Impact of season on the association between vitamin D levels at diagnosis and one-year remission in early Rheumatoid Arthritis.

The study evaluates associations between serum vitamin D metabolites at diagnosis and one-year remission, in early diagnosed rheumatoid arthritis(RA). The CIMESTRA-cohort comprised 160 newly diagnosed RA patients, treated aiming at remission. Vitamin D supplementation was recommended according to national guidelines. Dtotal(25OHD2 + 25OHD3) was dichotomized at 50 nmol/L, 1,25(OH)2D was categorized in tertiles. Primary outcome was remission(DAS28-CRP ≤ 2.6) after one year. Associations were evaluated using logistic regression, further adjusted for pre-specified potential confounders: Age, sex, symptom-duration before diagnosis, DAS28-CRP and season of diagnosis. Results are presented as Odds Ratios(OR) with 95% Confidence Intervals(95%CIs). In univariate analyses, neither Dtotal nor 1,25(OH)2D were associated with remission. In adjusted analyses, low Dtotal was associated with higher odds for remission; OR 2.6, 95%CI (1.1; 5.9) p = 0.03, with season impacting results the most. One-year remission was lower in patients with diagnosis established at winter. In conclusion, low Dtotal at diagnosis was associated with increased probability of achieving one-year remission in early RA when adjusting for covariates. Diagnosis in winter was associated with lower odds for one-year remission. Results suggest that season act as a contextual factor potentially confounding associations between vitamin D and RA disease-course. The finding of low Dtotal being associated with higher one-year remission remains speculative.

Improving antibiotic treatment of bacterial biofilm by hyperbaric oxygen therapy: Not just hot air.

Bacteria and fungi show substantial increased recalcitrance when growing as infectious biofilms. Chronic infections caused by biofilm growing microorganisms is considered a major problem of modern medicine. New strategies are needed to improve antibiotic treatment of biofilms. We have improved antibiotic treatment of bacterial biofilms by reviving the dormant bacteria and thereby make them susceptible to antibiotics by means of reoxygenation. Here we review the rationale for associating lack of oxygen with low susceptibility in infectious biofilm, and how hyperbaric oxygen therapy may result in reoxygenation leading to enhanced bactericidal activity of antibiotics. We address issues of feasibility and potential adverse effects regarding patient safety and development of resistance. Finally, we propose means for supplying reoxygenation to antibiotic treatment of infectious biofilm with the potential to benefit large groups of patients.

Sulfated hyaluronan/collagen I matrices enhance the osteogenic differentiation of human mesenchymal stromal cells in vitro even in the absence of dexamethasone.

Glycosaminoglycans (GAG) are multifunctional components of the extracellular matrix (ECM) involved in different steps of the regulation of cellular differentiation. In this study artificial extracellular matrices (aECM) consisting of collagen (Col) I and different GAG derivatives were used as a substrate for human mesenchymal stromal cells (hMSC) to study osteogenic differentiation in vitro. hMSC were cultured on aECM containing col and hyaluronan sulfates (HyaS) with increasing degrees of sulfation (DS(S)) and were compared with aECM containing col and the natural GAG hyaluronan or chondroitin 4-sulfate. hMSC were analyzed for osteogenic differentiation markers such as calcium phosphate deposition, tissue non-specific alkaline phosphatase (TNAP) and expression of runt-related transcription factor 2 (runx2), osteocalcin (ocn) and bone sialoprotein II (bspII). Compared with aECM containing Col and natural GAG all Col/HyaS-containing aECM induced an increase in calcium phosphate deposition, TNAP activity and tnap expression. These effects were also seen in the absence of dexamethasone (an established osteogenic supplement). The expression of runx2 and ocn was not altered and the expression of bspII was diminished on the col/HyaS-containing aECM. The impact of the Col/HyaS-containing aECM on hMSC differentiation was independent of the DS(S) of the HyaS derivatives, indicating the importance of the primary (C-6) hydroxyl group of N-acetylglucosamine. These results suggest that Col/HyaS-containing aECM are able to stimulate hMSC to undergo osteogenic differentiation even in the absence of dexamethasone, which makes these matrices an interesting tool for hMSC-based tissue engineering applications and biomaterial functionalizations to enhance bone formation.

Nitrogen management is essential to prevent tropical oil palm plantations from causing ground-level ozone pollution.

More than half the world's rainforest has been lost to agriculture since the Industrial Revolution. Among the most widespread tropical crops is oil palm (Elaeis guineensis): global production now exceeds 35 million tonnes per year. In Malaysia, for example, 13% of land area is now oil palm plantation, compared with 1% in 1974. There are enormous pressures to increase palm oil production for food, domestic products, and, especially, biofuels. Greater use of palm oil for biofuel production is predicated on the assumption that palm oil is an "environmentally friendly" fuel feedstock. Here we show, using measurements and models, that oil palm plantations in Malaysia directly emit more oxides of nitrogen and volatile organic compounds than rainforest. These compounds lead to the production of ground-level ozone (O(3)), an air pollutant that damages human health, plants, and materials, reduces crop productivity, and has effects on the Earth's climate. Our measurements show that, at present, O(3) concentrations do not differ significantly over rainforest and adjacent oil palm plantation landscapes. However, our model calculations predict that if concentrations of oxides of nitrogen in Borneo are allowed to reach those currently seen over rural North America and Europe, ground-level O(3) concentrations will reach 100 parts per billion (10(9)) volume (ppbv) and exceed levels known to be harmful to human health. Our study provides an early warning of the urgent need to develop policies that manage nitrogen emissions if the detrimental effects of palm oil production on air quality and climate are to be avoided.

Dietary fatty acid composition rather than vitamin E supplementation influence ex vivo cytokine and eicosanoid response of porcine alveolar macrophages.

This study examined the influence of different dietary fat sources (animal fat, sunflower oil, and fish oil) and supplementation of vitamin E (85, 150 and 300 mg all-rac-alpha-tocopheryl acetate/kg diet) on the ex vivo synthesis of eicosanoids and cytokines by porcine alveolar macrophages. Supplementation of vitamin E provoked an increase in the concentration of alpha-tocopherol of the macrophages irrespective of fat sources. Fish oil increased the macrophage n-3 content with 100% and 40%, and reduced the n-6 with 60% and 53% in comparison with sunflower oil and animal fat, respectively. Fish oil decreased the production of TNF-alpha, IL-8, LTB4, and PGE2 (but not IL-6) relative to the other dietary fat sources, and no difference was observed between sunflower oil and animal fat. Positive correlations were found between the n-6 fatty acid content and the production of PGE2, and the PGE2 production was positively correlated with TNF-alpha and IL-8. Negative correlations were found between the n-3 PUFA content and the concentration of PGE2, TNF-alpha and IL-8. In conclusion, dietary fish oil supplemented at a level of 5%, but not supplemental vitamin E, influenced the inflammatory responses of alveolar macrophages isolated from weaned pigs relatively to animal fat and sunflower oil.

Does timing of adjuvant chemotherapy influence the prognosis after early breast cancer? Results of the Danish Breast Cancer Cooperative Group (DBCG).

The purpose of this study was to examine the effect on survival of delaying the start of adjuvant chemotherapy for early breast cancer for up to 3 months after surgery. In the nation-wide clinical trials of the Danish Breast Cancer Cooperative Group, 7501 breast cancer patients received chemotherapy within 3 months of surgery between 1977 and 1999: 352 with classical cyclofosfamide, metotrexate and 5-fluorouracil (CMF); 6065 with CMF i.v. and 1084 with cyclofosfamide, epirubicin and 5-fluorouracil. For the analysis, the time between surgery and the start of chemotherapy was divided into four strata (1-3, 4, 5 and 6-13 weeks). The results show that within the three groups of chemotherapy, there was an even distribution of known prognostic factors across the four strata of initiation of chemotherapy. There was no pattern indicating a benefit from early start of chemotherapy. No significant interactions were found for subgroups of patients with a poorer prognosis (many involved lymph nodes, high-grade malignancies or hormone receptor negative disease). In conclusion, we have found no evidence for a survival benefit due to early initiation of adjuvant chemotherapy within the first 2-3 months after surgery.

The KOX zinc finger genes: genome wide mapping of 368 ZNF PAC clones with zinc finger gene clusters predominantly in 23 chromosomal loci are confirmed by human sequences annotated in EnsEMBL.

The chromosome locations of 368 human Kruppel-type zinc finger (ZNF) PAC clones were physically mapped by FISH to human chromosomes in support of recent efforts of assigning KOX cDNAs (KOX1-KOX32) to zinc finger gene clusters. Recent mapping results were validated and confirmed by sequence comparisons to zinc finger gene sequences automatically annotated in EnsEMBL. In toto, 799 Kruppel-type zinc finger genes have been annotated in EnsEMBL of which 290 genes are found to encode KRAB domains. Sequence homologies of the zinc finger domains were used to establish phylogenic trees of KOX zinc finger genes as well as of all KRAB containing human zinc finger and KOX genes documenting the evolution of KRAB zinc finger genes late in primate evolution. A list of 368 assigned ZNF PAC clones is available under http://www.pzr.uni-rostock.de/supplements.

Modulation of atherosclerotic risk factors by seal oil: a preliminary assessment.

We examined whether dietary supplementation with seal oil influenced the risk factors of atherosclerosis in healthy volunteers. Two intervention studies were carried out as preliminary steps in a larger project which aim at elucidating the disease preventive potential of seal oil. In study I ten healthy volunteers added 10 capsules of seal oil to their normal Western diet for six weeks. Blood tests were analysed for total-, HDL-, and LDL-cholesterol and plasma triglyceride, and the ratio of n-6/n-3 fatty acid was determined in plasma and erythrocyte membranes. In study II we examined the effect in five healthy volunteers who had only 5 capsules of seal oil daily for six weeks. As an additional test in study II, the effect on the proinflammatory TNF-alpha cytokine in lymphocytes was determined. A slightly decreased, however, not significant effect was observed for each of the cholesterol's after seal oil supplementation. In both studies plasma triglyceride, and the n-6/n-3 fatty acid ratio of plasma and erythrocytes were significantly reduced upon seal oil intake. During the intervention period of study II a distinct reduced level of TNF-alpha was observed in isolated lymphocytes. The examinations suggest that supplementation of seal oil, 10 capsules or 5 capsules/day, may have beneficial effects on factors thought to be associated with cardiovascular and thrombotic diseases.

[Use of self-organizing neural networks (Kohonen maps) for classification of voice acoustic signals exemplified by the infant voice with and without time-delayed auditory feedback]. / Anwendung selbstorganisierender neuronaler Netzwerke (Kohonen-Maps) zur Klassifizierung von Stimmschallsignalen am Beispiel der Säuglingsstimme mit und ohne zeitverzögerter auditiver Rückkopplung.

Subjective and auditory assessment of the voice is now more commonly being replaced by objective voice analysis. Because of the amount of data available from computer-aided voice analysis, subjective selection and interpretation of single data sets remain a matter of experience of the individual investigator. Since neuronal networks are widely used in telecommunication and speech recognition, we applied self-organizing Kohonen networks to classify voice patterns. In the phase of "learning," the Kohonen map is adapted to patterns of the primary signals obtained. If, in the phase of using the map, the input signal hits the field of the primary signals, it will resemble them closely. In this study, we recorded newborn and young infant cries using a DAT recorder and a high-quality microphone. The cries were elicited by wearing uncomfortable headphones ("cries of discomfort"). Spectrographic characteristics of the cries were classified by 20-step bark spectra and then applied to the neuronal networks. It was possible to recognize similarities of different cries of the same children and interindividual differences, as well as cries of children with profound hearing loss. In addition, delayed auditory feedback at 80 dB SL was presented to 27 children via headphone using a three-headed tape-recorder as a model for induced individual cry changes. However, it was not possible to classify short-term changes as in a delayed feedback procedure. Nevertheless, neuronal networks may be helpful as an additional tool in spectrographic voice analysis.

Long-term effect of dexfenfluramine on amino acid profiles and food selection in obese patients during weight loss.

In depressive disorders an association between basal pre-treatment plasma ratios of tryptophan (Trp) and tyrosine (Tyr) to other large neutral amino acids (LNAA) and the clinical efficacy of serotonergic acting drugs have been established. In order to clarify whether a similar relation exists in obesity and to elucidate the long-term effect of dexfenfluramine (dF) on plasma amino acid profiles and macronutrient selection, we examined 29 obese patients participating in a 12 months double-blind weight loss trial with either dexfenfluramine (dF) (30 mg/day) or placebo (PL) in conjunction with 4.2-5.0 MJ/d diet. Maximum weight loss was obtained after 6 months (dF 12.8 +/- 5.4 kg; PL 13.8 +/- 9.2 kg, x +/- s.d., ns). Plasma Trp/LNAA and Tyr/LNAA were found to be lower than in normal weight controls and were further reduced during treatment (p < 0.05), but without differences between dF and PL groups. Macronutrient selection was not affected by the dF treatment. In the placebo group weight loss was associated with a high pre-treatment energy intake and a high carbohydrate-protein ratio (p < 0.05). A decrease in dietary fat and increase in protein intake (%) and age was found to explain 82% of the variation in weight loss (p < 0.0005), whereas no correlation could be shown in the dF group. Pre-treatment plasma Trp/LNAA or Tyr/LNAA and weight loss were not correlated. In conclusion, neither food selection nor basal plasma amino acid profiles were predictors of weight loss during long-term treatment with dF as an adjuvant to energy restriction, and they were not affected by the drug treatment.

Naloxone stimulation test in women with hypothalamic amenorrhea: a preliminary report.

We researched the possibility of the induction of ovulation by means of chronic opioid receptor blockade in 4 women with hypothalamic amenorrhea. Daily 4 mg naloxone were given as a bolus injection intravenously. By means of continuous determination of LH, FSH, 17-beta-estradiol (E2) and progesterone as well as of sonographic folliculometry follicular growth and subsequent ovulation should have been proved. Neither we found alterations of the basal values of LH, FSH, E2 and progesterone, nor we observed a follicular growth. These results lead us to the conclusion to put a naloxone stimulation test before further therapy. In this way opioid mediated hypothalamic ovarian insufficiencies can be registered and a therapy optimum can be reached early.

Effect of aspartame and protein, administered in phenylalanine-equivalent doses, on plasma neutral amino acids, aspartate, insulin and glucose in man.

Six human males each received 0.56 g phenylalanine (Phe) in the form of 1.0 g aspartame or 12.2 g bovine albumin in 200 ml water or water alone. Venous blood samples collected before consumption and during the following 4 hr were assayed for plasma levels of large, neutral amino acids (LNAA), aspartate, insulin and glucose. The area under the curve for plasma Phe was 40% greater, although not significant, after aspartame compared with albumin intake. The indicated increased clearance rate of plasma Phe after albumin may be caused by the significant increase of insulin, on which aspartame had no effect. There was a significant main effect of aspartame for plasma tyrosine but not for tryptophan, valine, isoleucine or leucine. Plasma aspartate was significantly increased at 0.25 hr after the aspartame intake. The percentage Phe/LNAA decreased slightly in response to albumin but increased 55% after aspartame and remained significantly increased for 2 hr. Tyrosine/LNAA increased and tryptophan/LNAA decreased modestly after aspartame intake. The study showed that the intake of aspartame in a not unrealistically high dose produced a marked and persistent increase of the availability of Phe to the brain, which was not observed after protein intake. The study indicated, furthermore, that Phe was cleared faster from the plasma after consumption of protein compared with aspartame.

[Menstrual cycle, opioids and hypothalamic amenorrhea: from physiology to pathology]. / Der menstruelle Zyklus, die Opioide und die hypothalamische Amenorrhoe: von der Physiologie zur Pathologie.

The central part of menstrual cyclicity is the arcuate nucleus within the mediobasal hypothalamus, which is shown to be the origin of GnRH. This neuronal oscillator is influenced by many endogenous substances and its periodically activity is modulated by them. The endogenous opioids are such substances. They are widely distributed within the organism and are endogenous ligands of opiate receptors. The endogenous opioids participate in many somatic functions such as regulation of ovarian cyclicity. Furthermore they are causal involved in hypothalamic amenorrhea.

Experimental endocarditis in rabbits. 5. Results of long-term penicillin or streptomycin treatment of streptococcus faecalis endocarditis and the effect of long-term exposure of healthy rabbits to the same drugs.

A previously described model of experimental Streptococcus faecalis endocarditis in rabbits without an indwelling catheter during the infectious processes was used to study the effect of long-term treatment with antibiotics. Groups of animals infected with six different strains were treated for four weeks and the following parameters were determined: survival rate, bacterial concentration in blood and vegetations, signs at autopsy indicating congestive heart failure. Before the therapeutic experiments, the tolerance of the rabbit to long-term exposure of the drugs penicillin and streptomycin was considered in a group of non-infected animals. Two out of 20 rabbits died with enteritis during the penicillin exposure, and a general weight reduction was observed. Streptomycin was apparently completely harmless. There was no therapeutic effect of streptomycin on S. faecalis endocarditis due to strains all designated resistant to streptomycin by MIC, except in rabbits infected with a strain, which showed partial susceptibility to the drug by IC50. Regardless of the therapeutic effect, evidence was obtained for rapid development of increased resistance of the infecting strains towards streptomycin. After long-term treatment with penicillin in either low or high dose some of the animals survived and the valves were sterilized in 37% of the animals after low-dose and in 39% after high-dose. It was observed that congestive heart failure occurred with the greatest frequency and intensity after infection with proteolytic strains.