Phytoestrogens for hormone replacement therapy?

Due to some severe side effects “classical” hormone replacement therapy (HRT) is currently being challenged by a therapy with phytoestrogens. Particularly soy and red clover derived isoflavones are advertised as selective estrogen receptor modulators (SERMs) with only desired and no undesired estrogenic effects. Evidence that this is the case however is scarce. Most studies investigating climacteric complaints did not find beneficial effects. A proposed beneficial effect on mammary cancer is unproven. The majority of studies however indicate an antiosteoporotic effect of isoflavones, while putative beneficial effects in the cardiovascular system are questionable due to the fact that estradiol which—like isoflavones—increase HDL and decrease LDL concentrations appear not to prevent arteriosclerosis in the human. In the urogenital tract, including the vagina, soy and red clover derived isoflavones are without effects.

Cimicifuga racemosa extracts are traditionally used for the treatment of climacteric complaints. Evidence is now available that the yet unknown compounds in Cimicifuga racemosa extracts prevent climacteric complaints and may also have antiosteoporotic effects.     

What is wrong with replacement series?

Replacement series methods have been widely used in studies of plant competition. Recent work suggests that they are usually inadequate to assess competitive interactions and can be misleading. Response models relating yield per individual to the densities of the component species provide a methodology for answering many questions about mixtures and also focus attention on the need for clarity in defining terminology and interpreting results.     

Growth hormone - hormone replacement for the somatopause?

Twenty-four-hour growth hormone (GH) secretion reaches a peak at around puberty and by the age of 21 has begun to decrease. Thereafter the fall in GH secretion is progressive such that by the age of 60 most adults have total 24-hour secretion rates indistinguishable from those of hypopituitary patients with organic lesions in the pituitary gland. Patterns of GH secretion are similar to those in younger people but GH pulses are markedly reduced in amplitude. Sleep and exercise remain the major stimuli for GH secretion. The fall in GH secretion seen with ageing coincides with changes in body composition and lipid metabolism that are similar to those seen in adults with GH deficiency. In elderly subjects, although GH secretion is markedly reduced, remaining GH secretion correlates closely with body composition (particularly with lean body mass and inversely with central abdominal fat). Pioneering studies carried out by Rudman showed that GH administration to elderly subjects with low insulin-like growth factor-I levels resulted in reversal of many of the changes associated with GH deficiency, namely an increase in lean body mass and bone mineral density and a reduction in body fat and plasma cholesterol. These changes were remarkably similar to those shown a year earlier in adults with GH deficiency given GH replacement. Subsequent studies of GH replacement in elderly adults have confirmed Rudman's initial observations but have been dominated by side effects which have led to a high number of dropouts. It is now clear that the elderly are very sensitive to GH and the doses used need to be very low, increased very slowly and tailored to the individual needs of each patient. Using this more cautious approach, recent studies have been very positive. A series of papers from Blackman's group, presented at the US endocrine meeting in San Diego in 1999, investigated the effects of GH with or without testosterone supplements (in men) and oestrogen supplements (in women). Their results showed positive effects of GH on lean body mass, central fat, low-density lipoprotein cholesterol and aerobic capacity. In many instances there was a positive interaction between GH and hormone replacement with testosterone and oestrogen, but it appeared that GH showed the most potent anabolic effects. Clearly more studies are needed before GH replacement for the elderly becomes established. Safety issues will require close scrutiny, but the data available so far are sufficiently positive to undertake large multicentre, placebo-controlled trials, particularly looking at endpoints associated with prevention of frailty and loss of independence.     

Biosurfactants: a sustainable replacement for chemical surfactants?

Glycolipid biosurfactants produced by bacteria and yeasts provide significant opportunities to replace chemical surfactants with sustainable biologically produced alternatives in bulk commercial products such as laundry detergents and surface cleaners. Sophorolipids are already available in sufficient yield to make their use feasible while rhamnolipids and mannosylerythritol lipids require further development. The ability to tailor the biosurfactant produced to the specific needs of the product formulation will be an important future step.     

Mutual replacement of species in space in a grassland community: is there an evidence for functional complementarity of replacement groups?

Many plant communities show strong fine‐scale spatiotemporal dynamics due to frequent natality and mortality events. This process is often non‐random, implying that the community can be broken into groups within which species mutually replace each other in time and are distinct from the other such groups. We examined whether such groups fill separate niches and are functionally complementary in a species‐rich mountain grassland. We used cluster analysis of fine‐scale spatial data time series to discern which species were more likely to replace each other in space. Next, a four‐year removal experiment (removing one group in each experimental treatment, or similar amount of biomass across all groups) was used to determine whether simultaneous occurrence of all these groups would maintain a greater total biomass than if an entire group were eliminated. The results do not support the hypothesis that the simultaneous presence of groups of species that replace each other in space is necessary for the community to attain its maximum biomass. However, the experiment showed strong differences among the replacement groups in their capacity for opportunistic behaviour: some groups responded quickly to space made available by removal while others did not. Furthermore, there were strong differences between groups composed primarily of grasses and groups composed primarily of dicots. In spite of the large differences among these groups, they are not functionally complementary. We therefore conclude that replacement processes in this grassland community more closely resemble a neutral process with sets of species differing in the speed at which they fill empty spaces.     

When does ecosystem engineering cause invasion and species replacement?

Introduced exotic species can dominate communities and replace native species that should be better adapted to their local environment, a paradox that is usually explained by the absence of natural enemies and by habitat alteration resulting from anthropogenic disturbance. Additionally, introduced species can enhance their invasion success and impact on native species by modifying selection pressures in their new environment through ecosystem engineering. We analyse a simple dynamic model of indirect competition for habitat between a non-engineering resident species and an engineering exotic species. The conditions for invasion and competitive exclusion of the resident by the exotic species and the range of dynamic outcomes suggested by the model are determined by the form of density dependence. We give simple criteria for the success of the invading species on dimensionless quantities involving rates of ecosystem engineering and of habitat degradation. The model's predictions offer an additional explanation for a range of invasion dynamics reported in the literature, including lag times between introduction and establishment. One intriguing result is that a series of failed invasions may successively reduce environmental resistance to subsequent invasion, through a cumulative effect of habitat transformation. More work is needed to determine the frequency and conditions in which engineering is required for successful establishment, and whether highly-successful (or high-impact) invaders are more likely to possess ecosystem engineering traits.     

A genetic mechanism of species replacement in European waterfrogs?

Introduced Rana ridibunda currentlyreplace the native waterfrogs R. lessonaeand R. esculenta in several areas ofcentral Europe. The unusual reproductive systemin waterfrogs of the Rana esculentacomplex suggests that this replacement may bedriven by a genetic mechanism: Ranaesculenta, a hybrid between R. ridibundaand R. lessonae, eliminates the lessonae genome from the germline and clonallytransmits the ridibunda genome(hybridogenesis). Hybrids form mixedpopulations with R. lessonae (L-E-system)in which they persist by backcrossing with theparental species. Matings between hybrids areunsuccessful, because their ridibundagenomes contain fixed recessive deleteriousmutations. When introduced into a L-E-system,R. ridibunda can mate with both nativetaxa, producing R. ridibunda offspringwith R. esculenta, and R. esculentaoffspring with R. lessonae (primaryhybridizations). If primary hybrids arehybridogenetic, they produce viable R.ridibunda offspring in matings with otherhybrids, because their clonal genomes areunlikely to share the deleterious allelespresent in the ancient clones. Thus, R.ridibunda will increase in the population atthe expense of both native taxa, eventuallyleaving a pure R. ridibunda population.We provide three lines of evidence for thisprocess from a currently invaded population inSwitzerland: (1) Primary hybridizations takeplace, as roughly 10% of hybrids in thepopulation possess ridibunda genomesderived from the introduced frogs. (2)Hybridogenesis occurs in primary hybrids,although at a low frequency. (3) Many hybrid ×hybrid matings in the population indeed produceviable offspring. Hence, the proposed geneticmechanism appears to contribute to the speciesreplacement, although its importance may belimited.     

Implant–bone interface healing and adaptation in resurfacing hip replacement

Hip resurfacing demonstrates good survivorship as a treatment for young patients with osteoarthritis, but occasional implant loosening failures occur. On the femoral side there is radiographic evidence suggesting that the implant stem bears load, which is thought to lead to proximal stress shielding and adaptive bone remodelling. Previous attempts aimed at reproducing clinically observed bone adaptations in response to the implant have not recreated the full set of common radiographic changes, so a modified bone adaptation algorithm was developed in an attempt to replicate more closely the effects of the prosthesis on the host bone. The algorithm features combined implant–bone interface healing and continuum bone remodelling. It was observed that remodelling simulations that accounted for progressive gap filling at the implant–bone interface predicted the closest periprosthetic bone density changes to clinical X-rays and DEXA data. This model may contribute to improved understanding of clinical failure mechanisms with traditional hip resurfacing designs and enable more detailed pre-clinical analysis of new designs.     

Indolin-2-one p38α inhibitors III: bioisosteric amide replacement

Crystallographic structural information was used in the design and synthesis of a number of bioisosteric derivatives to replace the amide moiety in a lead series of p38α inhibitors which showed general hydrolytic instability in human liver preparations. Triazole derivative 13 was found to have moderate bioavailability in the rat and demonstrated potent in-vivo activity in an acute model of inflammation.     

Hormone replacement therapy--is there a place for its use in neurology?

Stroke remains the third leading cause of mortality in developed countries despite declining tendency over the past decades. As the leading cause of disability and second cause of dementia, primary prevention should be the main way to fight the disease, since therapy is not efficient enough. Several observations pointed to estrogen as a protective agent that may reduce stroke risk, however, studies have shown conflicting data. There is no strong evidence that hormone replacement therapy (HRT) increases stroke risk. Several studies have shown that HRT may reduce the risk of fatal stroke. Conflicting results have been found for Alzheimer's disease and HRT as well. An association between higher serum concentration of estradiol and decreased risk of cognitive decline has been found in some studies, supporting the hypothesis that estrogen concentration may play a significant role in brain protection. Having in mind results of recent randomized trials, it is suggested that HRT should not be recommended on general basis for the primary or secondary prevention of cardiovascular/cerebrovascular diseases or for primary prevention of degenerative diseases such as Alzheimer's disease. Osteoporosis, cognitive decline and climacteric symptoms that are likely to impact on quality of life, speak in favor for recommendation of HRT use. On the other side, family history of breast carcinoma, mastopathy, thromboembolism, in certain cases gallbladder disease, will discourage the commencement of HRT. Respecting the patient's preferences and having benefits and risks in mind as well as science advisory statements, individual counseling regarding HRT should be the leading concept in the healthcare of postmenopausal women.     

7-Hydroxydehydroepiandrosterone--a natural antiglucocorticoid and a candidate for steroid replacement therapy?

7-Hydroxylated metabolites of dehydroepiandrosterone (DHEA) are believed to be responsible for at least some immunomodulatory and antiglucocorticoid effects of DHEA and hence are considered candidates for hormone replacement therapy. Our experiments in vitro brought the evidence that 3beta, 7beta-dihydroxy-5-androsten-3-one (7beta-OH-DHEA), but not DHEA and its 7alpha-hydroxyisomer, could counteract the immunosuppressive effect of dexamethasone on the formation of plaques in culture of murine spleen lymphocytes. In another experiment, DHEA and after a 3-weeks pause 3beta-hydroxy-5-androstene-7,17-dione (7-oxo-DHEA) were applied transdermally to 6 male volunteers on 5 consecutive days. Blood levels of DHEA, its 7-hydroxylated metabolites, and in the first case also dehydroepiandrosterone sulphate (DHEAS), were measured before, during and one day after the end of treatment. Application of DHEA increased significantly not only DHEA and DHEAS, but also its both 7-hydroxyisomers. Application of 7-oxo-DHEA also led to a significant increase of both 7-hydroxyisomers of DHEA, with 7beta-OH-DHEA being the preferred metabolite the concentration of which was increased more than three times.     

Transcatheter aortic valve replacement with the 34 mm Medtronic Evolut valve

Objectives

To report our experience with the recently introduced 34?mm Evolut transcatheter aortic valve replacement (TAVR) prosthesis.

Background

A larger TAVR prosthesis has become available for the treatment of aortic stenosis (AVS) in larger native aortic annuli (up to 30?mm). Outcomes with this new device are still unreported.

Results

The first 25 transfemoral TAVRs performed by our team with the self-expandable 34?mm Evolut are presented. The majority of patients were male (84%) with a mean age of 81.3?±?5.6 years, a median logistic euro-SCORE of 14.7 (5.4-61.0), and a computed tomography measured mean perimeter-derived aortic annulus diameter of 27.1?±?1.4?mm (min. 25.0–max. 31.2?mm). We implanted one 34?mm Evolut in all patients. Median operative time and radiation time were 68.5 and 12.4?min respectively. To optimise final valve position and haemodynamic performance, at least one complete re-sheathing and re-positioning of the same valve was reported in 33.2%. New permanent pacemaker implantation (PPMI) was necessary in 28.5%. At Receiver Operating Characteristic (ROC) analysis, a minimal diameter of the left ventricular outflow tract <21.9?mm was a significant predictor for PPMI (specificity 82%; sensitivity 83%; p?=?0.005; Area Under the Curve (AUC)?=?0.9). Length of stay in hospital was 9.2?±?5.8 days and no in-hospital death was reported. At discharge, grade 1?+?para-valvular regurgitation was present in 32%, and no regurgitation in the remaining patients. Device success and early safety were 100% and 92% respectively.

Conclusions

TAVR with the 34?mm Evolut prosthesis has shown satisfactory acute outcomes. Although results are consistent with those observed with smaller Evolut prostheses, a trend for a higher PPMI rate has been noticed and could derive from a higher oversizing rate.

     

Apical Na+ permeability of frog skin during serosal Cl− replacement

Summary Gluconate substitution for serosal Cl^– reduces the transepithelial short-circuit current (I _sc) and depolarizes shortcircuited frog skins. These effects could result either from inhibition of basolateral K⁺ conductance, or from two actions to inhibit both apical Na⁺ permeability (P _Na ^ap ) and basolateral pump activity. We have addressed this question by studying whole-and split-thickness frog skins. Intracellular Na⁺ concentration (C _Na ^c ) andP _Na ^ap have been monitored by measuring the currentvoltage relationship for apical Na⁺ entry. This analysis was conducted by applying trains of voltage pulses, with pulse durations of 16 to 32 msec. Estimates ofP _Na ^ap ) and CNa/c were not detectably dependent on pulse duration over the range 16 to 80 msec. Serosal Cl^– replacement uniformly depolarized short-circuited tissues. The depolarization was associated with inhibition ofI _sc across each split skin, but only occasionally across the whole-thickness preparations. This difference may reflect the better ionic exchange between the bulk medium and the extracellular fluid in contact with the basolateral membranes, following removal of the underlying dermis in the split-skin preparations.P _Na ^ap was either unchanged or increased, and CNa/c either unchanged or reduced after the anionic replacement. These data are incompatible with the concept that serosal Cl^– replacement inhibitsP _Na ^ap and Na, K-pump activity. Gluconate substutition likely reduces cell volume, triggering inhibition of the basolateral K⁺ channels, consistent with the data and conclusions of S.A. Lewis, A.G. Butt, M.J. Bowler, J.P. Leader and A.D.C Macknight (J. Membrane Biol. 83:119–137, 1985) for toad bladder. The resulting depolarization reduces the electrical force favoring apical Na⁺ entry. The volume-conductance coupling serves to conserve volume by reducing K⁺ solute loss. Its molecular basis remains to be identified.