Pathogenesis of acute encephalopathy in acute hepatic porphyria.

Acute encephalopathy (AE) can be a manifestation of an acute porphyric attack. Clinical data were studied in 32 patients during AE with or without polyneuropathy (PNP) together with 12 subjects with PNP but no AE, and 17 with dysautonomia solely. Brain neuroimaging was done in 20 attacks during AE, and PEPT2 polymorphisms were studied in 56 subjects, 24 with AE. AE manifested as a triad of seizures, confusion and/or blurred vision. Symptoms lasting 1-5 days manifested 3-19 days from the onset of an attack. 55% of these patients had acute PNP independent of AE. Posterior reversible encephalopathy syndrome (PRES) was detected in 42% of the attacks. These patients were severely affected and hyponatremic (88%). Reversible segmental vasoconstriction was rare. There was no statistical difference in hypertension or urinary excretion of porphyrin precursors among the patients with or without AE. In 94% of the attacks with AE, liver transaminases were elevated significantly (1.5 to fivefold, P = 0.034) compared to a normal level in 87% of the attacks with dysautonomia, or in 25% of patients with PNP solely. PEPT2*2/2 haplotype was less common among patients with AE than without (8.3% vs. 25.8%, P = 0.159) and in patients with PNP than without (9.5% vs. 22.9%, P = 0.207), suggesting a minor role, if any, in acute neurotoxicity. In contrast, PEPT2*2/2 haplotype was commoner among patients with chronic kidney disease (P = 0.192). Acute endothelial dysfunction in porphyric encephalopathy could be explained by a combination of abrupt hypertension, SIADH, and acute metabolic and inflammatory factors of hepatic origin.

Long-term follow-up of acute porphyria in female patients: Update of clinical outcome and life expectancy.

BACKGROUND: Acute hepatic porphyria includes four inherited disorders caused by partial deficiencies of enzymes related to the heme biosynthesis. Clinical manifestations include acute attacks, occurring mainly among female patients. This study describes the diversity of acute symptoms, changes in triggering factors and life expectancy among female patients during the past five decades. METHODS: 107 Finnish female patients were enrolled into a retrospective, longitudinal study during 2015. Clinical, biochemical and genetic data was obtained from the medical reports, registry data and a questionnaire designed for the study. Causes of death were studied in additional 32 female patients. RESULTS: Of the 43 patients with hospitalization, 33% had non-complicated, 35% prolonged and 28% severe attacks with no correlation with the disease-causing mutation. Of the deceased patients, 31% died of an acute attack during 1957-1979. Thereafter the incidence and severity of acute attacks have decreased substantially. 55% of the subjects reported acute symptoms (dysautonomia and mental symptoms) without hospitalization, 29% had porphyria symptoms >10 times, and 23% within the last year. Despite 22% of the female patients had died of primary liver cancer, the life expectancy increased more than 10 years during the follow-up, and did not differ from the normal population at present. CONCLUSIONS: The incidence of acute attacks requiring hospitalization has decreased, but more than half of the female patients reported acute symptoms affecting their well-being. Symptoms are currently triggered by hormonal changes and weight loss emphasizing the importance of early recognition and active management to avoid disease exacerbation. Death due to primary liver cancer is common and should be screened regularly.

Simultaneous structuring and mineralization of silk fibroin scaffolds.

Silk fibroin is commonly used as scaffold material for tissue engineering applications. In combination with a mineralization with different calcium phosphate phases, it can also be applied as material for bone regeneration. Here, we present a study which was performed to produce mineralized silk fibroin scaffolds with controlled macroporosity. In contrast to former studies, our approach focused on a simultaneous gelation and mineralization of silk fibroin by immersion of frozen silk fibroin monoliths in acidic calcium phosphate solutions. This was achieved by thawing frozen silk fibroin monoliths in acidic calcium phosphate solution, leading to the precipitation of monocalcium phosphate within the silk fibroin matrix. In the second approach, a conversion of incorporated ß-tricalcium phosphate particles into brushite was successfully achieved. Furthermore, a controlled cryostructuring process of silk fibroin scaffolds was carried out leading to the formation of parallel-oriented pores with diameters of 30-50 µm.

Vorinostat combined with bexarotene for treatment of cutaneous T-cell lymphoma: in vitro and phase I clinical evidence supporting augmentation of retinoic acid receptor/retinoid X receptor activation by histone deacetylase inhibition.

The retinoid X receptor (RXR)-agonist bexarotene and the histone deacetylase inhibitor (HDACI) vorinostat are each established monotherapies for cutaneous T-cell lymphomas (CTCLs). We investigated the combination of HDACI and retinoic acid receptor (RAR)/RXR agonists in vitro and in a phase I, multicenter, open-label, two-part dose-escalation study. The combination of bexarotene with a HDACI in vitro leads to cooperative activation of gene transcription and reduction of cell viability in human tumor cell lines. The primary clinical objective was to determine the maximum tolerated dose (MTD) of bexarotene plus vorinostat in 23 patients with CTCLs. The MTD for part I was established at vorinostat 200 mg/day plus bexarotene 300 mg/m(2)/day. The MTD for part II was not reached. Four patients had an objective response and seven patients experienced pruritus relief. We conclude that concomitant administration of vorinostat and bexarotene is feasible only if lower doses of each drug are administered relative to the product label monotherapy doses.

The antibacterial substance, taurolidine in the second/third-line treatment of very advanced stage IV melanoma including brain metastases: results of a phase 2, open-label study.

The efficacy and tolerability of taurolidine, an antibacterial substance, was evaluated in a phase 2 trial enrolling patients with advanced melanoma. The treatment schedule consisted of daily taurolidine (20 g) administered intravenously for 5 days per week for 3 consecutive weeks followed by 1 week of rest. One cycle comprised of 28 days. A maximum of six cycles could be administered. Sixteen patients were assessable for tumor response, seven of whom had brain metastases. Three patients (18.8%) achieved disease stabilization, including a patient with a primary mucosal melanoma of the nasal cavity who had a marked locoregional response with disease stabilization of the distant metastases. Thirteen patients had disease progression. Median overall survival was 46±1 days. Adverse events were moderate and mainly gastrointestinal. Treatment with taurolidine has no activity in patients with advanced melanoma.

The daily walking distance of young doctors and their body mass index.

CONTEXT: Non-exercise physical activity thermogenesis (NEAT) has been shown to differ in obese and non-obese subjects. OBJECTIVE: To explore whether NEAT is determined by the body mass index (BMI) even within the normal range, we hypothesized that the daily walking distance of young doctors in training at a teaching hospital is inversely correlated with the BMI. DESIGN: Prospective, single blind, controlled trial. SETTING: Identical wards of a 400 bed university-based teaching hospital, highly standardized for patient number treated, the severity of disease, the clinical experience of the doctors and their time spent in the institution. INTERVENTION: The walking distance was measured daily by a pedometer over one week and standardized for the setting, workload, and insurance status. MAIN OUTCOME MEASURES: Mean daily walking distance as a measure of NEAT. RESULTS: The mean daily distance walked was 2323+/-627 m with a more than 4-fold difference between the daily maximum of 4310 m and the minimum of 1003 m. There was an inverse correlation of the walking distance with the BMI (Spearman rho=0.750, p=0.02), and with the time spent in the hospital (rho=-0.800, p=0.01), but not with the months of clinical experience, age, gender, number of patients, disease, severity nor with the insurance status of the patients cared for. There was no mean difference between the distance walked in the morning vs. in the afternoon nor was there a trend from Monday through Friday. CONCLUSION: The results of this pilot study indicate that NEAT is related to the BMI in the non-obese stage.

Tumour assessment in advanced melanoma: value of FDG-PET/CT in patients with elevated serum S-100B.

PURPOSE: To evaluate the usefulness of PET/CT in melanoma patients with an elevated serum S-100B tumour marker level. METHODS: Out of 165 consecutive high-risk melanoma patients referred for PET/CT imaging, 47 had elevated (>0.2 microg/l) S-100B serum levels and a contemporaneous 18F-FDG PET/CT scan. PET/CT scans were evaluated for the presence of metastases. To produce a composite reference standard, we used cytological, histological, MRI and PET/CT follow-up findings as well as clinical and S-100B follow-up. RESULTS: Among the 47 patients with increased S-100B levels, PET/CT correctly identified metastases in 38 (30 distant metastases and eight lymph node metastases). In one patient with cervical lymph node metastases, PET/CT was negative. Eight patients had no metastases and PET/CT correctly excluded metastases in all of them. Overall sensitivity for metastases was 97% (38/39), specificity 100% (8/8) and accuracy 98% (46/47). S-100B was significantly higher in patients with distant metastases (mean 1.93 microg/l, range 0.3-14.3 microg/l) than in patients with lymph node metastases (mean 0.49 microg/l, range 0.3-1.6 microg/l, p=0.003) or patients without metastases (mean 0.625 microg/l, range 0.3-2.6 microg/l, p=0.007). However, 6 of 14 patients with a tumour marker level of 0.3 microg/l had no metastases. CONCLUSION: In melanoma patients with elevated S-100B tumour marker levels, FDG-PET/CT accurately identifies lymph node or distant metastases and reliably excludes metastases. Because of the significant number of false positive S-100B tumour marker determinations (17%), we recommend repetition of tumour marker measurements if elevated S-100B levels occur before extensive imaging is used.

DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells.

The transcription factor FOXP3 is critical for development and function of regulatory T cells (Treg). Their number and functioning appears to be crucial in the prevention of autoimmunity and allergy, but also to be a negative prognostic marker for various solid tumors. Although expression of the transcription factor FOXP3 currently constitutes the best-known marker for Treg, in humans, transient expression is also observed in activated non-Treg. Extending our recent findings for the murine foxp3 locus, we observed epigenetic modification of several regions in the human FOXP3 locus exclusively occurring in Treg. Importantly, activated conventional CD4(+) T cells and TGF-beta-treated cells displayed no FOXP3 DNA demethylation despite expression of FOXP3, whereas subsets of Treg stable even upon extended in vitro expansion remained demethylated. To investigate whether a whole set of genes might be epigenetically imprinted in the Treg lineage, we conducted a genome-wide differential methylation hybridization analysis. Several genes were found displaying differential methylation between Treg and conventional T cells, but none beside FOXP3 turned out to be entirely specific to Treg when tested on a broad panel of cells and tissues. We conclude that FOXP3 DNA demethylation constitutes the most reliable criterion for natural Treg available at present.