Use of thiazolidinediones and the risk of bladder cancer among people with type 2 diabetes: a meta-analysis

Background:

Patients with type 2 diabetes have a 40% increased risk of bladder cancer. Thiazolidinediones, especially pioglitazone, may increase the risk. We conducted a systematic review and meta-analysis to evaluate the risk of bladder cancer among adults with type 2 diabetes taking thiazolidinediones.

Methods:

We searched key biomedical databases (including MEDLINE, Embase and Scopus) and sources of grey literature from inception through March 2012 for published and unpublished studies, without language restrictions. We included randomized controlled trials (RCTs), cohort studies and case–control studies that reported incident bladder cancer among people with type 2 diabetes who ever (v. never) were exposed to pioglitazone (main outcome), rosiglitazone or any thiazolidinedione.

Results:

Of the 1787 studies identified, we selected 4 RCTs, 5 cohort studies and 1 case–control study. The total number of patients was 2 657 365, of whom 3643 had newly diagnosed bladder cancer, for an overall incidence of 53.1 per 100 000 person-years. The one RCT that reported on pioglitazone use found no significant association with bladder cancer (risk ratio [RR] 2.36, 95% confidence interval [CI] 0.91–6.13). The cohort studies of thiazolidinediones (pooled RR 1.15, 95% CI 1.04–1.26; I² = 0%) and of pioglitazone specifically (pooled RR 1.22, 95% CI 1.07–1.39; I² = 0%) showed significant associations with bladder cancer. No significant association with bladder cancer was observed in the two RCTs that evaluated rosiglitazone use (pooled RR 0.87, 95% CI 0.34–2.23; I² = 0%).

Interpretation:

The limited evidence available supports the hypothesis that thiazolidinediones, particularly pioglitazone, are associated with an increased risk of bladder cancer among adults with type 2 diabetes.People with type 2 diabetes are at increased risk of several types of cancer, including a 40% increased risk of bladder cancer, compared with those without diabetes.^1,2 The strong association with bladder cancer is hypothesized to be a result of hyperinsulinemia, whereby elevated insulin levels in type 2 diabetes stimulate insulin receptors on neoplastic cells, promoting cancer growth and division.^1,3–5 Additional risk factors for bladder cancer include increased age, male sex, smoking, occupational and environmental exposures and urinary tract disease.⁶ Exogenous insulin and other glucose-lowering medications such as sulfonylureas, metformin and thiazolidinediones, may further modify the risk of bladder cancer.¹Data from the placebo-controlled PROactive trial of pioglitazone (PROspective pioglitAzone Clinical Trial in macroVascular Events) suggested a higher incidence of bladder cancer among pioglitazone users than among controls.⁷ Subsequent randomized controlled trials (RCTs) and observational studies have reported conflicting results for pioglitazone, with various studies reporting a significant increase,^8,9 a nonsignificant increase¹⁰ and even a decreased risk¹¹ of bladder cancer.To test the hypothesis that pioglitazone use is associated with an increased risk of bladder cancer, we conducted a systematic review and meta-analysis of RCTs and observational studies reporting bladder cancer among adults with type 2 diabetes taking pioglitazone. To clarify the possibility of a drug-class effect, we also examined data for all thiazolidinediones and for rosiglitazone alone.     

Do biotic interactions modulate ecosystem functioning along stress gradients? Insights from semi-arid plant and biological soil crust communities

Climate change will exacerbate the degree of abiotic stress experienced by semi-arid ecosystems. While abiotic stress profoundly affects biotic interactions, their potential role as modulators of ecosystem responses to climate change is largely unknown. Using plants and biological soil crusts, we tested the relative importance of facilitative–competitive interactions and other community attributes (cover, species richness and species evenness) as drivers of ecosystem functioning along stress gradients in semi-arid Mediterranean ecosystems. Biotic interactions shifted from facilitation to competition along stress gradients driven by water availability and temperature. These changes were, however, dependent on the spatial scale and the community considered. We found little evidence to suggest that biotic interactions are a major direct influence upon indicators of ecosystem functioning (soil respiration, organic carbon, water-holding capacity, compaction and the activity of enzymes related to the carbon, nitrogen and phosphorus cycles) along stress gradients. However, attributes such as cover and species richness showed a direct effect on ecosystem functioning. Our results do not agree with predictions emphasizing that the importance of plant–plant interactions will be increased under climate change in dry environments, and indicate that reductions in the cover of plant and biological soil crust communities will negatively impact ecosystems under future climatic conditions.     

Patterns of body temperatures: Is lizard thermoregulation chaotic?

We surveyed body temperature (T_b) fluctuations of 23 species of thermoregulating lizards (9 families, 305 individuals) for pattern similarities. Here we report that the T_b time-series patterns of all species and almost all individuals met both qualitative criteria and quantitative criteria (positive Lyapunov exponent and capacity and/or correlation dimensions less than 5, and Hurst exponent not equal to 0.5) for deterministic chaos. Chaotic thermoregulation appears controlled, but at unpredictable times becomes disturbed and exhibits nonlinear behaviors before returning to control. This chaotic pattern of regulation is common to sufficiently diverse species to suggest that it is likely a primitive lacertilian, and perhaps reptilian, physiological characteristic.     

Iron-histidine resonance raman band of deoxyheme proteins: effects of anharmonic coupling and glass-liquid phase transition

Weak anharmonic coupling of two soft molecular vibrations is shown to cause pronounced temperature dependence of the corresponding resonance Raman bands. The developed theory is used to interpret the temperature dependence of the iron-histidine band of deoxyheme proteins and model compounds. It is shown that anharmonic coupling of the iron-histidine and heme doming vibrations must cause pronounced broadening of the band, its asymmetry, and shift of its maximum to the red upon heating. It also can lead to a structured shape of this band at room temperature. Proper consideration of the anharmonic coupling allows simulation of the temperature dependence of the iron-histidine band shape of horse heart myoglobin in the temperature interval of 10-300 K, using the minimum number of necessary parameters. Analysis of this temperature dependence clearly shows that the iron-histidine band of deoxyheme proteins is sensitive to the glass-liquid phase transition in the protein hydration shell, which takes place at 160-190 K.     

Modelling the impact of the regulation of estuarine drift‐netting on the declared rod catch of Atlantic salmon Salmo salar L. in the River Usk

1. A novel method was used to determine if the statutory regulation of drift‐netting at the mouth of the River Usk in Wales was associated with a significant improvement in the stock and rod catch of salmon in the river upstream.
2. A linear regression model was constructed, in which the annual rod catch of salmon declared from the Usk between 1977 and 1988 was the dependent variable and the simultaneous annual catch declared from the nearby River Wye was the independent variable. The model was extrapolated to project the annual rod catches of salmon on the Usk, relative to the Wye, between 1989 and 1995.
3. The model accurately projected the actual rod catches declared from the Usk in 1989, 1990 and 1991. However, between 1992 and 1995 the declared catches deviated significantly ( P ≤ 0.05) from those projected by the model. The upsurge in rod catches declared after 1992 from the Usk, relative to the Wye was concomitant with the regulation of estuarine drift‐netting.
4. It was concluded that diminished estuarine exploitation had a beneficial impact on salmon angling success on the Usk. However, the utility of the model was restricted by inconsistencies in the methods used to generate the data, by changes in fishery management policies and by a lack of essential information on the interrelationships between catch, effort, stock and environmental conditions.     

Fluctuations in numbers of great white pelicans at Lake St Lucia in response to changing water-levels

In January 2004, Lake St Lucia, a major part of the Greater St Lucia Wetland Park, was reduced to a fraction of its normal capacity as a result of a severe drought in this region of KwaZulu-Natal, South Africa. After rains in the area, the lake level rose and then fluctuated considerably over the next 42 months. During the first 38 months the mouth of the estuary into the sea was closed. The area entered a second severe period of prolonged drought from mid 2005 through to the spring of 2006. Great white pelican ( Pelecanus onocrotalus Linnaeus, 1758 ) numbers and lake levels were monitored during these 42 months. Pelican numbers were highly variable ranging from 0 to 6000. When lake levels were very low or too high, no pelicans were present. Pelican numbers appeared more indicative of food availability. Implications of these trends to the management of the lake and the conservation of the avifauna are discussed. It is suggested that the great white pelican could be used as an indicator species for the fish dynamics of the lake at medium to low lake levels.     

The bias associated with the dispersion of length at age in the estimation of growth and mortality parameters from uni-modal length-frequency data

Values of M and M/K extracted from simulated uni-modal length-frequency data representing 28 fish stocks were biased. The bias exceeded 20% when the life span of the stock was <5 or >15 years.