Dietary and exercise interventions to improve quality of life, metabolic risk factors and androgen deficiency symptoms in men with prostate cancer undergoing androgen deprivation therapy

Introduction Lifestyle interventions might be useful in the management of adverse effects of androgen deprivation therapy (ADT) in men with prostate cancer. Objectives To examine the effects of dietary and exercise interventions on quality of life (QoL), metabolic risk factors and androgen deficiency symptoms in men with prostate cancer undergoing ADT. Methods CINAHL, Cochrane library, Medline and PsychINFO were searched to identify randomised controlled trials published from January, 2004 to October, 2014. Data extraction and methodological quality assessment was independently conducted by two reviewers. Meta-analysis was conducted using RevMan® 5.3.5. Results Of 2183 articles retrieved, 11 studies met the inclusion criteria and had low risk of bias.Nine studies evaluated exercise (resistance and/or aerobic and/or counselling) and three evaluated dietary supplementation. Median sample size =79 (33–121) and median intervention duration was 12 weeks (12–24). Exercise improved QoL measures (SMD 0.26, 95%CI −0.01 to 0.53) but not body composition, metabolic risk or vasomotor symptoms. Qualitative analysis indicated soy (or isoflavone) supplementation did not improve vasomotor symptoms; however, may improve QoL. Conclusions Few studies have evaluated the efficacy of lifestyle interventions in the management of adverse effects of ADT. We found inconclusive results for exercise in improving QoL and negative results for other outcomes. For soy-based products, we found negative results for modifying vasomotor symptoms and inconclusive results for improving QoL. Future work should investigate the best mode of exercise for improving QoL and other interventions such as dietary counselling should be investigated for their potential to modify these outcomes.

Successful topical tacrolimus (FK506) therapy in a child with pyoderma gangrenosum

The inflammatory skin disease pyoderma gangrenosum is characterized by destructive ulceration, typically occurring on the calves and thighs and less commonly on the buttocks and face. Lesions vary in size and may be multiple, often rapidly ulcerating to form deep painful wounds. Ulcers characteristically have ragged purple edges that overhang. In many patients a concomitant condition can be identified such as inflammatory bowel disease, rheumatoid arthritis, chronic autoimmune hepatitis, and various hematologic and solid tumours (1,2). Treatment of these ulcers in the past has been disappointing. The large lesions usually run a chronic course and heal very slowly, with traditional dressings often in combination with systemic steroids or immunosuppressants. Since 1998, a small number of case have been reported of adults with pyoderma gangrenosum whose lesions heal with the use of topical tacrolimus (FK506) (2–4). We report, to the best of our knowledge, the first successful treatment of a child with pyoderma gangrenosum using topical tacrolimus.

Nonlinear Enzyme Kinetics Can Lead to High Metabolic Flux Control Coefficients: Implications for the Evolution of Dominance

In a classic study, Kacser & Burns (1981, Genetics 97, 639-666) demonstrated that given certain plausible assumptions, the flux in a metabolic pathway was more or less indifferent to the activity of any of the enzymes in the pathway taken singly. It was inferred from this that the observed dominance of most wild-type alleles with respect to loss-of-function mutations did not require an adaptive, meaning selectionist, explanation. Cornish-Bowden (1987, J. theor. Biol. 125, 333-338) showed that the Kacser-Burns inference was not valid when substrate concentrations were large relative to the relevant Michaelis constants. We find that in a randomly constructed functional pathway, even when substrate levels are small, one can expect high values of control coefficients for metabolic flux in the presence of significant nonlinearities as exemplified by enzymes with Hill coefficients ranging from two to six, or by the existence of oscillatory loops. Under these conditions the flux can be quite sensitive to changes in enzyme activity as might be caused by inactivating one of the two alleles in a diploid. Therefore, the phenomenon of dominance cannot be a trivial ''default'' consequence of physiology but must be intimately linked to the manner in which metabolic networks have been moulded by natural selection.

Investigating the potential of Shikonin, a Chinese herbal medicine, as a novel scar remediation therapy

This project investigates for the first time the biological mechanisms underlying the anecdotal use of Shikonin, an active component extracted from the Chinese herbal medicine "Zi Cao", as a treatment for hypertrophic scars. Compelling molecular and cellular evidence was generated supporting the therapeutic value of Shikonin as a scar treatment, suggesting that further development of this agent is warranted.

Mycobacterium tuberculosis pantothenate kinase: possible changes in location of ligands during enzyme action

The crystal structures of complexes of Mycobacterium tuberculosis pantothenate kinase with the following ligands have been determined: (i) citrate; (ii) the nonhydrolysable ATP analogue AMPPCP and pantothenate (the initiation complex); (iii) ADP and phosphopantothenate resulting from phosphorylation of pantothenate by ATP in the crystal (the end complex); (iv) ATP and ADP, each with half occupancy, resulting from a quick soak of crystals in ATP (the intermediate complex); (v) CoA; (vi) ADP prepared by soaking and cocrystallization, which turned out to have identical structures, and (vii) ADP and pantothenate. Solution studies on CoA binding and catalytic activity have also been carried out. Unlike in the case of the homologous Escherichia coli enzyme, AMPPCP and ADP occupy different, though overlapping, locations in the respective complexes; the same is true of pantothenate in the initiation complex and phosphopantothenate in the end complex. The binding site of MtPanK is substantially preformed, while that of EcPanK exhibits considerabl plasticity. The difference in the behaviour of the E. coli and M. tuberculosis enzymes could be explained in terms of changes in local structure resulting from substitutions. It is unusual for two homologous enzymes to exhibit such striking differences in action. Therefore, the results have to be treated with caution. However, the changes in the locations of ligands exhibited by M. tuberculosis pantothenate kinase are remarkable and novel.

Reduction in arterial wall strain with aggressive lipid-lowering therapy in patients with carotid artery disease

Background: Inflammation and biomechanical factors have been associated with the development of vulnerable atherosclerotic plaques. Lipid-lowering therapy has been shown to be effective in stabilizing them by reducing plaque inflammation. Its effect on arterial wall strain, however, remains unknown. The aim of the present study was to investigate the role of high- and low-dose lipid-lowering therapy using an HMG-CoA reductase inhibitor, atorvastatin, on arterial wall strain. Methods and Results: Forty patients with carotid stenosis >40% were successfully followed up during the Atorvastatin Therapy: Effects on Reduction Of Macrophage Activity (ATHEROMA; ISRCTN64894118) Trial. All patients had plaque inflammation as shown by intraplaque accumulation of ultrasmall super paramagnetic particles of iron oxide on magnetic resonance imaging at baseline. Structural analysis was performed and change of strain was compared between high- and low-dose statin at 0 and 12 weeks. There was no significant difference in strain between the 2 groups at baseline (P=0.6). At 12 weeks, the maximum strain was significantly lower in the 80-mg group than in the 10-mg group (0.085±0.033 vs. 0.169±0.084; P=0.001). A significant reduction (26%) of maximum strain was observed in the 80-mg group at 12 weeks (0.018±0.02; P=0.01). Conclusions: Aggressive lipid-lowering therapy is associated with a significant reduction in arterial wall strain. The reduction in biomechanical strain may be associated with reductions in plaque inflammatory burden.

The ATHEROMA (Atorvastatin Therapy: Effects on Reduction of Macrophage Activity) Study. Evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease

Objectives: The aim of this study was to evaluate the effects of low-dose (10 mg) and high-dose (80 mg) atorvastatin on carotid plaque inflammation as determined by ultrasmall superparamagnetic iron oxide (USPIO)-enhanced carotid magnetic resonance imaging (MRI). The hypothesis was that treatment with 80 mg atorvastatin would demonstrate quantifiable changes in USPIO-enhanced MRI-defined inflammation within the first 3 months of therapy. Background: Preliminary studies indicate that USPIO-enhanced MRI can identify macrophage infiltration in human carotid atheroma in vivo and hence may be a surrogate marker of plaque inflammation. Methods: Forty-seven patients with carotid stenosis >40% on duplex ultrasonography and who demonstrated intraplaque accumulation of USPIO on MRI at baseline were randomly assigned in a balanced, double-blind manner to either 10 or 80 mg atorvastatin daily for 12 weeks. Baseline statin therapy was equivalent to 10 mg of atorvastatin or less. The primary end point was change from baseline in signal intensity (ΔSI) on USPIO-enhanced MRI in carotid plaque at 6 and 12 weeks. Results: Twenty patients completed 12 weeks of treatment in each group. A significant reduction from baseline in USPIO-defined inflammation was observed in the 80-mg group at both 6 weeks (ΔSI 0.13; p = 0.0003) and at 12 weeks (ΔSI 0.20; p < 0.0001). No difference was observed with the low-dose regimen. The 80-mg atorvastatin dose significantly reduced total cholesterol by 15% (p = 0.0003) and low-density lipoprotein cholesterol by 29% (p = 0.0001) at 12 weeks. Conclusions: Aggressive lipid-lowering therapy over a 3-month period is associated with significant reduction in USPIO-defined inflammation. USPIO-enhanced MRI methodology may be a useful imaging biomarker for the screening and assessment of therapeutic response to "anti-inflammatory" interventions in patients with atherosclerotic lesions. (Effects of Atorvastatin on Macrophage Activity and Plaque Inflammation Using Magnetic Resonance Imaging [ATHEROMA]; NCT00368589).

Dracocephalum moldavica L. and Melissa officinalis L. : Chemistry and Bioactivities Relevant in Alzheimer’s Disease Therapy

Oksidatiivisen stressin eli liiallisen reaktiivisten happiyhdisteiden määrän soluissa on jo pitkään arveltu olevan tärkeä Alzheimerin taudin kehittymiseen ja etenemiseen vaikuttava tekijä. Tämän vuoksi kiinnostus erilaisten antioksidanttien (yhdisteitä, jotka neutraloivat näitä happiradikaaleja soluissa) mahdollisia terapeuttisia ominaisuuksia Alzheimerin taudin hoidossa on tutkittu laajalti. Tähän mennessä ei kuitenkaan ole vielä onnistuttu löytämään antioksidanttia, joka olisi hyödyksi Alzheimerin taudin hoidossa. Tämän vuoksi on tärkeää pyrkiä löytämään uusia antioksidanttien lähteitä sekä tutkia niistä löytyviä aktiivisia yhdisteitä. Kiinnostus luonnon antioksidantteja kohtaan on kasvanut voimakkaasti viime aikoina. Huomio on kiinnittynyt erityisesti aromaattisista sekä lääkekasveista löytyviin antioksidantteihin. Lamiaceae- perheeseen kuuluvia tuoksuampiaisyrttiä (Dracocephalum moldavica L.) ja sitruunamelissaa (Melissa officinalis L.) on käytetty Iranissa pitkään sekä ruoanlaitossa että lääkinnässä, minkä vuoksi näiden kasvien uutteiden antioksidanttisisältöä päätettiin analysoida käyttäen useaa erilaista in vitro- menetelmää. Näissä kokeissa ilmeni, että uutteilla oli useita antioksidanttisia vaikutuksia. Näistä antioksidanttisista vaikutuksista vastaavia yhdisteitä pyrittiin tunnistamaan käyttäen HPLC-PDA- tekniikkaa, minkä seurauksena niiden havaittiin sisältävän erilaisia polyfenoleita, kuten hydroksyloituneita bentsoeeni- ja cinnamamidihapon johdannaisia sekä flavonoideja. Kummankin kasvin uutteissa runsaimmin esiintynyt yhdiste oli rosmariinihappo. Sitruunamelissaa (M. officinalis) on käytetty antiikin ajoista alkaen kognitiivisten toimintojen häiriöiden hoidossa. Perustuen tietoon kasvin käytöstä perinteisessä lääkinnässä, sen tehoa Alzheimerin taudin hoidossa on tutkittu viime aikoina kliinisin kokein. Sitruunamelissan todettiinkin olevan hyödyksi lievää ja keskivaikeaa Alzheimeimerin tautia sairastavien potilaiden hoidossa. Väitöskirjan osanan olevasta kooste-artikkelista käy ilmi, että tutkimalla lääkekasvien ominaisuuksia voidaan saada arvokkaita suuntaa-antavia vihjeitä Alzheimerin taudin lääkehoidon kehittämiseen. Tämän perusteella päätettiinkin testatata myös sitruunamelissauutteen kykyä estää asetyylikoliiniesteraasin (AChE) toimintaa, koska tämän entsyymin toiminna estämisen tiedetään olevan hyödyksi Alzheimerin taudin hoidossa. Uute kykeni estämään AChE:n toimintaa, minkä vuoksi uutteen sisältämiä komponentteja päätettiin tutkia terkemmin. Uute jaettiin erilaisiin fraktioihin käyttäen HPLC-menetelmää, minkä jälkeen testattiin jokaisen fraktion kykyä inhiboida AchE. Suurin osa fraktioista kykeni inhiboimaan AChE:n toimintaa selkeästi tehokkaammin, kuin raakauute. Kaikista tehokkainta fraktiota analysoitiin tarkemmin sen aktiivisten yhdisteiden tunnistamiseksi, minkä seurauksena sen sisältämät yhdisteet tunnistettiin cis ja trans-rosmariinihapoiksi. Tässä tutkimuksessa tunnistettujen yhdisteiden hyödyllisyyttä Alzheimerin taudin hoidossa tulisi seuraavaksi tutkia erilaisissa in vivo-malleissa. Lisäksi jäljellä olevien fraktioiden kemiallinen koostumus tulisi selvittää sekä antioksidanttiaktiivisuuden ja AChE:n toiminnan inhiboinnin välistä mahdollista yhteyttä tulisi tutkia tarkemmin. Tämä tutkimus osoittaa tuoksuampiasyrtin (D. moldavica) sekä sitruunamelissan (M. officinalis) sisältävän monenlaisia aktiivisia antioksidantteja. Lisäksi sitruunamelissan sisältämät yhdisteet kykenivät estämään asetyylikoliiniesteraasin (AchE) toimintaa. Nämä tulokset tukevat osaltaan väitöskirjan osana olevan kooste-artikkelin johtopäätöksiä, joiden mukaan etnofarmakologinen kasvitutkimus voi osoittautua erittäin hyödylliseksi kehitettäessä uutta lääkehoitoa Alzheimerin tautiin. Lisäksi tässä väitöskirjassa kuvattu tutkimus osoittaakin, että perinteisesti lääkekasvina käytettyä sitruunamelissaa voidaan mahdollisesti hyödyntää uusien Alzheimerin taudin hoitoon käytettävien lääkkeiden kehityksessä.

Evaluation of growth and changes in body composition following neonatal diagnosis of cystic fibrosis

Early deficits in nutritional status that might require specific treatment and early response to nutritional therapy were studied longitudinally in 25 infants with cystic fibrosis (CF) diagnosed by neonatal screening, using anthropometric and research body composition methodology, and evaluation of pancreatic function. At the time of confirmed diagnosis (mean 5.4 weeks), body mass, length, total body fat (TBF), and total body potassium (TBK) were all significantly reduced. Following diagnosis and commencement of therapy there was a normalization of weight, length, and TBK by 6-12 months of age, indicating catch-up growth. But in some individuals the response was incomplete, and as a group, mean total body fat remained significantly lower than normal at 1 year of age. Seven of 25 (28%) were pancreatic sufficient at diagnosis, and all but one had evidence of declining pancreatic function requiring the institution of pancreatic enzyme therapy during the next 1-9 months. The median age of commencement of enzyme therapy was 10 weeks (range 5 weeks to 11 months). These longitudinal assessments emphasize the dynamic changes occurring in absorptive function, body composition, and nutritional status following neonatal diagnosis of cystic fibrosis and may reflect previously described abnormalities of energy metabolism in this age group. Abnormal body composition is evident in most CF infants following diagnosis by neonatal screening but pancreatic damage may still be evolving. We suggest that early active nutritional therapy and surveillance for changes in pancreatic function are warranted in CF infants diagnosed by neonatal screening.

Paracrine action of sFLT-1 secreted by stably-transfected Ehrlich ascites tumor cells and therapy using sFLT-1 inhibits ascites tumor growth in vivo

Background Vascular endothelial growth factor (VEGF) is known to play a major role in angiogenesis. A soluble form of Flt-1, a VEGF receptor, is potentially useful as an antagonist of VEGF, and accumulating evidence suggests the applicability of sFlt-1 in tumor suppression. In the present study, we have developed and tested strategies targeted specifically to VEGF for the treatment of ascites formation.Methods As an initial strategy, we produced recombinant sFLT-1 in the baculovirus expression system and used it as a trap to sequester VEGF in the murine ascites carcinoma model. The effect of the treatment on the weight of the animal, cell number, ascites volume and proliferating endothelial cells was studied. The second strategy involved, producing Ehrlich ascites tumor (EAT) cells stably transfected with vectors carrying cDNA encoding truncated form of Flt-1 and using these cells to inhibit ascites tumors in a nude mouse model. Results The sFLT-1 produced by the baculovirus system showed potent antiangiogenic activity as assessed by rat cornea and tube formation assay. sFLT-1 treatment resulted in reduced peritoneal angiogenesis with a concomitant decrease in tumor cell number, volume of ascites, amount of free VEGF and the number of invasive tumor cells as assayed by CD31 staining. EAT cells stably transfected with truncated form of Flt-1 also effectively reduced the tumor burden in nude mice transplanted with these cells, and demonstrated a reduction in ascites formation and peritoneal angiogenesis. Conclusions The inhibition of peritoneal angiogenesis and tumor growth by sequestering VEGF with either sFlt-1 gene expression by recombinant EAT cells or by direct sFLT-1 protein therapy is shown to comprise a potential therapy. Copyright (C) 2009 John Wiley & Sons, Ltd.

A Genetic Analysis of Lysosomal Enzyme Activities in Brahman Cattle

Analyses of variance and co variance were carried out on the activities of three lysosomal enzymes in mononuclear blood cells from Brahman cattle. These were hexosaminidase (HEX), beta-D-galacto-sidase (GAL) and acid alpha-glucosidase (GLU) which had been measured in blood mononuclear cells from 1752 cattle from 6 herds in a Pompe's disease control programme. Herd of origin and date of bleeding significantly affected the level of activity of all enzymes. In addition, HEX and GAL were affected by age and HEX by the sex of the animal bled. Estimates of heritability from sire variances were 0.29:t 0.09 for HEX, 0.31 :t 0.09 for GAL and 0.44:t 0.09 for GLU. Genetic correlations between all enzymes were positive. The data indicate the existence of a major gene causing Pompe's disease and responsible for 16% of the genetic variation in GLU. One standard deviation of selection differential for high GLU should almost eliminate Pompe's disease from the population. The effi-ciency of selection would be aided by estimating the breeding value for GLU using measurements of HEX and GLU and taking account of an animal's sex, age, date of bleeding and herd of origin.

Enzymic Conversion of Agmatine to Putrescine inL athyrms satiuus seedlings - Purification and properties of a multifunctional enzyme (putrescine synthase)

The participation of a multifunctional enzy(am sein - gle polypeptide with multiple catalytic activities (14)) has been demonstrated in the conversion of agmatine to putrescine in Lathyrus sativus seedlings. This enzyme (putrescine synthase) with inherent activities of agmatine iminohydrolase, putrescine transcarbamylase, ornithine transcarbamylase, and carbamate has been purified to homogeneity anhda s M, = 55,000.

Structural Basis of Drug Resistance by Genetic Variants of HIV Type 1 Clade C Protease from India

Using computer modeling of three-dimensional structures and structural information available on the crystal structures of HIV-1 protease, we investigated the structural effects of mutations, in treatment-naive and treatment-exposed individuals from India and postulated mechanisms of resistance in clade C variants. A large number of models (14) have been generated by computational mutation of the available crystal structures of drug bound proteases. Localized energy minimization was carried out in and around the sites of mutation in order to optimize the geometry of interactions present. Most of the mutations result in structural differences at the flap that favors the semiopen state of the enzyme. Some of the mutations were also found to confer resistance by affecting the geometry of the active site. The E35D mutation affects the flap structure in clade B strains and E35N and E35K mutation, seen in our modeled strains, have a more profound effect. Common polymorphisms at positions 36 and 63 in clade C also affected flap structure. Apart from a few other residues Gln-58, Asn-83, Asn-88, and Gln-92 and their interactions are important for the transition from the closed to the open state. Development of protease inhibitors by structure-based design requires investigation of mechanisms operative for clade C to improve the efficacy of therapy.

Home monitoring for infants at risk of the sudden infant death syndrome

This study evaluates the effectiveness and social implications of home monitoring of 31 infants at risk of sudden infant death syndrome (SIDS). Thirteen siblings of children dying of SIDS, nine near miss SIDS infants and nine preterm infants with apnoea persisting beyond 40 weeks post conceptual age were monitored from a mean age of 15 days to a mean of 10 months. Chest movement detection monitors were used in 27 and thoracic impedance monitors in four. Genuine apnoeic episodes were reported by 21 families, and 13 infants required resuscitation. Apnoeic episodes occurred in all nine preterm infants but in only five (38%) of the siblings of SIDS (P<0.05). Troublesome false alarms were a major problem occurring with 61% of the infants and were more common with the preterm infants than the siblings of SIDS. All but two couples stated that the monitor decreased anxiety and improved their quality of life. Most parents accepted that the social restrictions imposed by the monitor were part of the caring process but four couples were highly resentful of the changes imposed on their lifestyle. The monitors used were far from ideal with malfunction occurring in 17, necessitating replacement in six, repair in six and cessation of monitoring in three. The parents became ingenious in modifying the monitors to their own individual requirements Although none of these 31 ‘at risk’ infants died the study sample was far too small to conclude whether home monitoring prevented any cases of SIDS.