The cost of walking downhill: Is the preferred gait energetically optimal?

Humans tend to prefer walking patterns that minimize energetic cost, but must also maintain stability to avoid falling over. The relative importance of these two goals in determining the preferred gait pattern is not currently clear. We investigated the relationship between energetic cost and stability during downhill walking, a context in which gravitational energy will assist propulsion but may also reduce stability. We hypothesized that humans will not minimize energetic cost when walking downhill, but will instead prefer a gait pattern that increases stability. Simulations of a dynamic walking model were used to determine whether stable downhill gaits could be achieved using a simple control strategy. Experimentally, twelve healthy subjects walked downhill at 1.25 m/s (0, 0.05, 0.10, and 0.15 gradients). For each slope, subjects performed normal and relaxed trials, in which they were instructed to reduce muscle activity and allow gravity to maximally assist their gait. We quantified energetic cost, stride timing, and leg muscle activity. In our model simulations, increase in slope reduced the required actuation but also decreased stability. Experimental subjects behaved more like the model when using the relaxed rather than the normal walking strategy; the relaxed strategy decreased energetic cost at the steeper slopes but increased stride period variability, an indicator of instability. These results indicate that subjects do not take optimal advantage of the propulsion provided by gravity to decrease energetic cost, but instead prefer a more stable and more costly gait pattern.     

Is there a role for culture in human behavioral ecology?

Most research in human behavioral ecology has been acultural, which raises the question of how best to incorporate the concept of culture into this approach. A necessary step in this direction is to pare the culture concept down to its ideational elements, excluding behavior and its material products (Durham 1991; Geertz 1973; Keesing 1974). The cultural and reproductive success hypothesis, though empirically successful (Irons 1993), is not a model for all of culture because of widespread discrepancies between behavior and culture to which it does not call attention. Cultural transmission models are also weakened by such discrepancies, but, more importantly, such models are most relevant to phenomena different from those central to human behavioral ecology. A better way to incorporate culture into human behavioral ecology is to see it as the context of human action and as a tool people use in social manipulation. The study of signal systems is a key to an understanding of social manipulation and to the incorporation of culture into human behavioral ecology. Examples of the manipulation of culture for reproductive benefit include Yanomamö kin term manipulation (Chagnon 1988), incest rules (Thornhill 1990, 1991), and the derogation of sexual competitors (Buss and Dedden 1990). The human behavioral ecological study of social manipulation in cultural contexts needs to be expanded. Two phenomena that might shed light on such manipulation are the Rashomon effect and the audience effect.     

Is metamorphosis a critical interval in the early life of marine fishes?

Synopsis Small volumes of food in ‘stomach’, large proportions of empty ‘stomachs’ and small maximum sizes of prey during metamorphosis of cod,Gadus morhua, all point to an energy crisis during this developmental interval. The small size of the developing stomach of the 10–14 mm long cod may be partly responsible for the above mentioned difficulties during metamorphosis. A hypothesis based on Hjort's ‘critical stage theory’ is proposed, adding another critical interval at metamorphosis. Based on the presented data on cod and reports on other species in the literature, the new critical interval is discussed for larvae of marine fish species in general.     

Evidence for a stromal-epithelial “lactate shuttle” in human tumors

Recently, we proposed a new mechanism for understanding the Warburg effect in cancer metabolism. In this new paradigm, cancer-associated fibroblasts undergo aerobic glycolysis, and extrude lactate to “feed” adjacent cancer cells, which then drives mitochondrial biogenesis and oxidative mitochondrial metabolism in cancer cells. Thus, there is vectorial transport of energy-rich substrates from the fibroblastic tumor stroma to anabolic cancer cells. A prediction of this hypothesis is that cancer-associated fibroblasts should express MCT4, a mono-carboxylate transporter that has been implicated in lactate efflux from glycolytic muscle fibers and astrocytes in the brain. To address this issue, we co-cultured MCF7 breast cancer cells with normal fibroblasts. Interestingly, our results directly show that breast cancer cells specifically induce the expression of MCT4 in cancer-associated fibroblasts; MCF7 cells alone and fibroblasts alone, both failed to express MCT4. We also show that the expression of MCT4 in cancer-associated fibroblasts is due to oxidative stress, and can be prevented by pre-treatment with the anti-oxidant N-acetyl-cysteine. In contrast to our results with MCT4, we see that MCT1, a transporter involved in lactate uptake, is specifically upregulated in MCF7 breast cancer cells when co-cultured with fibroblasts. Virtually identical results were also obtained with primary human breast cancer samples. In human breast cancers, MCT4 selectively labels the tumor stroma, e.g., the cancer-associated fibroblast compartment. Conversely, MCT1 was selectively expressed in the epithelial cancer cells within the same tumors. Functionally, we show that overexpression of MCT4 in fibroblasts protects both MCF7 cancer cells and fibroblasts against cell death, under co-culture conditions. Thus, we provide the first evidence for the existence of a stromal-epithelial lactate shuttle in human tumors, analogous to the lactate shuttles that are essential for the normal physiological function of muscle tissue and brain. These data are consistent with the “reverse Warburg effect,” which states that cancer-associated fibroblasts undergo aerobic glycolysis, thereby producing lactate, which is utilized as a metabolic substrate by adjacent cancer cells. In this model, “energy transfer” or “metabolic-coupling” between the tumor stroma and epithelial cancer cells “fuels” tumor growth and metastasis, via oxidative mitochondrial metabolism in anabolic cancer cells. Most importantly, our current findings provide a new rationale and novel strategy for anti-cancer therapies, by employing MCT inhibitors.     

Is there a gender difference of somatostatin-receptor density in the human brain?

Animal experiments and observations in human brains have convincingly shown that sexual differentiation not only concerns the genitalia but also the brain. This has been investigated also in the light of a possible explanation of a presumed biological aetiology of transsexuality. The volume of the central subdivision of the bed nucleus of the stria terminalis, a brain area that is essential for sexual behaviour, has been reported to be larger in men than in women. Additionally, the number of somatostatin expressing neurons in this region was shown to be higher in men than in women. As neuronal production of somatostatin is involved the idea is striking whether somatostatin-receptor density in the cortex of cerebral hemispheres might be related to gender identity. We investigated in vivo the density of somatostatin-receptors in selected regions of the human brain in both sexes by means of receptor scintigraphy. Basal ganglia tracer uptake of 111-In-Pentreotide was equally low in both genders at 0,80% +/ 0,26 (related to tracer uptake of the whole brain layer). Temporal cortex accumulated at 2,9% +/ 1,1 in men and at 2,3% +/ 0,76 in women. Frontal brain region had an uptake of 3,0% +/ 1,4 in male and of 2,5% +/ 1,3 in female. This shows a tendency in males for relatively augmented uptake indicating higher somatostatin receptor density in temporal and frontal cerebral cortex.     

Statistical Use in Clinical Studies: Is There Evidence of a Methodological Shift?

Background

Several studies indicate that the statistical education model and level in medical training fails to meet the demands of clinicians, especially when they want to understand published clinical research. We investigated how study designs and statistical methods in clinical studies have changed in the last twenty years, and we identified the current trends in study designs and statistical methods in clinical studies.

Methods

We reviewed 838 eligible clinical study articles that were published in 1990, 2000, and 2010 in four journals New England Journal of Medicine, Lancet, Journal of the American Medical Association and Nature Medicine. The study types, study designs, sample designs, data quality controls, statistical methods and statistical software were examined.

Results

Substantial changes occurred in the past twenty years. The majority of the studies focused on drug trials (61.6%, n = 516). In 1990, 2000, and 2010, there was an incremental increase in RCT studies (74.4%, 82.8%, and 84.0%, respectively, p = 0.013). Over time, there was increased attention on the details of selecting a sample and controlling bias, and there was a higher frequency of utilizing complex statistical methods. In 2010, the most common statistical methods were confidence interval for superiority and non-inferiority comparison (41.6%), survival analysis (28.5%), correction analysis for covariates (18.8%) and Logistic regression (15.3%).

Conclusions

These findings indicate that statistical measures in clinical studies are continuously developing and that the credibility of clinical study results is increasing. These findings provide information for future changes in statistical training in medical education.     

Is chymotrypsin output a better diagnostic index than the measurement of chymotrypsin in random stool?

This study compares the diagnostic utility of fecal chymotrypsin (CT) output in timed stool collections and random stools using a new photometric enzyme assay. The CT output (mean +/- SD, U/24 h) was 1,487 +/- 1,980 in 127 children with normal fat absorption and negative sweat-chloride test (mean age 45 months), and 1,804 +/- 1,452 in 27 cases with fat malabsorption due to nonpancreatic disease (mean age 41 months). 66 cases of cystic fibrosis (CF) were examined (mean age 119 months). Stool output in 19 newly diagnosed patients before therapy was 85 +/- 94, in 42 patients receiving enzyme replacement therapy was 3,462 +/- 2,841, and in 5 patients with pancreatic sufficiency 1,754 +/- 1,482. Using nonparametric statistics, 120 U/24 h was defined as the lower limit of the 95-percentile for stool CT output. Only 5 of the 127 patients with normal fat absorption had output below that limit. None of the patients with nonpancreatic malabsorption and only 1 treated CF patient had lower values. Sixteen of the newly diagnosed CF patients had stool CT less than 120 U/24 h. The sensitivity of the test is therefore 84% and its specificity 97% at this decision threshold. However, no diagnostic advantage is gained from measuring CT output in timed stool collections as compared to random stools.     

Cognitive effects of variations in pubertal timing: Is puberty a period of brain organization for human sex-typed cognition?

There is considerable interest in the organizational effects of pubertal sex hormones on human sex-related characteristics. Recent evidence from rodents suggests that there is a decreasing window of sensitivity to sex hormones throughout adolescence. If adolescence also represents a period of brain organization in human beings, then the timing of exposure to sex-typical hormones at puberty should have long-term effects on sex-typed characteristics: individuals with early timing should be more sex-typed than individuals with late timing. We tested this hypothesis in 320 young adults by relating their pubertal timing (retrospective comparison to peers) to cognitive abilities that show sex differences. Results provide partial support for the hypothesis. For men, pubertal timing was inversely related to scores on a test of three-dimensional mental rotations. Effects do not appear to be due to duration of hormone exposure (time since puberty), but other potential influences need further study.     

What Evidence Is There for the Homology of Protein-Protein Interactions?

The notion that sequence homology implies functional similarity underlies much of computational biology. In the case of protein-protein interactions, an interaction can be inferred between two proteins on the basis that sequence-similar proteins have been observed to interact. The use of transferred interactions is common, but the legitimacy of such inferred interactions is not clear. Here we investigate transferred interactions and whether data incompleteness explains the lack of evidence found for them. Using definitions of homology associated with functional annotation transfer, we estimate that conservation rates of interactions are low even after taking interactome incompleteness into account. For example, at a blastp -value threshold of , we estimate the conservation rate to be about between S. cerevisiae and H. sapiens. Our method also produces estimates of interactome sizes (which are similar to those previously proposed). Using our estimates of interaction conservation we estimate the rate at which protein-protein interactions are lost across species. To our knowledge, this is the first such study based on large-scale data. Previous work has suggested that interactions transferred within species are more reliable than interactions transferred across species. By controlling for factors that are specific to within-species interaction prediction, we propose that the transfer of interactions within species might be less reliable than transfers between species. Protein-protein interactions appear to be very rarely conserved unless very high sequence similarity is observed. Consequently, inferred interactions should be used with care.     

Evidence of a tipping point in a southern African savanna?

Many ecosystems exhibit threshold behaviour, where periods of relative stability are punctuated by rapid transitions between alternate stable states when an ecological threshold, or tipping point, is reached. This is of concern in grass-dominated habitats, many of which appear to be on the point of conversion to more wooded vegetation assemblages. However, changes in grass-dominated ecosystems are often difficult to interpret, because it is not always clear whether grasslands are ancient or are anthropogenically derived from past deforestation. As a result, the conservation, maintenance and restoration of ancient grasslands are sometimes neglected.In this study, the history of vegetation change in the savannas of the Hluhluwe-iMfolozi Park, KwaZulu-Natal, South Africa, are investigated by analysing stable carbon isotopes (δ¹³C) from soil profiles. Without exception, the data show that C₃ dominated thicket, forest, and densely wooded savanna now occur on sites that were previously C₄ grassland or open savanna. Although the drivers of this change are not clear, there is potential for management intervention because tree density can be manipulated through fire, a natural part of this dynamic landscape. The study identified two sites which are at a threshold between C₄ and C₃ dominance, and highlighted them as priorities for conservation management intervention.     

Evidence for hilltopping in bumblebees?

1. Male bumblebees are known to exhibit a range of mate‐location behaviours, including perching on prominent objects and darting at passing queens, patrolling of scent‐marked flight routes, and waiting outside nest entrances for virgin queens to emerge. Here we provide evidence for a fourth strategy, known as hilltopping. This behaviour is widely known from a range of invertebrates, but has not previously been described in bumblebees. 2. We studied the distribution of bumblebees along transects ascending four hills in Scotland and demonstrate that, relative to workers, males of four bumblebee species or species groups (Bombus lapidarius, B. monticola, B. pascuorum, and B. lucorum/magnus/cryptarum/terrestris) tend to congregate at or near the tops of hills. This is, to our knowledge, the first evidence for hilltopping in bumblebees and the first record of any putative mate‐locating behaviour for male B. pascuorum, a very common species in Europe. 3. We note that, in common with most previous studies of mate‐locating behaviour in bumblebees, attraction of virgin queens and mating were not observed.     

Is Telomere Length a Biomarker for Aging: Cross-Sectional Evidence from the West of Scotland?

Background

The search for biomarkers of aging (BoAs) has been largely unsuccessful to-date and there is widespread skepticism about the prospects of finding any that satisfy the criteria developed by the American Federation of Aging Research. This may be because the criteria are too strict or because a composite measure might be more appropriate. Telomere length has attracted a great deal of attention as a candidate BoA. We investigate whether it meets the criteria to be considered as a single biomarker of aging, and whether it makes a useful contribution to a composite measure.

Methodology/Principal Findings

Using data from a large population based study, we show that telomere length is associated with age, with several measures of physical and cognitive functioning that are related to normal aging, and with three measures of overall health. In the majority of cases, telomere length adds predictive power to that of age, although it was not nearly as good a predictor overall. We used principal components analysis to form two composites from the measures of functioning, one including telomere length and the other not including it. These composite BoAs were better predictors of the health outcomes than chronological age. There was little difference between the two composites.

Conclusions

Telomere length does not satisfy the strict criteria for a BoA, but does add predictive power to that of chronological age. Equivocal results from previous studies might be due to lack of power or the choice of measures examined together with a focus on single biomarkers. Composite biomarkers of aging have the potential to outperform age and should be considered for future research in this area.     

Is parainfluenza virus a threatening virus for human cancer cell lines?

Immortalized cell lines, such as human cancer cell lines, are an indispensable experimental resource for many types of biological and medical research. However, unless the cell line has been authenticated prior to use, interpretation of experimental results may be problematic. The potential problems this may cause are illustrated by studies in which authentication of cell lines has not been carried out. For example, immortalized cell lines may unknowingly be infected with viruses that alter their characteristics. In fact, parainfluenza virus type 5 (PIV5) poses a threat to the use of immortalized cell lines in biological and medical research; PIV5 infection significantly alters cellular physiology associated with the response to interferon. If PIV5 infection is widespread in immortalized cell lines, then a very large number of published studies might have to be re-evaluated. Fortunately, analyses of a large number of immortalized cell lines indicate that PIV5 infection is not widespread.     

The walking dead: Is hydroethidine a suitable viability dye for intra-erythrocytic Plasmodium falciparum?

Hydroethidine has been used as a viability dye in various haemoparasites, including Plasmodium species. We compared flow cytometric quantification by hydroethidine and thiazole orange in P. falciparum. Dead parasites that did not develop or replicate exhibited high levels of DNA fragmentation and abnormal microscopic morphology, but were detected as viable ring-stage parasites by hydroethidine. Hydroethidine quantification was similar to thiazole orange, a DNA-binding dye that stains live and dead parasites. Data obtained cast concerns on hydroethidine as a suitable viability dye in P. falciparum and highlight the necessity of proper gating in flow cytometric studies quantifying parasitaemia.     

Is adenosine a second metabolic substrate for human red blood cells?

Adenosine is present in the micromolar range in human plasma. In this study, metabolism of adenosine, which was maintained between 0.62 +/- 0.03 and 2.92 +/- 0.43 microM by means of a continuous infusion using a Harvard infusion pump, was investigated in human red blood cells. It was found that lactate production increases linearly as the adenosine concentration was raised. Cells infused with an average adenosine concentration of 2 microM produced lactate comparable to that produced by 5 mM glucose. The extent to which ATP concentration is maintained by adenosine also depends on its concentration. After a 4 h infusion with an average adenosine concentration of 0.7 microM, ATP content amounts to 75% of the glucose control. Raising the adenosine infusion concentration to 1.5 microM results in a full maintenance of ATP levels and at concentrations higher than 1.5 microM, adenosine produces a net synthesis of ATP. A net synthesis of ATP also occurs with adenosine concentration below 1.5 microM, if supplemented with glucose. In contrast, inosine infusion provides only a partial support of ATP and fails to produce a net synthesis of ATP in the presence of glucose. In addition, the presence of purine nucleoside and glucose together influence the metabolism of each other, depending on inorganic phosphate content (Pi). At a Pi concentration of 1 mM, the glucose consumption rate is reduced by approx. 25% by purine nucleoside infusion and vice versa. In sharp contrast, glucose consumption at 16 mM Pi is potentiated by adenosine. These findings suggest that plasma adenosine contributes significantly to human red cell energetics, even though it is present at a concentration several orders of magnitude lower than glucose.     

Is there any scientific evidence for the use of glucosamine in the management of human osteoarthritis?

Glucosamine in its acetylated form is a natural constituent of some glycosaminoglycans (for example, hyaluronic acid and keratan sulfate) in the proteoglycans found in articular cartilage, intervertebral disc and synovial fluid. Glucosamine can be extracted and stabilized by chemical modification and used as a drug or a nutraceutical. It has been approved for the treatment of osteoarthritis (OA) in Europe to promote cartilage and joint health and is sold over the counter as a dietary supplement in the United States. Various formulations of glucosamine have been tested, including glucosamine sulfate and glucosamine hydrochloride. In vitro and in vivo studies have uncovered glucosamine's mechanisms of action on articular tissues (cartilage, synovial membrane and subchondral bone) and justified its efficacy by demonstrating structure-modifying and anti-inflammatory effects at high concentrations. However, results from clinical trials have raised many concerns. Pharmacokinetic studies have shown that glucosamine is easily absorbed, but the current treatment doses (for example, 1,500 mg/day) barely reach the required therapeutic concentration in plasma and tissue. The symptomatic effect size of glucosamine varies greatly depending on the formulation used and the quality of clinical trials. Importantly, the effect size reduces when evidence is accumulated chronologically and evidence for the structure-modifying effects of glucosamine are sparse. Hence, glucosamine was at first recommended by EULAR and OARSI for the management of knee pain and structure improvement in OA patients, but not in the most recent NICE guidelines. Consequently, the published recommendations for the management of OA require revision. Glucosamine is generally safe and although there are concerns about potential allergic and salt-related side effects of some formulations, no major adverse events have been reported so far. This paper examines all the in vitro and in vivo evidence for the mechanism of action of glucosamine as well as reviews the results of clinical trials. The pharmacokinetics, side effects and differences observed with different formulations of glucosamine and combination therapies are also considered. Finally, the importance of study design and criteria of evaluation are highlighted as new compounds represent new interesting options for the management of OA.