Adiponectin is a negative regulator of bone mineral and bone strength in growing mice

Obesity is associated with increased bone mineral density (BMD) but the mechanism for this is unclear. Serum levels of the adipokine adiponectin are inversely correlated with obesity, but results from studies on its relationship to bone mass are conflicting. The objective of this study was to compare bone mineral content (BMC), BMD and biomechanical strength properties of femur and lumbar vertebrae in 8- and 16-week old adiponectin transgenic mice (AdTg). These mice exhibit significantly elevated circulating adiponectin but have similar body weights compared to wild-type (WT) littermates that were used as controls. Female AdTg mice displayed significantly lower femur BMC at 8 and 16 weeks of age and femur neck peak load was significantly lower in 8-week old AdTg mice of both genders compared to controls. The peak load from compression testing of an individual lumbar vertebra was significantly lower in female AdTg mice compared to WT at 8 weeks, and this difference persisted at 16 weeks of age. In addition, lumbar vertebrae BMC was significantly lower in 16-week old male AdTg mice compared to WT although vertebra peak load was not different. Serum adiponectin levels were inversely correlated with femur BMC. In summary, elevated circulating adiponectin inhibits the acquisition of bone mass in growing mice and results in decreased biomechanical measures of functional strength that are surrogate measures of susceptibility to fractures. These results support a role for circulating adiponectin as a metabolic link that can explain, at least in part, the positive relationship between obesity and both bone mass and reduced susceptibility to fractures.     

Cardiac survival in anoxia-tolerant vertebrates: An electrophysiological perspective

Certain vertebrates, such as freshwater turtles of the genus Chrysemys and Trachemys and crucian carp (Carassius carassius), have anoxia-tolerant hearts that continue to function throughout prolonged periods of anoxia (up to many months) due to successful balancing of cellular ATP supply and demand. In the present review, we summarize the current and limited understanding of the cellular mechanisms underlying this cardiac anoxia tolerance. What emerges is that cold temperature substantially modifies cardiac electrophysiology to precondition the heart for winter anoxia. Intrinsic heart rate is slowed and density of sarcolemmal ion currents substantially modified to alter cardiac action potential (AP) characteristics. These changes depress cardiac activity and reduce the energetic costs associated with ion pumping. In contrast, anoxia per se results in limited changes to cardiac AP shape or ion current densities in turtle and crucian carp, suggesting that anoxic modifications of cardiac electrophysiology to reduce ATP demand are not extensive. Additionally, as knowledge of cellular physiology in non-mammalian vertebrates is still in its infancy, we briefly discuss the cellular defense mechanisms towards the acidosis that accompanies anoxia as well as mammalian cardiac models of hypoxia/ischemia tolerance. By examining if fundamental cellular mechanisms have been conserved during the evolution of anoxia tolerance we hope to have provided a framework for the design of future experiments investigating cardiac cellular mechanisms of anoxia survival.     

Plant electrical memory

Electrical signaling, short-term memory and rapid closure of the carnivorous plant Dionaea muscipula Ellis (Venus flytrap) have been attracting the attention of researchers since the XIX century. We found that the electrical stimulus between a midrib and a lobe closes the Venus flytrap upper leaf without mechanical stimulation of trigger hairs. The closing time of Venus flytrap by electrical stimulation is the same as mechanically induced closing. Transmission of a single electrical charge between a lobe and the midrib causes closure of the trap and induces an electrical signal propagating between both lobes and midrib. The Venus flytrap can accumulate small subthreshold charges, and when the threshold value is reached, the trap closes. Repeated application of smaller charges demonstrates the summation of stimuli. The cumulative character of electrical stimuli points to the existence of short-term electrical memory in the Venus flytrap.Key words: plant memory, electrophysiology, electrical signaling, venus flytrap, Dionaea muscipula ellisPlants are capable of intelligent responses to complex environmental signals.^1–27 Signaling and memory play fundamental roles in plant responses. The existence of different forms of plant memory is well known.^1–22 Depending on the duration of memory retention, there are three types of memory in plants: sensory memory, short term memory and long term memory. A few examples of studies involving plant memory are: transgeneration memory of stress,^1,6,10 immunological memory of tobacco plants²² and mountain birches,¹⁸ storage and recall functions in seedlings,⁹ chromatin remodelling in plant development,^4,19 vernalization and epigenetic memory of winter,^12,13 induced resistance and susceptibility to herbivory,² memory response in ABA-entrained plants,⁶ memory of stimulus,^16,17 and systematic acquired resistance in plants exposed to a pathogen.²² Cellular memory is an example of long term memory and is a long-term maintenance of a particular pattern of gene expression. Chromatin dynamics including histone modification, histone replacement and chromatin remodeling play key roles in cellular memory.⁴ Plants are intelligent organisms and capable of functions such as learning, individuality, plasticity and memory.⁵ There are a few mathematical models of plant learning and memory.^14,15 Some plants exhibit clues of an electrical memory as well.We found that Venus flytrap has a short term electrical memory^20,21 Rapid closure of the carnivorous plant Dionaea muscipula Ellis (Venus flytrap) has been attracting the attention of researchers and as a result its mechanism has been widely investigated. When an insect touches the trigger hairs, these mechanosensors generate an electrical signal that acts as an action potential, which activates the trap closing. Macfarlane²³ found that two mechanical stimuli required for the trap closing should be applied within an interval from 0.75 s to 20 s. Brown and Sharp²⁴ found that at high temperature of 35–40°C usually only one mechanical stimulus is required.The inducement of non-excitability after excitation and the summation of subthreshold irritations were developed in the vegetative and animal kingdoms in protoplasmic structures prior to morphological differentiation of nervous tissues. These protoplasmic structures merged into the organs of a nervous system and adjusted the interfacing of the organism with the environment. Some neuromotoric components include acetylcholine neurotransmitters, cellular messenger calmodulin, cellular motors actin and myosin, voltage-gated channels, and sensors for touch, light, gravity and temperature.^25–27 Although this nerve-like cellular equipment has not reached the same great complexity as in animal nerves, a simple neural network has been formed within the plasma membrane of a phloem or plasmodesmata enabling it to communicate efficiently over long distances.^5,26,27 The reason why plants have developed pathways for electrical signal transmission most probably lies in the necessity to respond rapidly to environmental stress factors. Different environmental stimuli evoke specific responses in living cells, which have the capacity to transmit a signal to the responding region. In contrast to chemical signals such as hormones, electrical signals are able to rapidly transmit information over long distances.²⁷ Electrical potentials have been measured at the tissue and whole plant levels.²⁶Using our new charge injection method,²⁰ it was evident that the application of an electrical stimulus between the midrib (positive potential) and a lobe (negative potential) causes Venus flytrap to close the trap without any mechanical stimulation. The average stimulation pulse voltage sufficient for rapid closure of the Venus flytrap was 1.50 V (standard deviation is 0.01 V, n = 50) for 1 s. The inverted polarity pulse with negative voltage applied to the midrib did not close the plant. Applying impulses in the same voltage range with different polarities for pulses of up to 100 s did not open the plant. It was found that energy for trap closure is generated by ATP hydrolysis. ATP is used by the motor cells for a fast transport of protons. The amount of ATP drops from 950 µM per midrib before mechanical stimulation to 650 µM per midrib after stimulation and closure.²⁸ However, it is not clear if electrical stimulation triggers closing process in the motor cells, or contributes energy to the closing action.The action potential delivers sufficient electrical charge to the midrib,²¹ which can activate the osmotic motor. To check this hypothesis, we measured effects of transmitted charge from the charged capacitors between the lobe and the midrib of Venus flytrap. Transmission of a single electrical charge (mean 13.63 µC, median 14.00 µC, std. dev. 1.51 µC, n = 41) causes trap closure and induces an electrical signal propagating between the lobes and the midrib. The electrical signal in the lobes was not an action potential, because its amplitude depended on the applied voltage from the charged capacitor. Charge induced closing of a trap plant can be repeated 2–3 times on the same Venus flytrap plant after reopening. Transmission of a single electrical charge (mean 13.63 µC, median 14.00 µC, std. dev. 1.51 µC, n = 41) causes the trap to close and induces an electrical signal that propagates between the lobe and the midrib. Figure 1 illustrates that the Venus flytrap can accumulate small charges, and when the threshold value is reached, the trap closes. A summation of stimuli is demonstrated through the repetitive application of smaller charges. If we apply two or more consecutive injections of electrical charge within a period of less than 50 s, the trap will close when a total of 14 µC charge is reached.Open in a separate windowFigure 1Mechanism of the Dionaea trap closure.Repeated application of smaller charges demonstrates a summation of stimuli. If we apply two or more injections of electrical charges within a period of less then 20 s, the Venus flytrap upper leaf closes as soon as the total of 14 µC charge is transmitted. Similar phenomenon was reported by Czaja,²⁹ who determined the intensity of threshold stimuli to be 2.4 µC for a closing electrostimulation of another carnivorous plant Aldrovanda vesiculosa, and 0.91 µC for an opening electrostimulation. Our attempts to open the Venus flytrap upper leaf by changing polarity of injected charge and increasing the charge from 14 µC to 100 µC were not successful. Usually, the trap opens a few days after closing in the same way as after mechanically stimulated closing.Previous work by Brown and Sharp²⁴ indicated that electrical shock between lower and upper leaves can cause the Venus flytrap to close, but in their article, the amplitude and polarity of applied voltage, charge and electrical current were not reported. The trap did not close when we applied the same electrostimulation between the upper and lower leaves as we applied between a midrib and a lobe, even when the injected charge was increased from 14 µC to 750 µC. It is probable that the electroshock induced by Brown and Sharp²⁴ had a very high voltage or electrical current.It is common knowledge that the leaves of the Venus flytrap actively employ turgor pressure and hydrodynamic flow for fast movement and catching insects. In these processes the upper and lower surfaces of the leaf behave quite differently. During the trap closing, the loss of turgor by parenchyma lying beneath the upper epidermis, accompanied by the active expansion of the tissues of the lower layers of parenchyma near the under epidermis, closes the trap. The cells on the inner face of the trap jettison their cargo of water, shrink and allow the trap lobe to fold over. The cells of the lower epidermis expand rapidly, folding the trap lobe over. These anatomical features constitute the basis of the new hydroelastic curvature model.²⁰In terms of electrophysiology, Venus flytrap responses can be considered in three stages: (i) stimulus perception, (ii) signal transmission and (iii) induction of response (Fig. 1).     

Canadians' Representation of Chemical,Biological, Radiological,Nuclear, and Explosive (CBRNE) Terrorism: A Content Analysis

The global threat of terrorism raises questions about preparedness and risk communication in the context of public health and security. Although experts discriminate between chemical, biological, radiological, nuclear, and explosive (CNRNE) terrorist events, little is known about how the Canadian public represents these forms of terrorism. A stratified random sample of 1502 Canadians participated in a telephone survey on CBRNE terrorism. A word association technique was used to assess first words or images that came to mind while thinking about different types of terrorist scenarios. Content analysis of this data revealed a number of potential uncertainties and misconceptions regarding different types of terrorism scenarios. Despite most frequently providing agents in response questions surrounding chemical or biological terrorism, respondents frequently confounded agents of biological and chemical nature. Similarly, different aspects of nuclear events were not consistently distinguished. Most notably, however, a sizable proportion of respondents had difficulty providing word associations to the different types of terrorist events or only provided vague responses that closely mirrored the scenario in question. Finally, images regarding the potential impacts of scenarios were infrequent. Implications for risk communication and preparedness are discussed; in particular, the need to provide the public with more detailed information regarding the nature of different forms of CBRNE terrorism and how to best prepare for a potential event.     

The influence of experiential knowledge on prenatal screening and testing decisions

Minimal research focuses on the process of decision making in the context of prenatal screening and testing. This paper outlines an important contextual influence on these decisions. Specifically, we propose that experiential knowledge, particularly about pregnancy, screening, and disability, has a significant influence on prenatal screening and testing decisions. Drawing upon 38 semistructured interviews with women, this study explored how women made prenatal screening and testing decisions. Qualitative data analysis revealed two types of experiential knowledge, empathetic and embodied, which played a pivotal role in women's thinking about the value of prenatal tests and whether or not they accepted the offer of screening, testing, or both. We conclude that prenatal genetic counseling could benefit from an exploration of clients' experiential knowledge, both empathetic and embodied forms.     

Variation in woody plant δ13C along a topoedaphic gradient in a subtropical savanna parkland

δ¹³C values of C₃ plants are indicators of plant carbon–water relations that integrate plant responses to environmental conditions. However, few studies have quantified spatial variation in plant δ¹³C at the landscape scale. We determined variation in leaf δ¹³C, leaf nitrogen per leaf area (N_area), and specific leaf area (SLA) in April and August 2005 for all individuals of three common woody species within a 308 × 12-m belt transect spanning an upland–lowland topoedaphic gradient in a subtropical savanna in southern Texas. Clay content, available soil moisture, and soil total N were all negatively correlated with elevation. The δ¹³C values of Prosopis glandulosa (deciduous N₂-fixing tree legume), Condalia hookeri (evergreen shrub), and Zanthoxylum fagara (evergreen shrub) leaves increased 1–4‰ with decreasing elevation, with the δ¹³C value of P. glandulosa leaves being 1–3‰ higher than those of the two shrub species. Contrary to theory and results from previous studies, δ¹³C values were highest where soil water was most available, suggesting that some other variable was overriding or interacting with water availability. Leaf N_area was positively correlated with leaf δ¹³C of all species (p < 0.01) and appeared to exert the strongest control over δ¹³C along this topoedaphic gradient. Since leaf N_area is positively related to photosynthetic capacity, plants with high leaf N_area are likely to have low p _I/p _a ratios and therefore higher δ¹³C values, assuming stomatal conductance is constant. Specific leaf area was not correlated significantly with leaf δ¹³C. Following a progressive growing season drought in July/August, leaf δ¹³C decreased. The lower δ¹³C in August may reflect the accumulation of ¹³C-depleted epicuticular leaf wax. We suggest control of leaf δ¹³C along this topoedaphic gradient is mediated by leaf N_area rather than by stomatal conductance limitations associated with water availability.     

Teaching professionalism: a tale of three schools

This article compares professionalism education from the vantage points of three different disciplines: medicine, law, and business. In particular, it asks how each of these professions conceives of "professionalism," and how these different conceptions affect what is taught to graduate students. The object of professionalism education differs among these three disciplines, as do the specific challenges to professionalism and professionalism education. The article offers examples of how professionalism is taught in medicine, law, and business, and what each profession might learn from the others in developing their professionalism education and pedagogy.     

An integrated approach to the prediction of chemotherapeutic response in patients with breast cancer

Background

A major challenge in oncology is the selection of the most effective chemotherapeutic agents for individual patients, while the administration of ineffective chemotherapy increases mortality and decreases quality of life in cancer patients. This emphasizes the need to evaluate every patient''s probability of responding to each chemotherapeutic agent and limiting the agents used to those most likely to be effective.

Methods and Results

Using gene expression data on the NCI-60 and corresponding drug sensitivity, mRNA and microRNA profiles were developed representing sensitivity to individual chemotherapeutic agents. The mRNA signatures were tested in an independent cohort of 133 breast cancer patients treated with the TFAC (paclitaxel, 5-fluorouracil, adriamycin, and cyclophosphamide) chemotherapy regimen. To further dissect the biology of resistance, we applied signatures of oncogenic pathway activation and performed hierarchical clustering. We then used mRNA signatures of chemotherapy sensitivity to identify alternative therapeutics for patients resistant to TFAC. Profiles from mRNA and microRNA expression data represent distinct biologic mechanisms of resistance to common cytotoxic agents. The individual mRNA signatures were validated in an independent dataset of breast tumors (P = 0.002, NPV = 82%). When the accuracy of the signatures was analyzed based on molecular variables, the predictive ability was found to be greater in basal-like than non basal-like patients (P = 0.03 and P = 0.06). Samples from patients with co-activated Myc and E2F represented the cohort with the lowest percentage (8%) of responders. Using mRNA signatures of sensitivity to other cytotoxic agents, we predict that TFAC non-responders are more likely to be sensitive to docetaxel (P = 0.04), representing a viable alternative therapy.

Conclusions

Our results suggest that the optimal strategy for chemotherapy sensitivity prediction integrates molecular variables such as ER and HER2 status with corresponding microRNA and mRNA expression profiles. Importantly, we also present evidence to support the concept that analysis of molecular variables can present a rational strategy to identifying alternative therapeutic opportunities.     

Differential distribution of muscle and skin sympathetic nerve activity in patients with end-stage renal disease

End-stage renal disease (ESRD) is characterized by resting sympathetic overactivity. Baseline muscle sympathetic nerve activity (MSNA), which is governed by baroreflexes and chemoreflexes, is elevated in ESRD. Whether resting skin sympathetic nerve activity (SSNA), which is independent from baroreflex and chemoreflex control, is also elevated has never been reported in renal failure. The purpose of this study was to determine whether sympathetic overactivity of ESRD is generalized to include the skin distribution. We measured sympathetic nerve activity to both muscle and skin using microneurography in eight ESRD patients and eight controls. MSNA was significantly (P = 0.025) greater in ESRD (37.3 +/- 3.6 bursts/min) when compared with controls (23.1 +/- 4.4 bursts/min). However, SSNA was not elevated in ESRD (ESRD vs. controls, 17.6 +/- 2.2 vs. 16.1 +/- 1.7 bustst/min, P = 0.61). Similar results were obtained when MSNA was quantified as bursts per 100 heartbeats. We report the novel finding that although sympathetic activity directed to muscle is significantly elevated, activity directed to skin is not elevated in ESRD. The differential distribution of sympathetic outflow to the muscle vs. skin in ESRD is similar to the pattern seen in other disease states characterized by sympathetic overactivity such as heart failure and obesity.