Impact of intravenous fish oil on omega-3 fatty acids and their derived lipid metabolites in patients with parenteral nutrition.

BACKGROUND: Long-term parenteral nutrition (PN) can lead to intestinal failure-associated liver disease (IFALD). Omega-3 (n-3) polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were shown to prevent IFALD. EPA-derived and DHA-derived oxylipins could contribute to this protective effect. METHODS: We analyzed the effect of parenteral fish oil on oxylipins in patients with chronic intestinal failure receiving PN (n = 8). Patients first received no fish oil for 8 weeks and then switched to PN with 25% of fat as fish oil for another 8 weeks. Fatty acid profiles of red blood cells, PUFA-derived oxylipins generated by cyclooxygenase, lipoxygenase (LOX), and cytochrome P450 (CYP) pathways, inflammatory markers, and liver function were assessed before and during fish-oil PN. RESULTS: EPA plus DHA in erythrocytes (the Omega-3 Index) was high with a median of 11.96% at baseline and decreased to 9.57% without fish oil in PN. Addition of fish oil in PN increased the median Omega-3-Index to 12.75%. EPA-derived and DHA-derived CYP-dependent and LOX-dependent metabolites increased significantly with fish oil in PN, with less pronounced changes in arachidonic acid and its oxylipins. There were no significant changes of inflammation and liver function parameters. CONCLUSIONS: This study shows that fish oil-containing PN leads to primarily CYP- and LOX-dependent n-3 PUFA-derived inflammation-dampening oxylipins arising from EPA and DHA. Within this short (16-week) study, there were no significant changes in inflammation and clinical readout parameters.

Mutations in AIFM1 cause an X-linked childhood cerebellar ataxia partially responsive to riboflavin.

BACKGROUND: AIFM1 encodes a mitochondrial flavoprotein with a dual role (NADH oxidoreductase and regulator of apoptosis), which uses riboflavin as a cofactor. Mutations in the X-linked AIFM1 were reported in relation to two main phenotypes: a severe infantile mitochondrial encephalomyopathy and an early-onset axonal sensorimotor neuropathy with hearing loss. In this paper we report two unrelated males harboring AIFM1 mutations (one of which is novel) who display distinct phenotypes including progressive ataxia which partially improved with riboflavin treatment. METHODS: For both patients trio whole exome sequencing was performed. Validation and segregation were performed with Sanger sequencing. Following the diagnosis, patients were treated with up to 200 mg riboflavin/day for 12 months. Ataxia was assessed by the ICARS scale at baseline, and 6 and 12 months following treatment. RESULTS: Patient 1 presented at the age of 5 years with auditory neuropathy, followed by progressive ataxia, vermian atrophy and axonal neuropathy. Patient 2 presented at the age of 4.5 years with severe limb and palatal myoclonus, followed by ataxia, cerebellar atrophy, ophthalmoplegia, sensorineural hearing loss, hyporeflexia and cardiomyopathy. Two deleterious missense mutations were found in the AIFM1 gene: p. Met340Thr mutation located in the FAD dependent oxidoreductase domain and the novel p. Thr141Ile mutation located in a highly conserved DNA binding motif. Ataxia score, decreased by 39% in patient 1 and 20% in patient 2 following 12 months of treatment. CONCLUSION: AIFM1 mutations cause childhood cerebellar ataxia, which may be partially treatable in some patients with high dose riboflavin.

Tolerability of a new fast updosed immunologically enhanced subcutaneous immunotherapy formulation with an optimized allergen to adjuvant ratio under routine practice conditions: a noninterventional observational study.

BACKGROUND AND OBJECTIVES: A fast updosed immunologically enhanced subcutaneous immunotherapy (SCIT) formulation with an optimized allergen to aluminium hydroxide ratio was first introduced in September 2009 in Germany. A large randomized controlled trial showed that the formulation had considerable immunologic effects and good tolerability. In this open-label, uncontrolled, noninterventional study, tolerability was investigated during routine application. PATIENTS AND METHODS: Patients with allergic rhinoconjunctivitis and/or asthma were treated with pollen and mite allergens using a 5-injection updosing schedule (AVANZ: 300, 600, 3000, 6000 and 15 000 SQ+ units) with weekly intervals, followed by a maintenance schedule with injections of 15,000 SQ+ units.Adverse events (AEs) were recorded by physicians, and symptoms and use of symptomatic medication were analyzed before the start of therapy and after an average 8-month treatment period. RESULTS: SCIT was documented by 362 allergists in 1036 patients between September 2009 and February 2011. AEs mainly consisted of local reactions during updosing (in 24.5% of patients). Systemic reactions were observed during updosing (8.4%) and maintenance therapy (1.7%), the most frequent of which was dyspnea. Overall, tolerability and the effect of treatment were rated as good or very good by 94.9% and 86.6% of patients and by 96.2% and 89.6% of physicians, respectively. CONCLUSIONS: In this open-label, noninterventional study, fast updosed immunologically enhanced SCIT (AVANZ) was well tolerated in a large group of patients.

A prospective, randomized, double-blind, placebo-controlled multi-centre study on the efficacy and safety of sublingual immunotherapy (SLIT) in children with seasonal allergic rhinoconjunctivitis to grass pollen.

BACKGROUND: Especially in childhood, sublingual immunotherapy (SLIT) could offer advantages over subcutaneous therapy. However, limited data on its efficacy is available. METHODS: In four German centres 97 children (age 3-14 years) with allergic rhinoconjunctivitis to grass pollen were enrolled in a prospective, double-blind trial comparing SLIT (Pangramin SLIT; ALK-SCHERAX, 0.5 microg major allergens, three times per week, 32 months) with placebo. Primary endpoint was a multiple symptom-medication score for changes in seasonal diary entries between the first and third year of the study (SLIT n=39; placebo n=38). RESULTS: The multiple symptom-medication score was significantly reduced by SLIT to 77.3% of the placebo group (P=0.0498). The subsequent analysis of the single endpoints did not reveal significant differences for symptom scores in favour of SLIT (85.1% of placebo group; P=0.22). However, the medication score improved significantly (67.1% of placebo group; P=0.0025). Furthermore, secondary endpoints assessing in vivo immune responses did not differ significantly between the groups. However, retrospective analysis showed some inhomogeneity for clinical and in vitro parameters at the beginning of the study. Allergic side effects with possible relation to the study drug were reported in both groups (SLIT 49%, placebo 27%, P=0.026). CONCLUSION: Our study indicates that SLIT had a positive effect on the reduction of a multiple symptom-medication score, mainly by significantly reducing rescue medication use, but had no significant effect on symptoms alone in children with rhinoconjunctivitis to grass pollen compared with a placebo.

Cystosarcoma phyllodes malignum: a case report of a successive triple modality treatment.

This paper reports on a woman with a rapidly growing recurrent cystosarcoma phyllodes malignum after two major attempts of surgery. In this situation, neoadjuvant hyperfractionated radiotherapy, superficial hyperthermia and ifosfamide were administered. Toxicity was mild. Resection of the tumour bed revealed a pathologically complete response with an actual disease free follow-up of 48 months.

[Extract of the Echinacea purpurea herb: an allopathic phytoimmunostimulant]. / Presssaft aus dem Kraut von Echinacea purpurea: ein allopathisches Phytoimmunstimulans.

In Northamerican folk medicine Echinacea purpurea L. Moench (purple coneflower) was used as a medicinal plant. Nowadays various formulations containing stabilized or dried pressed juice from Echinacea purpurea as an active ingredient are often administered to treat common colds. These preparations are very well tolerated and safe. Allergic reactions, mainly reversible skin reactions, may occur especially in persons showing hypersensibility after contact with plants from the Compositae family. Pharmacological data let assume purple coneflower pressed juice preparations stimulate the innate immune system and increase the resistance to common colds. In this context the stimulation of the oxidative burst as well as the modulation on monokine secretion by the pressed juice of purple coneflower are reviewed. Also relevant clinical studies are presented concerning the treatment of infections respectively of common cold.

Identification of Melissa officinalis Subspecies by DNA Fingerprinting.

The random amplified polymorphic DNA analysis (RAPD) is a method to study genetic variability within and between populations and species on the basis of the amplification of anonymous fragments from genomic DNA templates by means of polymerase chain reaction (PCR). We applied RAPD analysis in order to distinguish medicinal plant subspecies at the level of their genomes. In this study we investigated various samples of two MELISSA subspecies and showed that RAPD analysis is a fast and reliable method to distinguish subspecies on the pharmaceutical market that have been previously classified according to the distribution pattern of compounds present in the lemon balm oil.

Characterization of Echinacea species and detection of possible adulterations by RAPD analysis.

In this report we describe the discrimination of all three pharmaceutically relevant Echinacea species by random amplified polymorphic DNA (RAPD) analysis. Genomic DNA prepared from either fresh root material or dried roots was probed in polymerase chain reactions (PCR) using several arbitrary primers. Distinct banding patterns were obtained for E. purpurea, E. angustifolia var. angustifolia, and E. pallida, respectively. Individual Echinacea drugs could be identified within mixtures containing variable amounts of individual drugs. We propose to use RAPD analysis as a rapid and reliable test for proving the identity of Echinacea root drugs.

Tree-pollen allergy is efficiently treated by short-term immunotherapy (STI) with seven preseasonal injections of molecular standardized allergens.

The efficacy and tolerance of short-term immunotherapy (STI) by seven preseasonal injections of tree-pollen allergens (ALK7 Frühblühermischung) was investigated in a double-blind, placebo-controlled, multicenter study with 111 rhinoconjunctivitis patients. Nasal and bronchial symptoms simultaneously analyzed, and nasal symptoms as a single end point, but not the overall score of nasal, bronchial, and conjunctival symptoms, showed a significantly lower increase with STI during birch-pollen exposure (both P=0.033, n=105, Mann-Whitney U-test). However, a selective analysis with patients from centers with high recruitment figures (n> or =10 patients, n=29 STI, n=32 placebo) showed a significantly lower increase of nasal, bronchial, and overall symptom score (STI 11.0 vs placebo 18.0, P=0.001, U-test). STI had equidirected effects on conjunctival, nasal, and bronchial symptoms analyzed as multiple end points, although conjunctival symptoms were not significantly different as a single end point. The seasonal increase in drug use was reduced by 62% in the STI group compared with placebo (P=0.032, t-test). Specific IgG4 increased only after STI (P<0.001); IgE was not significantly different. Eosinophil cationic protein remained unchanged with STI, but significantly increased with placebo in the pollen season (P=0.003). STI was well tolerated. In conclusion, STI was shown to be efficacious and safe for the treatment of patients with tree-pollen rhinoconjunctivitis.

Carbazole antibiotics synthesis in a Streptomyces tendae bald mutant, created by acriflavine treatment.

Acriflavine treatment on Streptomyces tendae generated a bald mutant (bld-1) with an altered antibiotic pattern. The parental strain produced nikkomycins and juglomycins, whereas the mutant bld-1 was only capable of juglomycin synthesis. The existence of a mutant defective in morphogenesis and in nikkomycin biosynthesis suggests a common regulation of these processes. An interesting finding of this study is that mutant bld-1 produced two carbazole derivatives, hitherto never seen in cultures of the parental strain. It seems likely that the DNA intercalating dye acriflavine, by mutagenesis, had activated cryptic genes which are involved in carbazole synthesis. The two carbazole derivatives were identified as the neuronal cell protecting compounds CS-79B and carquinostatin A, recently isolated from a wild-type of S. exfoliatus. We found that both substances showed antibacterial activity.

[Leptin--an interim evaluation]. / Leptin--eine Zwischenbilanz.

The discovery of leptin, the product of the obese (ob)-gene, has broadened the horizons of research on energy balance. This hormone, produced and secreted by adipose tissue and some placental cells, finds its way to the hypothalamus, where it binds to the leptin receptors and signals satiety through the neuroendocrine axis. The fact that adipose tissue is not merely a storage depot, but also an important endocrine tissue, has revived the interest in the "lipostatic" theory of body fat regulation and has initiated many research efforts in the field of obesity, anorexia nervosa, bulimia, reproduction and haematology.

The National Institutes of Health Anticonvulsant Drug Development Program: screening for efficacy.

The procedures employed by the ASP provide detailed information pertaining to the anticonvulsant profile of new candidate substances. In addition, the results obtained from tolerance and liver microsomal studies furnish critical information for predicting whether tolerance and/or serious drug-drug interactions are likely to develop following long-term administration of a candidate substance. Finally, in vitro mechanism-of-action studies supply preliminary information regarding the site of action of promising new anticonvulsant drugs. It is anticipated that the testing protocol outlined above will identify safer and mechanistically novel substances to enhance significantly the quality of life of those epilepsy patients still suffering from uncontrolled seizure disorders and/or experiencing significant adverse drug effects.

Short-term immunotherapy: a prospective, randomized, double-blind, placebo-controlled multicenter study of molecular standardized grass and rye allergens in patients with grass pollen-induced allergic rhinitis.

BACKGROUND: Short-term immunotherapy (STI) can be beneficial for patients who are noncompliant with long-term specific immunotherapy. OBJECTIVE: The efficacy and tolerance of STI with seven preseasonal injections of molecular standardized allergens from grass and rye pollen has been investigated in a double-blind, placebo-controlled multicenter study with 87 patients at 12 German University hospitals. METHODS: Symptoms of the eyes, nose, and bronchi and use of symptomatic drugs were documented daily in diaries by patients with allergic rhinitis to grass and/or rye pollen and without bronchial asthma. Patients were monitored by skin prick test titration and measurement of levels of specific IgE and IgG4. RESULTS: The median nasal score for the 10 weeks with the strongest symptoms during the grass pollen season was significantly lower (p = 0.014) with 35.0 for STI (n = 41) versus 69.0 for placebo (n = 40); the overall symptom score was 54.0 for STI versus 97.5 for placebo (p = 0.020). Only STI-treated patients exposed to less than 40 pollen grains per cubic meter per week showed a significantly lower nasal symptom score of 39.0 versus 75.0 for placebo (p = 0.006); these patients also had fewer nasal symptoms and less use of topical nasal drugs (p < 0.001). The threshold dose in skin prick tests was significantly higher, being 9.06 histamine equivalent for skin prick test (HEP) for STI-treated patients who received the maximum dose (n = 22) versus 4.33 HEP for placebo (p = 0.005). Specific IgE levels were significantly higher, being 55.9 SU/ml for STI versus 39.2 SU/ml for placebo after seven injections (p = 0.006) and level of specific IgG4 was 5.36% for STI versus 1.28% for placebo (p < 0.001). No severe systemic reactions were observed. CONCLUSION: STI with seven preseasonal injections with molecular standardized allergens is effective and well tolerated.

Quantitative salivary gland scintigraphy in the diagnosis of parenchymal damage after treatment with radioiodine.

This study was undertaken to quantify salivary gland parenchymal damage after radioiodine treatment with a standard protective regimen of ascorbic acid. Altogether, 106 patients underwent quantitative salivary gland scintigraphy with 99Tcm-pertechnetate prior to and 3 months after radioiodine therapy. Parenchymal function was quantified by calculating 99Tcm-pertechnetate uptake 13 min post-injection. Patients received 131I doses ranging from 400 MBq to 24 GBq (cumulative). Among the patients who received large doses of 131I, severe parenchymal destruction could be visually analysed as well as quantitatively evaluated. In contrast, after low-dose radioiodine treatment, mild parenchymal impairment was demonstrated by quantitative evaluation only. In conclusion, standardized quantitative salivary gland scintigraphy is essential for the reliable detection of mild parenchymal malfunction. Despite the standard protection regimen using ascorbic acid as a sialogogue, radioiodine therapy induces loss of salivary gland parenchymal function even with low doses of 131I.

Construction, expression, and immunogenicity of chimeric HIV-1 virus-like particles.

The group-specific antigens Pr55gag of human immunodeficiency virus type-1 (HIV-1) self-assemble into noninfectious virus-like particles (VLP) that are released from various eucaryotic cells by budding. Deletion analysis of Pr55gag mutants revealed three domains into which sequences of the third variable domain V3 or the CD4-binding domain of the gp120 external glycoprotein can be inserted without destroying the capacity of the chimeric proteins to assemble to VLP. Immunization of rabbits with different types of purified chimeric VLP without adjuvants raised a strong antibody response to the Pr55gag carrier component. The magnitude of the antibody response to the inserted gp 120 epitopes strictly depended on their position within the gag polyprotein. These antisera exhibited only weak neutralizing activity. However, BALB/c mice immunized by different routes with different types of chimeric Pr55gag/V3 VLP without adjuvants developed a strong MHC class I (Dd)-restricted, cytolytic CD8+ T-cell (CTL) reactivity against a known epitope within the V3 domain. When the recombinant antigen was emulsified in mineral oil (incomplete Freund's adjuvant) or adsorbed in aluminium hydroxide, its immunogenicity for CTL was drastically reduced or completely abrogated. The magnitude of the V3-specific CTL response was not influenced by the position of the V3 domain within the Pr55gag-carrier moiety; the flanking residues, hence, did not influence processing of the exogenous antigen for MHC class I-restricted peptide presentation. These results indicate ways for the rational design and optimal delivery of CTL-stimulating HIV candidate vaccines.

In vivo P-31-MR-spectroscopy of focal hepatic lesions. Effectiveness of tumor detection in clinical practice and experimental studies of surface coil characteristics and localization technique.

RATIONALE AND OBJECTIVES: The influence of partial tumor sampling in a volume of interest (VOI) on the ratios of phosphorus metabolites was examined by localized phosphorus magnetic resonance spectroscopy (P-31-MRS). Experiments were performed to investigate the characteristics of the surface coil used and precession of spatial localization. METHODS: A total of 24 patients with liver metastases and 20 volunteers were studied by P-31-MRS. Patients were divided in two groups: VOI < 50% (n = 8) and VOI > 50% (n = 16) occupied by tumor. For evaluation of the surface coil and localization method (image selected in vivo spectroscopy), phantom studies were performed. RESULTS: Superficial focal liver tumors were detectable with a surface coil at a distance within the coil radius. The image selected in vivo spectroscopy permitted the study of phosphorus metabolism in a defined VOI, phosphomonoester/beta-adenosine triphosphate and phosphodiester/beta-adenosine triphosphate were elevated significantly in spectra of both patient groups. CONCLUSIONS: Detection of small tumor volumes within a VOI filled by less than 50% of the tumor is possible, with results statistically different from that in normal volunteers.

Investigation of genotoxic effects of the anti-asthmatic and anti-inflammatory drugs Apocynin and Acetosyringenin in the Salmonella typhimurium mutagenicity assay and the SCE-test with human lymphocytes.

We examined the possible genotoxicity of the recently isolated or developed anti-asthmatic and anti-inflammatory substances Apocynin (CAS 498-02-2) and Acetosyringenin (CAS 2478-38-8) using short term test systems. Apocynin is a constituent of Picrorhiza kurroa, a plant from the Himalaya region. Acetosyringenin is its methoxylated synthetic derivative. The test systems used were the Salmonella typhimurium mutagenicity assay (Ames test) with the tester strains TA 97, TA 98, TA 100, and TA 102, and the sister chromatid exchange assay (SCE-Test) performed with human peripheral lymphocytes. The genetic endpoints covered by these test systems are the induction of gene mutations and the induction of SCEs, which is interpreted as an indicator for DNA-damaging properties of the test compound. The results obtained with Apocynin and Acetosyringenin do not demonstrate genotoxic activities of these compounds regarding the investigated endpoints.

Immunization of chimpanzees with the HIV-1 glycoprotein gp160 induces long-lasting T-cell memory.

The goal of the present study was to investigate the antigen-specific T-cell response to the recombinant HIV envelope glycoprotein (gp160) and to test the effect of various adjuvant formulations on the efficiency of T-cell priming as well as on magnitude and longevity of the gp160-specific T-cell response. Our studies revealed that, in combination with an appropriate adjuvant (lipid-based adjuvant or mineral carrier complex), immunization with recombinant gp160 led to the appearance of gp160-primed T cells. The T-cell response obtained was substantial (proliferative response of greater than 100,000 delta dpm after one primary and two booster immunizations), gp160-specific (proliferation only in response to gp160, no proliferation after addition of a mock gp160 preparation), and long-lasting (T cell responses of greater than 50,000 delta dpm were observed more than one year after the last booster). The results presented here differ from those of previous studies in that they show the presence of substantial and long-lasting T-cell memory toward the immunogen gp160. Therefore further investigations on the use of these preparations as HIV candidate vaccines appear to be justified.

[Effectiveness of various combination therapies in patients with coronary heart disease]. / Effektivität verschiedener Kombinationstherapien bei Patienten mit koronarer Herzerkrankung.

There is only a limited number of studies available comparing the effectiveness of various combinations of anti-ischemic and antianginal substances in the same patients with coronary artery disease and stable angina pectoris and even these are restricted to either only a few drugs or a single point in time for testing. Accordingly, this study was undertaken to determine to what extent the combination of two or three drugs with different anti-ischemic mechanisms of action such as the long-acting form of the beta-blocker metoprolol and isosorbide dinitrate (ISDN) in sustained-release form as well as the calcium channel blockers nisoldipine and diltiazem in sustained-release form, which previously have not been tested in combination, are capable of enhancing effectiveness and prolonging duration of action. In a double-blind, randomized, crossover study in eleven patients with documented coronary artery disease and stable angina pectoris the effects of monotherapy with 200 mg metoprolol in long-acting form were compared with those of combined treatment with 120 mg ISDN sustained-release or 10 mg nisoldipine or 120 mg diltiazem sustained-release as well as ISDN and nisoldipine and finally, ISDN and diltiazem by means of an intraindividual analysis. For assessment of anti-ischemic and antianginal effects, symptom-limited exercise testing was carried out before as well as three, eight, twelve and 24 hours after medication. The parameters analyzed were ST-segment depression at the highest comparable workload, ischemia-free and symptom-free exercise capacity (one minute prior to ST-segment depression of 1 mm or onset of angina pectoris) as well as the systolic blood pressure--heart rate product at the highest comparable workload and at the highest ischemia-free workload, that is one minute prior to an ischemic reaction of 1 mm. Based on the ST-segment depression, all combinations of two drugs (metoprolol and ISDN at three hours; metoprolol and diltiazem at eight hours) led to a significant or at least relative increase of effectiveness. On comparison of the various double combinations, those with nisoldipine showed an early dissipation of action which, twelve hours after administration, was significantly less marked than those with diltiazem. Of the two tested triple combinations, metoprolol, ISDN and diltiazem was either significantly more effective than the various double combinations (metoprolol and ISDN or metoprolol and nisoldipine, both at eight and twelve hours; metoprolol and diltiazem, twelve hours) or relatively more effective and showed clear prolongation of the effects in excess of twelve hours.(ABSTRACT TRUNCATED AT 400 WORDS)