Effects of Omega-3 Fatty Acids on Resting Cerebral Perfusion in Patients with Mild Cognitive Impairment: A Randomized Controlled Trial.

Alteration of cerebral perfusion can be considered as a possible therapeutic target in mild cognitive impairment. This randomized, placebo-controlled, double-blind proof-of-concept study assessed effects of omega-3 fatty acids on cerebral perfusion in patients with mild cognitive impairment. In thirteen patients (omega:n=5; placebo:n=8) cerebral perfusion was measured before and after 26-weeks intervention within posterior cortical regions using magnetic resonance imaging. There was a medium effect of intervention on cerebral blood flow (η2=0.122) and blood volume (η2=0.098). The omega group showed an increase in blood flow (mean difference: 0.02 [corresponds to 26.1%], 95% confidence interval:0.00-0.05) and blood volume (mean difference: 0.08 [corresponds to 18.5%], 95% confidence interval:0.01-0.15), which was not observed in the placebo group. These preliminary findings suggest that omega-3 fatty acids supplementation may improve perfusion in cerebral regions typically affected in mild cognitive impairment.Regulation of perfusion may help to maintain brain structure and function and potentially delay conversion to dementia.

Poly - (l) - glutamic acid drug delivery system for the intravesical therapy of bladder cancer using WGA as targeting moiety.

In the management of bladder cancer, surgical resection of the tumour is usually followed by intravesical instillation of immunomodulatives and/or chemotherapeutics. The purpose of this local intravesical therapy is to eliminate residual malignant cells after surgical intervention. The main limitation of a localised adjuvant therapy is the insufficient concentration of the active pharmaceutical ingredient (API) in malignant cells due to the unique structure of the human urothelium making it an exclusively hard to overcome barrier in the human body. Different strategies such as electromotive drug administration or local hyperthermia are employed to ameliorate intravesical drug uptake. Previous studies on biorecognitive targeting showed promising results for lectin-, especially wheat germ agglutinin (WGA), mediated drug delivery. Here, we present a targeted conjugate that provides enough binding sites for a possible API as well as high cytoadhesive and cytoinvasive potential. The conjugate should comprise the following components: First WGA, as the targeting moiety, second poly-l-glutamic acid (PGA) as a polymeric backbone providing more than 300 possible binding sites for an API and third fluorescein cadaverine (Fc), a fluorescent dye we coupled to PGA rendering the conjugate traceable. After purification via size exclusion chromatography (SEC) the WGA containing and therefore binding conjugate was isolated from the reaction mix. In flow-cytometric and fluorimetric experiments with single cells and cell monolayers, respectively, binding and internalisation of the conjugate representing a high molecular weight (>100kDa) could be demonstrated. Fluorescent PGA without the WGA component showed neither binding nor internalisation potential. Microscopic colocalization studies with cell monolayers and single cells confirmed the cytoadhesive and cytoinvasive potential of the WGA containing conjugate. In accordance with the results of specificity studies the interaction between the conjugate and the cell surface depended solely on the WGA component of the conjugate. With the help of this targeted drug delivery system limiting factors of intravesical adjuvant therapy could eventually be overcome and thereby treatment efficacy of instillative chemotherapy could be improved. In addition, traceable drug conjugates might bear interesting advantages for theranostic purposes in the treatment of bladder cancer.

Prospective association between the dietary inflammatory index and metabolic syndrome: findings from the SU.VI.MAX study.

BACKGROUND AND AIMS: The prevention of the metabolic syndrome (MetS) is of major concern and nutrition has been shown to modulate at least partly MetS risk. Our objective was to investigate whether a pro-inflammatory diet was associated with a higher risk of MetS and its components in a large cohort of French adults. METHODS AND RESULTS: A total of 3726 participants from the Supplémentation en Vitamines et Minéraux AntioXydants (SU.VI.MAX) cohort were included in this study. The MetS status was identified at baseline and after 13 years of follow-up using self-reported medication, data from clinical investigations and biological measurements. The dietary inflammatory index (DII) was computed using repeated 24 h-dietary records (n = 10.1 ± 3.1). Logistic and linear regression analyses were conducted to assess the prospective association of the DII (as Q, quartiles) with the incidence of MetS and with the traits contributing to the MetS-definition (blood pressure, glycaemia, triglycerides, HDL-cholesterol, waist circumference). A diet with pro-inflammatory properties, as expressed by higher DII scores, was significantly associated with a higher risk of developing the MetS (OR comparing Q4 to Q1: 1.39, 95% confidence interval 1.01-1.92, P = 0.047). Moreover, higher DII scores were associated with higher systolic and diastolic blood pressure (Ptrend across quartiles = 0.03 and 0.05, respectively) and triglycerides (Ptrend = 0.01), and with lower HDL-cholesterol (Ptrend = 0.03). CONCLUSION: A higher DII score was prospectively associated with a higher risk of MetS, with associations with blood pressure, triglycerides and HDL-cholesterol. Promotion of a healthy diet exhibiting anti-inflammatory properties may contribute to prevent cardio-metabolic disorders.

Innovative newborn health technology for resource-limited environments.

OBJECTIVES: To review medical devices addressing newborn health in resource-poor settings, and to identify existing and potential barriers to their actual and efficient use in these settings. METHODS: We searched Pubmed as our principal electronic reference library and dedicated databases such as Maternova and the Maternal and Neonatal Directed Assessment of Technology. We also researched standard public search engines. Studies and grey literature reports describing devices for use in a low- or middle-income country context were eligible for inclusion. RESULTS: Few devices are currently described in the peer-reviewed medical or public health literature. The majority of newborn-specific devices were found in the grey literature. Most sources described infant warmers, neonatal resuscitators, and phototherapy devices. Other devices address the diagnosis of infectious diseases, monitoring of oxygen saturation, assisted ventilation, prevention of mother-to-child transmission of HIV, assisted childbirth, weight or temperature assessment, and others. CONCLUSION: Many medical devices designed for newborns in the developing world are under development or in the early stages of production, but the vast majority of them are not available when and where they are needed. Making them available to mothers, newborns, and birth attendants in resource-limited countries at the time and place of birth will require innovative and creative production, distribution, and implementation approaches.

[Interdisciplinary recommendations for the treatment of metastatic renal cell carcinoma]. / Interdisziplinäre Empfehlungen zur Behandlung des metastasierten Nierenzellkarzinoms.

With the introduction of targeted therapies, a paradigm shift for the treatment of metastatic renal cell cancer has taken place. New compounds like sunitinib, sorafenib, bevacizumab and temsirolimus have become established as new therapeutic standards. An interdisciplinary consensus conference was held to discuss treatment sequences and open questions. Results from the 2007 conference provided the basis for the 2008 meeting. The results of the 2008 conference are presented as short theses.

[Prevention of prostate cancer]. / Prävention des Prostatakarzinoms.

Prostate cancer has become the most frequently diagnosed male cancer next to non-melanotic skin cancer in the Western world. Preventive measures would therefore have important potential effects on the incidence and prevalence of this disease. A potential for effective prevention of prostate cancer is currently seen in dietary changes and perhaps in dietary supplementation with vitamins D and E or selenium. Pharmacological prevention seems a possibility with drugs acting on intraprostatic testosterone metabolism. Several large randomised trials are ongoing to clarify the potential for successful prostate cancer prevention.

Lectin-mediated drug delivery: influence of mucin on cytoadhesion of plant lectins in vitro.

As the mucous layer represents the first barrier to peroral lectin-mediated drug delivery, the influence of mucin on the cytoadhesive properties of lectins was studied in vitro by establishing a rapid and simple microplate format assay using pig gastric mucin (PGM) for coating the wells. The lectin-binding capacity of mucin followed the order WGA>>UEA-I>>LCA=STL>PNA>DBA. The PGM-binding of wheat germ agglutinin (WGA) was strongly dependent on pH being highest at pH 5.0. In comparison, PGM-binding of WGA was about 15% at gastric pH and 60-70% at intestinal pH. This points to unimpeded gastric transit of WGA-grafted formulations and favorable conditions within the intestine for binding to mucus coated enterocytes. Moreover the WGA-PGM interaction was concentration-dependent, specific and fully reversible. According to a competitive assay in the presence of Caco-2 monolayers, the PGM-binding of WGA was saturated and influenced by the lectin-concentration yielding 28% Caco-2 bound WGA (125 ng WGA/0.29 cm(2) monolayer) and 68% Caco-2 bound WGA (4 microg WGA/0.29 cm(2) monolayer), respectively. Following on from these results, lectins are expected to suffer at least partially from premature inactivation by shed off mucus like bioadhesives of the first generation, however initial but reversible mucus-binding of lectins offers partititioning to the cell membrane followed by uptake into the enterocyte.

Is transurethral vaporesection of the prostate better than standard transurethral resection?

OBJECTIVE: The aim of this study was to undertake an evaluation of the comparative efficacy and morbidity of transurethral vaporesection (TUVRP) and standard transurethral resection (TURP), two resection techniques using loops of different thickness and power settings. METHODS: In a prospective study, 185 patients with lower urinary tract symptoms suggestive of bladder outlet obstruction and benign prostatic enlargement were randomized to undergo either TUVRP or standard TURP. Inclusion criteria were benign prostatic enlargement, moderate or severe lower urinary tract symptoms and/or a significant urinary residual (>60 ml), while patients with previous prostatic surgery, prostate cancer or neurogenic bladder disorders were excluded. Prostate size, residual urine, urinary flow rate and symptoms as well as associated bother (using the International Prostate Symptom Score (IPSS) and the American Urological Association Bother Score (AUA-BS)) were assessed preoperatively. Intraoperative blood loss and fluid absorption were evaluated by measuring serum hemoglobin and respiratory alcohol concentration. Patients were followed for 1 year with the evaluation of flow rates, residual urine volumes, symptom scores and complications at 3, 6 and 12 months. RESULTS: A significant difference was seen in the weight of the resected tissue (TURP 30.3 g vs. TUVRP 21.9 g, p<0.003). There were no significant differences in blood loss, intraoperative fluid absorption or procedure time between TUVRP and TURP, although more patients in the TURP group required blood transfusions (13 vs. 7) and mean procedure time was longer for TUVRP (71.0 vs. 65.9 min). The postoperative improvements in IPSS, AUA-BS, residual and Q(max) were significant in both groups (p<0.01 for each) but without difference between the two groups. The rate of complications (urinary tract infections, urethral stricture, reintervention rate) during follow-up was the same in both groups. CONCLUSIONS: In this prospective randomized comparison of the clinical outcome and morbidity of standard TURP versus TUVRP, there were no significant differences in any of the parameters evaluated except for the weight of the resected tissue.

Is there a relationship between the amount of tissue removed at transurethral resection of the prostate and clinical improvement in benign prostatic hyperplasia.

OBJECTIVE: To assess in a prospective trial the influence of the amount of tissue resected at transurethral resection of the prostate (TURP) for benign prostatic enlargement on the symptom improvement as assessed by symptom scores. METHODS: Between December 1996 and August 1998 a total of 138 men (mean age 68.2, range 53-89) with symptomatic benign prostatic enlargement who underwent TURP participated in this prospective study. Patients were assessed preoperatively with the International Prostate Symptom Score (IPSS), the American Urological Association Bother Score (AUA-BS) and the Benign Prostatic Hyperplasia Impact Index (BPH-II) as well as urinary flow rate measurements (Qmax) and prostate volume (PV) and residual urine determination by ultrasound. The amount of tissue resected was weighed. Patients were followed with reevaluation of Q(max), residual urine and the symptom and bother scores at 3 and 6 months. RESULTS: A close correlation between preoperative PV (mean 49.0 ml, SD 22.0, range 13-140) and the resected tissue weight (RTW, mean 24.7 g, SD 18.0, range 6-128) was seen (r = 0.75, p < 0.001). Age was correlated with preoperative PV (r = 0.23, p < 0.05). While significant mean improvements in Q(max), residual volume and IPSS, AUA-BS and BPH-II were found 3 and 6 months postoperatively, a negative correlation was seen between the RTW and the IPSS, the AUA-BS and the BPH-II 3 months after TURP (r = -0.23, p < 0.024; r = -0.23, p < 0.025; r = -0.20, p = 0.05). No statistically significant correlation was seen between symptom change and the percentage of PV removed or the residual prostatic weight. Classification of the patients into groups depending on preoperative PV (< 30, 31-50, 51-70 and >70 ml) showed a tendency for patients with larger PV to gain more symptom improvement postoperatively. CONCLUSIONS: Early symptom improvement after TURP will depend on the amount of tissue removed but the relationship is weak and affected by several other confounding factors. Apparently, the symptomatic improvement after TURP is not primarily dependent on the relative completeness of the resection. Patients with larger prostates and larger RTW tend to gain more symptomatic benefit from TURP than do patients with smaller prostates.

Paraventricular hypothalamic alpha-melanocyte-stimulating hormone and MTII reduce feeding without causing aversive effects.

alpha-Melanocyte-stimulating hormone (alpha-MSH) appears to play a tonic inhibitory role in feeding and energy storage. MTII, a specific synthetic MC3-R/MC4-R agonist, has similar effects on feeding in rats. The current studies demonstrate that PVN administration of alpha-MSH or MTII decreases nocturnal and NPY-stimulated food intake without causing aversive effects. Co-administration with NPY of 600 pmol alpha-MSH or 1 pmol MTII into the PVN caused a significant decrease in NPY-induced feeding. PVN administration of MTII or alpha-MSH at doses effective to suppress feeding did not cause conditioned taste aversion (CTA). ICV administration of alpha-MSH, however, did cause weak CTA. These results indicate that the potent effects on feeding of MC3-R and MC4-R agonists when injected into the PVN are not due to aversive effects.

Lectin-mediated drug targeting: quantification of binding and internalization of Wheat germ agglutinin and Solanum tuberosum lectin using Caco-2 and HT-29 cells.

For the potential use of Wheat germ agglutinin (WGA) and Solanum tuberosum lectin (STL) as auxiliary excipients for targeting drugs to colonocytes, the number of Caco-2 and HT-29-bound lectins was determined by fluorimetry using fluorescein-labelled derivatives of the N-acetylglucosamine-specific lectins. After 1 h of incubation, the WGA-binding capacity of 5 x 10(4) Caco-2 cells was 26.9 +/- 0.5 pmol at 4 degrees C and 27.2 +/- 1.0 pmol at 37 degrees C respectively. In comparison, 19.5 +/- 2.9 pmol (37 degrees C) and 16.7 +/- 0.9 pmol (4 degrees C) WGA were bound within 1 h to 5 x 10(4) HT-29 cells referring to about 80% of the total amount of WGA bound within 4 h of incubation. In contrast, binding of STL to the colon carcinoma cell lines was independent of incubation times and temperatures tested exhibiting a binding rate of 8.4 +/- 0.6 pmol (HT-29) and 9.9 +/- 0.8 pmol (Caco-2) STL/5 x 10(4) cells. As determined by flow cytometry, non-specific binding is lower than 1.0% (WGA) and 3.4% (STL). Uptake and intracellular accumulation of the lectins were investigated by confocal laser scanning microscopy at 4 degrees C and 37 degrees C respectively. A decrease of initially membrane-bound lectins concurrent with increasing cytoplasmic enrichment by time was observed by digital cell image analysis. Due to specific and numerically sufficient adhesion as well as internalization, WGA and STL are anticipated as targeting tools in lectin-mediated drug delivery systems.

Influence of long-term supplementation with alpha-linolenic acid on myocardial lipid peroxidation and antioxidative capacity in spontaneously hypertensive rats.

The ischaemic vulnerability of the heart of spontaneously hypertensive rats (SHR) is enhanced after feeding an alpha-linolenic acid (LNA) enriched diet. Because oxygen radical-induced reactions (e.g. lipid peroxidation) are involved in the ischaemic damage, an increased susceptibility of the SHR heart to such damaging reactions might be the reason. As a sign of the enhanced susceptibility to lipid peroxidation of LNA-fed SHR, we found (measured as TBARS) higher plasma and heart lipid peroxide levels (3.84 +/- 0.50 micromol/l vs 2.98 +/- 0.78 micromol/l and 507 +/- 127 nmol/g prot. vs 215 +/- 80 nmol/g prot., respectively) after feeding LNA. Using Fe2+/Vit. C to induce lipid peroxidation in myocardial tissue homogenates, we demonstrated the enhanced susceptibility to lipid peroxidation of the LNA-fed SHR heart (68 +/- 12 nmol/min x g prot. vs 40 +/- 8 nmol/min x g prot.) also in vitro. The myocardial enrichment of n-3 polyunsaturated fatty acids (PUFA) resulting in a higher peroxidation index (PI 227 vs. 170) and the loss in myocardial activities of the antioxidative enzymes (SOD: 76 +/- 24 U x 10(3)/g prot. vs 235 +/- 150 U x 10(3)/g prot.; GSH-Px: 32 +/- 5 U/g prot. vs 110 +/- 30 U/g prot.) by feeding LNA could be the cause of the increase in myocardial susceptibility to lipid peroxidation of PUFA supplemented SHR.

Effects of adding various oils to the diet on growth, feed conversion and chemical composition of carp (Cyprinus carpio).

The suitability of various vegetable and fish oils was tested as feed components for one-summer-old carp fingerlings. Five diets were used: a basal diet, which served as control feed, was supplemented with 10% corn-germ oil, 10% sunflower oil, 10% fish oil or 10% rapeseed oil, respectively. By means of the lipid supplementation the crude protein content decreased from 35.5% in the basal diet to 31.9% in the test diets, whereas the gross energy level increased from 16.3 to 18.9 MJ/kg. The diets were fed over a period of 84 feeding days and water temperature was 23 degrees C. Weight gain, feed conversion ratio and protein utilization were superior in all groups of carp which received the fat-enriched high energy diets. Considering the gain in % of the initial weight, the control fish reached less than 400% whereas all carp in the test groups, which consumed the oil-enriched diets, reached 455 to 485%. A significant influence of the kind of lipid on growth and feed conversion could not be recognized. The lipid-enriched diets with higher energy content resulted in increased fat levels of the carp. Fatty acid composition of the carp reflected that of the diets. In the control group and the fish oil group the levels of palmitic, palmitoleic, eicosapentaenoic and docosahexaenoic acid were especially high corresponding to the fatty acid profile of the diets. In carp fed the diets supplied with corn-germ oil and sunflower oil linoleic acid was dominant whereas the carp fed the rapeseed diet were characterized by a high level of oleic acid.

Different changes of n-6 fatty acids in lipoproteins from hyperlipemic subjects after diets supplemented with n-3 fatty acids.

After diets supplemented with canned mackerel or herring, in a cross-over design, containing different amounts of long-chain n-3 fatty acids (eicosapentaenoic acid, C20:5n-3-EPA, and docosahexaenoic acid, C22(6)n-3-DHA) an increase of both EPA and DHA was confirmed in triglycerides (TG), cholesterol esters (CE) and phospholipids (PL) of very low density (VLDL) and low density lipoproteins (LDL) as well as in high density lipoproteins (HDL) from hyperlipidemic subjects. An unexpected finding was the simultaneous increase of arachidonic acid (C20:4n-6-AA) in TG and CE and its constant portion in PL of lipoproteins, whereas linoleic acid (C18:2n-6-LA) appeared lower in CE and in PL of VLDL + LDL and HDL. In general, the changes were minor after a diet supplemented with canned herring providing a lower dose of n-3 fatty acids. The results indicate dose-related changes not only of n-3 fatty acids, but also of n-6 fatty acids in serum lipids after fish diets. This different behavior of LA and AA in serum lipids might be a new aspect in the interrelations and the dietary modulation of both families of polyunsaturated fatty acids (PUFA). The accumulation of AA in neutral lipids could be linked with an elevation of prostaglandin I2, which was found apart from an increased formation of prostaglandin I3 after diets supplemented with n-3 fatty acids. The concomitant increase of prostaglandins I2 and I3 spotlights widely ignored interrelations within the eicosanoid pathway, which become evident after diets enriched with long-chain n-3 fatty acids.