech presentation]. / Azidobasisches Gleichgewicht des Feten bei Beckenendlagengeburt

Acid-base balance of fetus in capillary and umbilical blood has been examined in two series of newborns: 30 newborns delivered by breech presentation and 15 newborns delivered spontaneously by vetex presentation without complications. Following parameters have been evaluated: pH, pCO2, BE and HCO3 (actual bicarbonate content). Differences between the parameters of acid-base balance, mainly the values of pH and pCO2 in capillary blood and in a. umbilicalis of the fetus direct to the fact that acidosis of the fetus with elevated values of pCO2 is a typical finding in labors by breech presentation and is due to compression of umbilical vessels during labor.