Evaluation of oxidative stress and genetic instability among residents near mobile phone base stations in Germany.

Human exposure to radiofrequency electromagnetic fields (RF-EMF) is restricted to prevent thermal effects in the tissue. However, at very low intensity exposure "non-thermal" biological effects, like oxidative stress, DNA or chromosomal aberrations, etc. collectively termed genomic-instability can occur after few hours. Little is known about chronic (years long) exposure with non-thermal RF-EMF. We identified two neighboring housing estates in a rural region with residents exposed to either relatively low (control-group) or relatively high (exposed-group) RF-EMF emitted from nearby mobile phone base stations (MPBS). 24 healthy adults that lived in their homes at least for 5 years volunteered. The homes were surveyed for common types of EMF, blood samples were tested for oxidative status, transient DNA alterations, permanent chromosomal damage, and specific cancer related genetic markers, like MLL gene rearrangements. We documented possible confounders, like age, sex, nutrition, life-exposure to ionizing radiation (X-rays), occupational exposures, etc. The groups matched well, age, sex, lifestyle and occupational risk factors were similar. The years long exposure had no measurable effect on MLL gene rearrangements and c-Abl-gene transcription modification. Associated with higher exposure, we found higher levels of lipid oxidation and oxidative DNA-lesions, though not statistically significant. DNA double strand breaks, micronuclei, ring chromosomes, and acentric chromosomes were not significantly different between the groups. Chromosomal aberrations like dicentric chromosomes (p=0.007), chromatid gaps (p=0.019), chromosomal fragments (p<0.001) and the total of chromosomal aberrations (p<0.001) were significantly higher in the exposed group. No potential confounder interfered with these findings. Increased rates of chromosomal aberrations as linked to excess exposure with ionizing radiation may also occur with non-ionizing radiation exposure. Biological endpoints can be informative for designing exposure limitation strategies. Further research is warranted to investigate the dose-effect-relationship between both, exposure intensity and exposure time, to account for endpoint accumulations after years of exposure. As established for ionizing radiation, chromosomal aberrations could contribute to the definition of protection thresholds, as their rate reflects exposure intensity and exposure time.

PMA - Zeolite (Clinoptilolite) in the Management of Irritable Bowel Syndrome - a Non-Interventional Study.

In clinical practice, the treatment of patients with irritable bowel syndrome (IBS) can be very challenging. The aims of the present non-interventional study (NIS) were to investigate the tolerability and efficacy of PMA-zeolite under everyday conditions in patients with diarrheic IBS type (IBS-D) or constipated type (IBS-C) or mixed type (IBS-M). METHODS: To document prospective data on tolerability and symptom frequency in the frame of a nationwide NIS, we recruited 204 IBS patients. The study focused on the IBS-related quality of life (measured by the SF-36 questionnaire) and improvements of IBS-related symptoms according to specific ROM-III criteria and stool consistency (Bristol stool scale). The participants documented their abdominal pain, bloating, number of bowel movements, and stool consistency through a web-based internet platform (initial and exit questionnaires) and daily diary entries over the period of intake (8 weeks). RESULTS: A total of 82.2% of the recruited patients had filled in the questionnaires before and after the 8-week treatment with PMA-zeolite. Seven of the eight subscales of the SF-36 improved significantly (p<0,001); the reduction in abdominal pain was especially significant (p<0,001). The diary entries confirmed the reduction in abdominal pain and revealed a significant reduction in days with bloating (p<0,001). The Bristol-stool-scale analysis showed improvements; particularly, patients with IBS-D benefited from the treatment (p<0,001). CONCLUSION: The treatment duration of 8 weeks was well tolerated by most patients. Under everyday life conditions, PMA-zeolite alleviated the global IBS-related symptoms and raised the quality of life (QOL). The PMA-zeolite, thus, may represent a good adjuvant therapeutic option for patients with irritable bowel syndrome.

Supplementation of Caricol®-Gastro reduces chronic gastritis disease associated pain.

OBJECTIVE: Papaya and oats are natural food and used in traditional medicine in many parts of the world. Papaya has a high content of enzymes supporting digestive function. Oats are a source of minerals, beta-glucan fibres, immunmodulatory and antiinflammatory probiotic substances. Caricol®-Gastro combines both constituents, it was designed as vegan organic preparation for intestinal inflammatory diseases. We performed a randomized, double blind placebo controlled clinical trial to investigate the potential of Caricol®-Gastro as add on therapy in patients with diagnosed chronic gastritis. METHODS: 60 Patients with endoscopically confirmed mild chronic disease were recruited. A structured interview documented the baseline data. Then the patients were allocated to the verum or placebo group by handing out a numbered study package with the study substance for the daily intake at home. A single dose was 20 g, taken twice per day. After 30 days the participants were interviewed again. RESULTS: After the intake phase the disease related symptoms were found improved in both groups, indicating a strong placebo effect. However, the pain load reduction in the Caricol®-Gastro group was significantly larger (p=0.048). DISCUSSION: Due to the inherent biological activities of ingredients of papaya and of oats and their known effects (anti-inflammatory, epithelial integrity), the observed beneficial effects may be owed to the constituents synergisms to reduce chronic inflammation. We conclude, that the regular intake is a safe add on therapeutic option for patients with chronic gastritis to support standard medical care.

Mood improving Potential of a Vitamin Trace Element Composition--A randomized, double blind, placebo controlled clinical study with healthy volunteers.

OBJECTIVES: Neurotransmitters regulate mood, attention vigilance and other clinical symptoms linked with depression. Various medications ameliorate symptoms of depression and mood disorders by interference with the serotonic metabolism. Serotonin metabolism depends on nutritional cofactors such as pyridoxin together with essential mineral and trace elements. Both, inflammation and metabolic conditions seem to affect the bioavailability of serotonin crucially. We hypothesized that serotonin supply depends on relevant gastrointestinal precursor absorption and on the availability of nutritive antiinflammatory cofactors. METHODS: We performed a randomized placebo controlled clinical trial in healthy participants to study the bioavailabilty of ingredients of the multivitamin and trace element LaVita' in a prospective randomized placebo controlled double blind trial to establish the mood ameliorating potential. Serotonin and its precursor tryptophan were measured in dry blood samples. Serum parameters like chromium and zinc, as well as vitamin D, vitamin B3 and B6 were determined before intake, and after 3 months and 6 months consumption of the test substances. RESULTS: After 3 months a slight increase of tryptophan (p=0.059) and a significant increase of serum serotonin (p < 0.013) was observed in the verum group. After 6 months the verum group showed a highly significant mean increase in niacin (p < 0.001) and the cofactors of serotonin metabolism pyridoxin (p=0.03), chromium p < 0.01), and zinc (p < 0.001). Serotonin levels droped after 6 months indicating a low risk for overdosing. CONCLUSION: We conclude that a continuous supply with ingredients from the natural source compound LaVita' may contribute to mood improving neurotransmitter activity.

Prevention of "nitrosative stress" by a nutritional supplement (LaVita®) - a randomized placebo controlled double blind clinical trial with healthy volunteers.

BACKGROUND: A common pathomechanism involved in many degenerative manifestations of non-communicable diseases is nitrosative stress, giving rise to a chronic insidious inflammation causing silent inflammation at a cellular level. The release of nitric oxide inhibits multiple enzyme reactions with reduced oxidative phosphorylation and mitochondrial ATP depletion. MATERIAL AND METHODS: We hypothesized that enzyme-inhibition can be alleviated by micronutrient supply, and studied laboratory parameters associated with nitrosative stress (nitrotyrosine, mitochondrial activity) after a micronutrient supplementation (a multivitamin mineral and trace element formulation as verum: LaVita®) and a placebo in healthy volunteers (n=150) for six months. RESULTS: Mean nitrotyrosine levels dropped significantly after 3 month in the verum and placebo group, whereas mitochondrial activity increased after three month in the verum group (p=0,087), but not in the placebo group (p=0,990). Ubiquinone - an essential ingredient for mitochondrial function- increased after six months in the verum group, but not after placebo consumption (p=0,001). Serum zinc and cellular zinc increased steadily after 3 and 6 month verum intake (p<0,001). As the enzyme superoxide dismutase (SOD) is mainly involved in the formation of nitrosative stress (peroxides) we measured the activity, and found significant differences in the placebo and verum group after 3 and 6 month (p=0,050 and p=0,003 respectively). CONCLUSION: We conclude that a balanced combination of vital nutrients may reduce nitrosative stress and silent inflammation, and consequently the risk for various forms of degenerative diseases.

Bioavailabilty of a liquid Vitamin Trace Element Composition in healthy volunteers.

BACKGROUND: Many Vitamins and minerals for dietary supplements lack a standard scientific and regulatory definition that accurately reflects the bioavailabilities in humans. Especially the bioavailability of natural compounds in complex mixtures, where the different ingredients may interfere with each other, is unknown. METHODS: To learn more about the bioavailability of the ingredients in the complex compound LaVita® we examined blood levels of subjects, who ingested the multivitamin and trace element composition for 6 month continuously. Blood samples for the analysis of the ingredients were taken before, during, and after administration. RESULTS: Our data indicated a significant increase of most ingredients after 3 month, and additional three months, except for Vitamin (B9 Folic acid). The semivitamins Q10 and carnitine increased in the first 3 month (both p<0.001). While carnitine dropped during the second term, Q10 levels increased further slowly. After three months a significant increase was observed for iron (serum p=0.039; blood cells p=0.025), Selenium (serum p=0.048; cells p=0.006), and chromium (serum p=0.029). Zinc - known to interfere with the iron resorption - increased slowly in the first term of 3 months, but was raised significantly after 6 months (serum and blood cells, each p<0.001). The Copper/Zink ratio dropped accordingly (p<0.001). CONCLUSION: We conclude that resorption interference between specific ingredients, and after resorption redistribution of specific ingredients to various tissue compartments precludes a linear increase of the respective serum parameters. We observed no deleterious resorption competitions for individual compounds. No parameter reached critical levels. We conclude that the test substance (LaVita®) is a sufficiently safe composite for long term consumption.

Neuroprotective impact of a vitamin trace element composition - a randomized, double blind, placebo controlled clinical trial with healthy volunteers.

OBJECTIVES: Neurotoxic metabolites and oxidative and nitrosative stress reactions play a crucial role in the pathways leading to neuronal cell death and neurodegeneration. The bioavailability of the many antioxidant ingredients a vitamin and trace element composition was investigated, to reveal the neuroprotective (preventive) potential of the composition. METHODS: We recruited 159 healthy volunteers, assigned them randomly and double blind to a placebo and verum group. Physicians excluded volunteers with severe chronic diseases or interfeering medications. 142 participants finished the six month trial. Laboratory parameters were determined 1) before participation, and 2) after three and 3) six months. We confirmed the bioavailability of ingredients, and determined metabolic parameters associated with the integrity of the blood brain barrier, mitochondrial deficiency (Q 10), neurodegeneration (homocystein), and antioxidative capacity (e.g. lipidperoxidation), and superoxiddismutase activity. RESULTS: Starting from baseleine, after three months neuroprotective ingredients increased within their physiological borders, folic acid (p<0.003), pyridoxin (p<0.001), cobalamin (p=0.001), and the fat soluble vitamin tocopherol (p<0.001). In parallel, homocytein decreased after 3 and 6 months (p<0.001, and p<0.025, respectively). Other paramters like zinc reacted slower, significant changes were observed only after 6 months. CONCLUSION: The observed metabolic changes and alteration of the oxidative status after 3 and six month of regular intake underlines the compositions' potential to ameliorate neurodegenerative processes. We conclude that the subsitution of vitamins and trace-elements with natural source in a proper manner may be effective for neuroprotection in healthy population.

Papaya preparation (Caricol®) in digestive disorders.

OBJECTIVE: Papaya (Carica papaya L.) is used as a natural remedy in abnormal digestion in tropical and industrialized countries. Besides this wide distribution little evidence has been produced with reference to its physiological effect in humans and the proof of efficacy. Former clinical observations had revealed positive effects for patients with constipation, heartburn, and symptoms of irritable bowel syndrome (IBS) after eating papaya preparations. In line with these former positive clinical observations, we studied the clinical effects of the papaya preparation Caricol® in a double blind placebo controlled study design. METHODS: In this study the participants were volunteers, with chronic (prevailing) indigestions and dysfunctions in the gastrointestinal tract. During the trial the intake of the substance of intent and placebo was 20 ml daily for 40 days. The endpoints were the frequency of 22 symptoms recorded before and after the documented intake recorded by questionnaire. RESULTS: The symptoms "Constipation", "Bloating", and "Heartburn" were defined as primary and frequency of "painful (straining) bowel movements" as secondary endpoint. The participation ended after the intake period within two days ("early returnees"). Wash out effects were observed in "late returnees", who returned with a delay of 8.6 (±5.95 days). In the verum group early returnees revealed statistically significant improvements of the symptoms "constipation" and "bloating". The analysis of "heartburn" felt short of significant improvement because of the small number of included cases with this criteria (N=13, p=0.114). None of the significant benefits were observed after the washout phase. CONCLUSION: We conclude from these results, that the papaya preparation (Caricol®) contributes to the maintenance of digestive tract physiology. It ameliorates various functional disturbances, like symptoms of IBS. The mechanism of this digestive tract physiology support is discussed.

PMA-zeolite can modulate inflammation associated markers in irritable bowel disease - an explorative randomized, double blinded, controlled pilot trial.

OBJECTIVES: Preclinical and clinical data suggest, that the microporous mineral with large inner surface and ion exchanger capability PMA-(Panaceo-micro-activation)-zeolite can bind irritating and inflammation associated chime-constituents. We hypothesised whether or not it can ameliorate subclinical inflammation, and investigated the potential in the management of patients with Irritable Bowel syndrome (IBS). METHODS: The trial design was prospective, randomized, controlled, double-blinded, pilot study with 41 patients. They received orally 3 g of the medicinal product PMA-zeolite or microcrystalline cellulose (control) twice a day. At baseline and after three months the symptom load, blood and stool parameters, like high sensitivity C-reactive protein (hsCRP), zonulin, α1-antitrypsin, interleukin IL-10, and changes in the gut microbiome were determined by means of ANOVA, ANCOVA and non parametric statistical analyses. RESULTS: The IBS-associated symptom scores decreased significantly in both groups (p=0,001) indicating a strong placebo effect. In the verum but not in the placebo group various inflammation related laboratory parameters decreased. The gross statistical comparison revealed a reduction of α1-antitrypsin significant (p=0,037), a lowered inflammation marker hsCRP, paralleled specific microbiome changes (Lactobacillus, Bifidobacteria, and Firmicutes). CONCLUSIONS: The decrease of blood hsCRP and decreased stool α1-antitrypsin suggest that PMA-zeolite possibly can lower inflammation in the gut of IBS patients. The corresponding increase of the immune modulating species Bifidobacteria and Lactobacillus and the reduction of Firmicutes also point at an inflammation ameliorating effect and a possible mucous layer strengthening effect. The protocol of this explorative pilot study is feasible for a sufficiently powered trial on inflammation amelioration in IBS patients.

Increased protein synthesis by cells exposed to a 1,800-MHz radio-frequency mobile phone electromagnetic field, detected by proteome profiling.

PURPOSE: To investigate whether or not low intensity radio frequency electromagnetic field exposure (RF-EME) associated with mobile phone use can affect human cells, we used a sensitive proteome analysis method to study changes in protein synthesis in cultured human cells. METHODS: Four different cell kinds were exposed to 2 W/kg specific absorption rate in medium containing 35S-methionine/cysteine, and autoradiography of 2D gel spots was used to measure the increased synthesis of individual proteins. RESULTS: While short-term RF-EME did not significantly alter the proteome, an 8-h exposure caused a significant increase in protein synthesis in Jurkat T-cells and human fibroblasts, and to a lesser extent in activated primary human mononuclear cells. Quiescent (metabolically inactive) mononuclear cells, did not detectably respond to RF-EME. Since RF exposure induced a temperature increase of less than 0.15 degrees C, we suggest that the observed cellular response is a so called "athermal" effect of RF-EME. CONCLUSION: Our finding of an association between metabolic activity and the observed cellular reaction to low intensity RF-EME may reconcile conflicting results of previous studies. We further postulate that the observed increased protein synthesis reflects an increased rate of protein turnover stemming from protein folding problems caused by the interference of radio-frequency electromagnetic fields with hydrogen bonds. Our observations do not directly imply a health risk. However, vis-a-vis a synopsis of reports on cells stress and DNA breaks, after short and longer exposure, on active and inactive cells, our findings may contribute to the re-evaluation of previous reports.

In vitro anti-cancer activity of two ethno-pharmacological healing plants from Guatemala Pluchea odorata and Phlebodium decumanum.

Many traditional healing plants successfully passed several hundred years of empirical testing against specific diseases and thereby demonstrating that they are well tolerated in humans. Although quite a few ethno-pharmacological plants are applied against a variety of conditions there are still numerous plants that have not been cross-tested in diseases apart from the traditional applications. Herein we demonstrate the anti-neoplastic potential of two healing plants used by the Maya of the Guatemala/Belize area against severe inflammatory conditions such as neuritis, rheumatism, arthritis, coughs, bruises and tumours. Phlebodium decumanum and Pluchea odorata were collected, dried and freeze dried, and extracted with five solvents of increasing polarity. We tested HL-60 and MCF-7 cells, the inhibition of proliferation and the induction of cell death were investigated as hallmark endpoints to measure the efficiency of anti-cancer drugs. Western blot and FACS analyses elucidated the underlying mechanisms. While extracts of P. decumanum showed only moderate anti-cancer activity and were therefore not further analysed, particularly the dichloromethane extract of P. odorata inhibited the cell cycle in G2-M which correlated with the activation of checkpoint kinase 2, and down-regulation of Cdc25A and cyclin D1 as well as inactivation of Erk1/2. In HL-60 and MCF-7 cells this extract was a very strong inducer of cell death activating caspase-3 followed by PARP signature type cleavage. The initiating death trigger was likely the stabilization of microtubules monitored by the rapid acetylation of alpha-tubulin, which was even more pronounced than that triggered by taxol. The dichloromethane extract of P. odorata contains apolar constituents which inhibit inflammatory responses and exhibit anti-cancer activity. The strong proapoptotic potential warrants further bioassay-guided fractionation to discover and test the active principle(s).

Potential of the multivitamin-mineral-trace element composition LaVita® before, during and after pregnancy.

OBJECTIVES: Pregnancy is a period in life with a high demand of micronutrients. A prophylactic supplementation of folic acid to reduce the risk of neurological malformations in the newborn is common practice. The array of essential micronutrients during pregnancy includes neurotropic vitamins (Vitamin B6, B12 and folic acid), minerals like iron, and trace elements like zinc. As the serum level of most micronutritients is actively regulated by the organism, a prophylactic broad supplementation with a mild, but effective supplementation typically does not pose any risk for exaggerated serum levels, therefore prophylactic intake may be prefered to blood screening and specific interventions. METHODS: To investigate the ingredients' bioavailability of the complex vitamin-mineral-trace element composition LaVita® we recruited healthy volunteers for six months and observed the changes of pregnancy relevant parameters by means of laboratory measures. The study design was prospective, double blind, placebo controlled, and included a "male group control". We determined baseline parameters of folate, vitamin B6 and vitamin B12, iron, zinc, homocysteine and Hb-alpha-1c. After three and six months of daily intake of the study substance the blood tests were repeated and compared to the baseline levels. RESULTS: The regular intake resulted in an increase of the supplemented substances' serum levels. The metabolic parameter homocysteine decreased significantly, Hb-alpha-1c was slightly lowered. CONCLUSION: The regular intake filled up the respective storage compartments and reservoirs in the tissues, and improved the metabolic status. Female participants tended to benefit more than male. We conclude that the composition is safe, and warrants optimized micronutrient supply during pregnancy or postnatal breastfeeding.

[Achtsame Massage und Achtsamkeitsschulung (Insightouch®) bei Depressionen, psychosomatischen und Bindungsstörungen].

Hintergrund: Bindungsstörungen können das Auftreten von Angst und Depression begünstigen, lassen sich aber durch korrigierende emotionale Erfahrungen verändern. Eine Massage - insbesondere wenn beide, Masseur (m/w) und Klient, sich in einem Zustand der Achtsamkeit befinden - kann eine solche korrigierende Erfahrung vermitteln. In der vorliegenden Interventionsstudie wurden die Auswirkungen von Insightouch® - einer Kombination von achtsamkeitsbasierter Massage mit Achtsamkeitsschulung - untersucht. Teilnehmer und Methoden: Wir rekrutierten 36 Personen mit psychischen Beschwerden, geringer Bindungsfähigkeit und geringer Achtsamkeit. In Intervallen von 8 Wochen wurden mittels validierter Fragebögen Parameter wie psychosomatische Symptome (Brief Symptom Inventory), Bindungsqualitäten (Adult Attachment Scale) und Achtsamkeit (Freiburger Achtsamkeitsfragebogen) erhoben. Die Hälfte der Teilnehmer (Gruppe A) startete mit der 8-wöchigen Behandlungsphase; nach weiteren 8 Wochen ohne Behandlung wurde die Nachhaltigkeit der Behandlungswirkung dokumentiert. Die Teilnehmer der Gruppe B starteten mit einer 8-wöchigen Wartephase (Kontrollphase ohne Behandlung), gefolgt von der Behandlungsphase. Ergebnisse: Während sich nach der Kontrollphase keine signifikanten Änderungen zeigten, bewirkte die aktive Behandlung statistisch signifikante Besserungen der 1) Symptomatik, 2) Bindungsdefizite und 3) Achtsamkeit. Nach der 8-wöchigen Nachbeobachtungsphase waren die psychischen und die bindungsbezogenen Symptome weiter verbessert; die behandlungsbedingt erhöhte Fähigkeit zur Achtsamkeit blieb hoch. Schlussfolgerung: Insightouch als primär nonverbale Intervention erhöht die Bindungsfähigkeit, verbessert psychosomatische Symptome und erhöht nachhaltig die Fähigkeit zur Achtsamkeit.

Association of vasoactive intestinal peptide with polymer-grafted liposomes: structural aspects for pulmonary delivery.

A polymer-grafted liposomal formulation that has the potential to be developed for aerosolic pulmonary delivery of vasoactive intestinal peptide (VIP), a potent vasodilatory neuropeptide, is described. As VIP is prone to rapid proteolytic degradation in the microenvironment of the lung a proper delivery system is required to increase the half-life and bioavailability of the peptide. Here we investigate structural parameters of unilamellar liposomes composed of palmitoyl-oleoyl-phosphatidylcholine, lyso-stearyl-phosphatidylglycerol and distearyl-phosphatidyl-ethanolamine covalently linked to polyethylene glycol 2000, and report on VIP-lipid interaction mechanisms. We found that the cationic VIP is efficiently entrapped by the negatively charged spherical liposomes and becomes converted to an amphipathic alpha-helix. By fluorescence spectroscopy using single Trp-modified VIP we could show that VIP is closely associated to the membrane. Our data suggest that the N-terminal random-coiled domain is embedded in the interfacial headgroup region of the phospholipid bilayer. By doing so, neither the bilayer thickness of the lipid membrane nor the mobility of the phospholipid acyl chains are affected as shown by small angle X-ray scattering and electron spin resonance spectroscopy. Finally, in an ex vivo lung arterial model system we found that liposomal-associated VIP is recognized by its receptors to induce vasodilatory effects with comparable high relaxation efficiency as free VIP but with a significantly retarded dilatation kinetics. In conclusion, we have designed and characterized a liposomal formulation that is qualified to entrap biologically active VIP and displays structural features to be considered for delivery of VIP to the lung.

Liposomal vasoactive intestinal peptide for lung application: protection from proteolytic degradation.

Inhalative administration of vasoactive intestinal peptide (VIP) is a promising approach for the treatment of severe lung diseases. However, the clinical use of VIP is limited by the fact that the peptide is prone to rapid degradation mechanisms and proteolytic digestion. Accordingly, VIP exhibits a very short period of activity in the lung. To overcome this problem, we have designed a liposomal drug delivery system for VIP and characterized it in terms of its potential to protect VIP from enzymatic cleavage. The proteolytic conditions of the lung, the target site of aerosolic administered VIP, were mimicked by bronchoalveolar lavage fluid (BALF), a lung surfactant solution, obtained by fiberoptic bronchoscopy. Thus, the stability of VIP was assessed by its resistance to enzymatic degradation in BALF, using a combination of high pressure liquid chromatography with mass spectrometry. We found that free VIP was rapidly digested, whereas liposomal-associated VIP remained intact. By fluorescence spectroscopic techniques using fluorescent-labelled VIP we got strong indications that the tight association of VIP with the lipid membrane is only minimally affected upon incubation with BALF. Loading capacity and stability of EtCy3-VIP loaded liposomes were measured by fluorescence fluctuation spectroscopy. Finally, the protective properties of the liposomes were also expressed in the maintained biological activity of the peptide incubated with BALF.

Inhalable liposomal formulation for vasoactive intestinal peptide.

Inhalation of vasoactive intestinal peptide (VIP) was suggested as promising treatment option of various lung diseases like asthma and pulmonary hypertension. However, the medical use of peptides is limited by their short half-life due to rapid enzymatic degradation in the airways. For that reason, we recently developed unilamellar nano-sized VIP-loaded liposomes (VLL). Now we investigated their applicability for inhalation purposes. After nebulisation by a mouthpiece ventilation inhaler we found the particle size almost unaffected, being in a size range appropriate for bronchiolar deposition; we observed no peptide release due to nebulisation. The VIP release kinetics from VLL were tested by an ex vivo vasorelaxation model. Exposure to target organs revealed an immediate response, which was significantly retarded for VLL as compared to free VIP (p=0.001). Using vasorelaxation as endpoint, we observed a sustained release and an extended pharmacological effect compared to equimolar free VIP. The liposomes have the potential to improve VIP inhalation therapy by providing a "dispersible peptide depot" in the bronchi. Thereby, the release of VIP from liposomes may be triggered by exposure to cells, i.e. directly by ligand-receptor interactions.

Facial esthetics and the assignment of personality traits before and after orthognathic surgery rated on video clips.

Typically, before and after surgical correction faces are assessed on still images by surgeons, orthodontists, the patients, and family members. We hypothesized that judgment of faces in motion and by naïve raters may closer reflect the impact on patients' real life, and the treatment impact on e.g. career chances. Therefore we assessed faces from dysgnathic patients (Class II, III and Laterognathia) on video clips. Class I faces served as anchor and controls. Each patient's face was assessed twice before and after treatment in changing sequence, by 155 naïve raters with similar age to the patients. The raters provided independent estimates on aesthetic trait pairs like ugly /beautiful, and personality trait pairs like dominant /flexible. Furthermore the perception of attractiveness, intelligence, health, the persons' erotic aura, faithfulness, and five additional items were rated. We estimated the significance of the perceived treatment related differences and the respective effect size by general linear models for repeated measures. The obtained results were comparable to our previous rating on still images. There was an overall trend, that faces in video clips are rated along common stereotypes to a lesser extent than photographs. We observed significant class differences and treatment related changes of most aesthetic traits (e.g. beauty, attractiveness), these were comparable to intelligence, erotic aura and to some extend healthy appearance. While some personality traits (e.g. faithfulness) did not differ between the classes and between baseline and after treatment, we found that the intervention significantly and effectively altered the perception of the personality trait self-confidence. The effect size was highest in Class III patients, smallest in Class II patients, and in between for patients with Laterognathia. All dysgnathic patients benefitted from orthognathic surgery. We conclude that motion can mitigate marked stereotypes but does not entirely offset the mostly negative perception of dysgnathic faces.

Vasoactive intestinal peptide gene alterations in patients with idiopathic pulmonary arterial hypertension.

Pulmonary arterial hypertension is a progressive disease, characterised by increased proliferation of pulmonary artery smooth muscle cells, vasoconstriction and remodelling of the vascular wall leading to right heart failure and death. The idiopathic form is rare (idiopathic arterial primary hypertension (IPAH); formerly PPH, MIM# 178600). Our group correlated a deficiency in vasoactive intestinal peptide (VIP; MIM# 192320) levels in serum and lung tissue with the pathogenesis of IPAH. The aim of this study was to investigate the relevance of genetic alterations in VIP to the development of IPAH. We screened 10 patients (age 4-66 years) for alterations in the coding, the noncoding regions and the enhancer region of the VIP gene by direct sequencing. In eight of 10 patients, we found alterations compared to the wild-type sequence. We detected nine alterations. In the noncoding regions, eight alterations were in the introns 1, 2, 3 and 4 (g.448G>A g.501C>T g.764T>C g.2267A>T g.2390C>T g.3144T>C g.3912A>G g.4857A>G). In the coding regions, a single alteration in the 3' untranslated region in exon 7 (g.8129T>C) was observed in five patients. It appeared in 46% of the control group. The frequency of this alteration in the coding region of the VIP gene could therefore not be correlated with the appearance of IPAH. Apart from the importance of VIP signalling, genetic and/or environmental modifiers might therefore contribute to the development and perpetuation of the disease.

Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension.

Primary pulmonary hypertension is a fatal disease causing progressive right heart failure within 3 years after diagnosis. We describe a new concept for treatment of the disease using vasoactive intestinal peptide, a neuropeptide primarily functioning as a neurotransmitter that acts as a potent systemic and pulmonary vasodilator. Our rationale is based on the finding of a deficiency of the peptide in serum and lung tissue of patients with primary pulmonary hypertension, as evidenced by radioimmunoassay and immunohistochemistry. The relevance of this finding is underlined by an upregulation of corresponding receptor sites as shown by Northern blot analysis, Western blot analysis, and immunological techniques. Consequently, the substitution with the hormone results in substantial improvement of hemodynamic and prognostic parameters of the disease without side effects. It decreased the mean pulmonary artery pressure in our eight study patients, increased cardiac output, and mixed venous oxygen saturation. Our data provide enough proof for further investigation of vasoactive intestinal peptide and its role in primary pulmonary hypertension.

Involvement of endothelial NO in the dilator effect of VIP on rat isolated pulmonary artery.

The endothelium and its interaction with smooth muscle play a central role in the local control of the pulmonary vasculature, and endothelial dysfunction is thought to contribute to pulmonary hypertension and chronic obstructive pulmonary disease. Vasoactive intestinal peptide (VIP), a 28-amino acid neuropeptide, relaxes the rat pulmonary artery, but there is controversy as to whether or not this action of VIP depends on the endothelium. The aim of this study, therefore, was to investigate the role of the endothelium and nitric oxide (NO), the major endothelium-derived relaxing factor, in the dilator action of VIP on the rat isolated pulmonary artery. Pulmonary artery preparations pre-contracted by the alpha(1)-adrenoceptor agonist L-phenylephrine were relaxed by VIP (0.003-1 microM) and acetylcholine (0.003-10 microM) in a concentration-dependent manner. Mechanical removal of the endothelium reduced the maximal response to VIP by about 50% and practically abolished the response to acetylcholine. Inhibition of NO synthesis by N(omega)-nitro-L-arginine methyl ester (0.5 mM) had a similar effect, abolishing the vasorelaxation caused by acetylcholine and attenuating the vasorelaxation caused by VIP by about 50%. From these data it is concluded that the relaxant action of VIP on the rat isolated pulmonary artery depends in part on the presence of the endothelium and that this part is mediated by endothelial NO.