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1.  Changes in Women’s Facial Skin Color over the Ovulatory Cycle are Not Detectable by the Human Visual System 
PLoS ONE  2015;10(7):e0130093.
Human ovulation is not advertised, as it is in several primate species, by conspicuous sexual swellings. However, there is increasing evidence that the attractiveness of women’s body odor, voice, and facial appearance peak during the fertile phase of their ovulatory cycle. Cycle effects on facial attractiveness may be underpinned by changes in facial skin color, but it is not clear if skin color varies cyclically in humans or if any changes are detectable. To test these questions we photographed women daily for at least one cycle. Changes in facial skin redness and luminance were then quantified by mapping the digital images to human long, medium, and shortwave visual receptors. We find cyclic variation in skin redness, but not luminance. Redness decreases rapidly after menstrual onset, increases in the days before ovulation, and remains high through the luteal phase. However, we also show that this variation is unlikely to be detectable by the human visual system. We conclude that changes in skin color are not responsible for the effects of the ovulatory cycle on women’s attractiveness.
PMCID: PMC4489916  PMID: 26134671
2.  Signal honesty and predation risk among a closely related group of aposematic species 
Scientific Reports  2015;5:11021.
Many animals have bright colours to warn predators that they have defences and are not worth attacking. However, it remains unclear whether the strength of warning colours reliably indicate levels of defence. Few studies have unambiguously established if warning signals are honest, and have rarely considered predator vision or conspicuousness against the background. Importantly, little data exists either on how differences in signal strength translate into survival advantages. Ladybirds exhibit impressive variation in coloration both among and within species. Here we demonstrate that different levels of toxicity exist among and within ladybird species, and that signal contrast against the background is a good predictor of toxicity, showing that the colours are honest signals. Furthermore, field experiments with ladybird models created with regards to predator vision show that models with lower conspicuousness were attacked more frequently. This provides one of the most comprehensive studies on signal honesty in warning coloration to date.
PMCID: PMC4457162  PMID: 26046332
3.  Camouflage and Individual Variation in Shore Crabs (Carcinus maenas) from Different Habitats 
PLoS ONE  2014;9(12):e115586.
Camouflage is widespread throughout the natural world and conceals animals from predators in a vast range of habitats. Because successful camouflage usually involves matching aspects of the background environment, species and populations should evolve appearances tuned to their local habitat, termed phenotype-environment associations. However, although this has been studied in various species, little work has objectively quantified the appearances of camouflaged animals from different habitats, or related this to factors such as ontogeny and individual variation. Here, we tested for phenotype-environment associations in the common shore crab (Carcinus maenas), a species highly variable in appearance and found in a wide range of habitats. We used field surveys and digital image analysis of the colors and patterns of crabs found in four locations around Cornwall in the UK to quantify how individuals vary with habitat (predominantly rockpool, mussel bed, and mudflat). We find that individuals from sites comprising different backgrounds show substantial differences in several aspects of color and pattern, and that this is also dependent on life stage (adult or juvenile). Furthermore, the level of individual variation is dependent on site and life stage, with juvenile crabs often more variable than adults, and individuals from more homogenous habitats less diverse. Ours is the most comprehensive study to date exploring phenotype-environment associations for camouflage and individual variation in a species, and we discuss the implications of our results in terms of the mechanisms and selection pressures that may drive this.
PMCID: PMC4281232  PMID: 25551233
4.  Character displacement of Cercopithecini primate visual signals 
Nature communications  2014;5:4266.
Animal visual signals have the potential to act as an isolating barrier to prevent interbreeding of populations through a role in species recognition. Within communities of competing species, species recognition signals are predicted to undergo character displacement, becoming more visually distinctive from each other, however this pattern has rarely been identified. Using computational face recognition algorithms to model primate face processing, we demonstrate that the face patterns of guenons (tribe: Cercopithecini) have evolved under selection to become more visually distinctive from those of other guenon species with whom they are sympatric. The relationship between the appearances of sympatric species suggests that distinguishing conspecifics from other guenon species has been a major driver of diversification in guenon face appearance. Visual signals that have undergone character displacement may have had an important role in the tribe’s radiation, keeping populations that became geographically separated reproductively isolated on secondary contact.
PMCID: PMC4110701  PMID: 24967517
5.  Preoperative Physical Activity Level Has No Relationship to the Degree of Recovery One Year after Primary Total Hip or Knee Arthroplasty: A Cohort Study 
PLoS ONE  2014;9(12):e115559.
When it comes to prevalidation, it is assumed that a higher preoperative level of physical activity leads to better postoperative recovery. However current literature is inconclusive about the effect of prevalidation on functional recovery of patients with primary osteoarthritis (OA) who underwent a THA or TKA. Therefore the aim of this study is to analyse one of the major assumptions underlying the potential effectiveness of prevalidation namely the relationship between preoperative physical activity level and postoperative recovery one year after THA or TKA in a group of 658 OA patients.
Methods and Results
From 2006 to 2012, 1061 patients underwent a primary THA or TKA at University Medical Center Groningen. Preoperative and one-year postoperative patients filled in the SQUASH questionnaire to get an impression of their physical activity level, and the WOMAC questionnaire to obtain insight into degree of recovery. Missing data were multiply imputed. No relationship was found between the preoperative total (B-coefficient = 0.03, CI95% = −0.033–0.093) and leisure-time physical activity level (B-coefficient = 0.042, CI95% = −0.009–0.093) neither for preoperative compliance with the Dutch Recommendation for Health-Enhancing Physical Activity (B-coefficient = 0.002, CI95% = −0.053–0.057), and the degree of recovery one year after surgery.
The preoperative physical activity level had no relation with the degree of recovery one year after THA or TKA. The results do not support one of the major assumptions behind prevalidation, which assumes that a higher preoperative physical activity level will lead to a better recovery after THA or TKA.
PMCID: PMC4275174  PMID: 25535744
6.  Computer-assisted surgery in orthopedic oncology 
Acta Orthopaedica  2014;85(6):663-669.
Background and purpose —
In orthopedic oncology, computer-assisted surgery (CAS) can be considered an alternative to fluoroscopy and direct measurement for orientation, planning, and margin control. However, only small case series reporting specific applications have been published. We therefore describe possible applications of CAS and report preliminary results in 130 procedures.
Patients and methods —
We conducted a retrospective cohort study of all oncological CAS procedures in a single institution from November 2006 to March 2013. Mean follow-up time was 32 months. We categorized and analyzed 130 procedures for clinical parameters. The categories were image-based intralesional treatment, image-based resection, image-based resection and reconstruction, and imageless resection and reconstruction.
Results —
Application to intralesional treatment showed 1 inadequate curettage and 1 (other) recurrence in 63 cases. Image-based resections in 42 cases showed 40 R0 margins; 16 in 17 pelvic resections. Image-based reconstruction facilitated graft creation with a mean reconstruction accuracy of 0.9 mm in one case. Imageless CAS was helpful in resection planning and length- and joint line reconstruction for tumor prostheses.
Interpretation —
CAS is a promising new development. Preliminary results show a high number of R0 resections and low short-term recurrence rates for curettage.
PMCID: PMC4259032  PMID: 25140984
7.  Obstructive Sleep Apnea and Diabetic Nephropathy 
Diabetes Care  2013;36(11):3718-3725.
Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). Obstructive sleep apnea (OSA) is common in type 2 diabetes and increases oxidative stress. Hence, OSA could promote the development and progression of DN.
This was a cohort study in adults with type 2 diabetes. Patients with known OSA or ESRD were excluded. DN was defined as the presence of albuminuria or an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. DN progression was based on eGFR measurements. OSA was defined as apnea hypopnea index (AHI) ≥5 events/h. Serum nitrotyrosine abundance (a marker of nitrosative stress) was measured by ELISA.
A total of 224 patients were included. OSA and DN prevalence was 64.3 and 40.2, respectively. DN prevalence was higher in patients with OSA (OSA+) compared with those without OSA (OSA−) (49.3% vs. 23.8%, P < 0.001). After adjustment, OSA (odds ratio 2.64 [95% CI 1.13–6.16], P = 0.02) remained independently associated with DN. After an average follow-up of 2.5 (0.7) years, eGFR decline was greater in OSA+ compared with OSA− patients (median −6.8% [interquartile range −16.1 to 2.2] vs. −1.6% [−7.7 to 5.3%], P = 0.002). After adjusting, both baseline OSA (B = −3.8, P = 0.044) and AHI (B = −4.6, P = 0.02) remained independent predictors of study-end eGFR. Baseline serum nitrotyrosine abundance (B = −0.24, P = 0.015) was an independent predictor of study-end eGFR after adjustment.
OSA is independently associated with DN in type 2 diabetes. eGFR declined faster in patients with OSA. Nitrosative stress may provide a pathogenetic link between OSA and DN. Interventional studies assessing the impact of OSA treatment on DN are needed.
PMCID: PMC3816897  PMID: 24062320
8.  Rockpool Gobies Change Colour for Camouflage 
PLoS ONE  2014;9(10):e110325.
Camouflage is found in a wide range of species living in numerous habitat types, offering protection from visually guided predators. This includes many species from the intertidal zone, which must cope with background types diverse in appearance and with multiple predator groups foraging at high and low tide. Many animals are capable of either relatively slow (hours, days, weeks) or rapid (seconds and minutes) colour change in order to better resemble the background against which they are found, but most work has been restricted to a few species or taxa. It is often suggested that many small intertidal fish are capable of colour change for camouflage, yet little experimental work has addressed this. Here, we test rock gobies (Gobius paganellus) for colour change abilities, and whether they can tune their appearance to match the background. In two experiments, we place gobies on backgrounds of different brightness (black or white), and of different colours (red and blue) and use digital image analysis and modelling of predator (avian) vision to quantify colour and luminance (perceived lightness) changes and camouflage. We find that gobies are capable of rapid colour change (occurring within one minute), and that they can change their luminance on lighter or darker backgrounds. When presented on backgrounds of different colours, gobies also change their colour (hue and saturation) while keeping luminance the same. These changes lead to predicted improvements in camouflage match to the background. Our study shows that small rockpool fish are capable of rapid visual change for concealment, and that this may be an important mechanism in many species to avoid predation, especially in complex heterogeneous environments.
PMCID: PMC4198244  PMID: 25333382
9.  Assessment of Prosthesis Alignment after Revision Total Knee Arthroplasty Using EOS 2D and 3D Imaging: A Reliability Study 
PLoS ONE  2014;9(9):e104613.
A new low-dose X-ray device, called EOS, has been introduced for determining lower-limb alignment in 2D and 3D. Reliability has not yet been assessed when using EOS on lower limbs containing a knee prosthesis. Therefore purpose of this study was to determine intraobserver and interobserver reliability of EOS 2D and 3D knee prosthesis alignment measurements after revision total knee arthroplasty (rTKA).
Forty anteroposterior and lateral images of 37 rTKA patients were included. Two observers independently performed measurements on these images twice. Varus/valgus angles were measured in 2D (VV2D) and 3D (VV3D). Intraclass correlation coefficients and the Bland and Altman method were used to determine reliability. T-tests were used to test potential differences.
Intraobserver and interobserver reliability were excellent for VV2D and VV3D. No significant difference or bias between the first and second measurements or the two observers was found. A significant mean and absolute difference of respectively 1.00° and 1.61° existed between 2D and 3D measurements.
EOS provides reliable varus/valgus measurements in 2D and 3D for the alignment of the knee joint with a knee prosthesis. However, significant differences exist between varus/valgus measurements in 2D and 3D.
PMCID: PMC4172435  PMID: 25247714
10.  Motion dazzle and the effects of target patterning on capture success 
Stripes and other high contrast patterns found on animals have been hypothesised to cause “motion dazzle”, a type of defensive coloration that operates when in motion, causing predators to misjudge the speed and direction of object movement. Several recent studies have found some support for this idea, but little is currently understood about the mechanisms underlying this effect. Using humans as model ‘predators’ in a touch screen experiment we investigated further the effectiveness of striped targets in preventing capture, and considered how stripes compare to other types of patterning in order to understand what aspects of target patterning are important in making a target difficult to capture.
We find that striped targets are among the most difficult to capture, but that other patterning types are also highly effective at preventing capture in this task. Several target types, including background sampled targets and targets with a ‘spot’ on were significantly easier to capture than striped targets. We also show differences in capture attempt rates between different target types, but we find no differences in learning rates between target types.
We conclude that striped targets are effective in preventing capture, but are not uniquely difficult to catch, with luminance matched grey targets also showing a similar capture rate. We show that key factors in making capture easier are a lack of average background luminance matching and having trackable ‘features’ on the target body. We also find that striped patterns are attempted relatively quickly, despite being difficult to catch. We discuss these findings in relation to the motion dazzle hypothesis and how capture rates may be affected more generally by pattern type.
PMCID: PMC4172783  PMID: 25213150
Motion dazzle; Vision; Animal coloration
11.  Signaling in multiple modalities in male rhesus macaques: sex skin coloration and barks in relation to androgen levels, social status, and mating behavior 
Behavioral ecology and sociobiology  2013;67(9):1457-1469.
The past decade has seen an increasing shift in animal communication towards more studies that incorporate aspects of signaling in multiple modalities. Although nonhuman primates are an excellent group for studying the extent to which different aspects of condition may be signaled in different modalities, and how such information may be integrated during mate choice, very few studies of primate species have incorporated such analyses. Here, we present data from free-ranging male rhesus macaques on sex skin coloration (modeled to receiver perception), bark vocal signals, androgen levels, morphometric variables, dominance status, and female mate choice. We show that, consistent with data on females, most intra- and interindividual variation in sex skin appearance occurs in luminance rather than color. Sex skin luminance was significantly correlated across different skin regions. Sex skin luminance did not correlate with the majority of bark parameters, suggesting the potential for the two signals to convey different information. Sex skin appearance was not related to androgen levels although we found some evidence for links between androgen levels and bark parameters, several of which were also related to morphometric variables. We found no evidence that either signal was related to male dominance rank or used in female mate choice, though more direct measures of female proceptive behavior are needed. Overall, the function of male sex skin coloration in this species remains unclear. Our study is among the first nonhuman primate studies to incorporate measurements of multiple signals in multiple modalities, and we encourage other authors to incorporate such analyses into their work.
PMCID: PMC4084859  PMID: 25013266
Coloration; Luminance; Vocal signals; Multimodal; Primate; Rhesus macaques
12.  Wall lizards display conspicuous signals to conspecifics and reduce detection by avian predators 
Behavioral Ecology  2014;25(6):1325-1337.
Visual signals are often under conflicting selection to be hidden from predators while being conspicuous to mates and rivals. Here, we investigated whether 3 different island populations of Aegean wall lizards (Podarcis erhardii) with variable coloration among diverse island habitats exhibit simultaneous camouflage and sexual signals. We examined whether signals appear better tuned to conspecific vision as opposed to that of avian predators, and whether background-matching camouflage and sexual signals are partitioned to specific body regions. This could facilitate both covert sexual signaling and camouflage according to the viewing perspectives of predators and conspecifics. We found that lizards typically appeared twice as conspicuous to conspecifics than to avian predators against the same visual background, largely due to lizards’ enhanced sensitivity to ultraviolet, suggesting that P. erhardii signals are tuned to conspecific vision to reduce detection by predators. Males were more conspicuous than females to both predators and conspecifics. In 2 populations, male backs were relatively more camouflaged to predators compared to signaling flanks, whereas in females, exposed and concealed surfaces were camouflaged to predators and generally did not differ in background matching. These findings indicate that lizard coloration evolves under the competing demands of natural and sexual selection to promote signals that are visible to conspecifics while being less perceptible to avian predators. They also elucidate how interactions between natural and sexual selection influence signal detectability and partitioning to different body regions, highlighting the importance of considering receiver vision, viewing perspectives, and signaling environments in studies of signal evolution.
Lay Summary
Lizards and their predators see the world differently, allowing lizards (Podarcis erhardii) to display bright sexual signals that are less visible to hunting birds. Males are more conspicuous than females, but reduce their visibility to predators by having camouflaged backs and restricting brighter signals to their sides, which makes them less visible to birds hunting from above while still being highly visible to mates and rivals on the ground.
PMCID: PMC4235580  PMID: 25419083
camouflage; color variation; communication; signal partitioning; trade-offs; vision.
13.  Adherence to and effectiveness of an individually tailored home-based exercise program for frail older adults, driven by mobility monitoring: design of a prospective cohort study 
BMC Public Health  2014;14:570.
With the number of older adults in society rising, frailty becomes an increasingly prevalent health condition. Regular physical activity can prevent functional decline and reduce frailty symptoms. In particular, home-based exercise programs can be beneficial in reducing frailty of older adults and fall risk, and in improving associated physiological parameters. However, adherence to home-based exercise programs is generally low among older adults. Current developments in technology can assist in enlarging adherence to home-based exercise programs. This paper presents the rationale and design of a study evaluating the adherence to and effectiveness of an individually tailored, home-based physical activity program for frail older adults driven by mobility monitoring through a necklace-worn physical activity sensor and remote feedback using a tablet PC.
Fifty transitionally frail community-dwelling older adults will join a 6-month home-based physical activity program in which exercises are provided in the form of exercise videos on a tablet PC and daily activity is monitored by means of a necklace-worn motion sensor. Participants exercise 5 times a week. Exercises are built up in levels and are individually tailored in consultation with a coach through weekly telephone contact.
The physical activity program driven by mobility monitoring through a necklace-worn sensor and remote feedback using a tablet PC is an innovative method for physical activity stimulation in frail older adults. We hypothesize that, if participants are sufficiently adherent, the program will result in higher daily physical activity and higher strength and balance assessed by physical tests compared to baseline. If adherence to and effectiveness of the program is considered sufficient, the next step would be to evaluate the effectiveness with a randomised controlled trial. The knowledge gained in this study can be used to develop and fine-tune the application of innovative technology in home-based exercise programs.
Trial registration
Nederlands Trial Register (NTR); trial number 4265. The study was prospectively registered (registration date 14/11/2013).
PMCID: PMC4066276  PMID: 24908049
Home-based physical activity program; Remote coaching; Daily activity; Objective measurement; Frail older adults
14.  The development of a comprehensive multidisciplinary care pathway for patients with a hip fracture: design and results of a clinical trial 
Hip fractures frequently occur in older persons and severely decrease life expectancy and independence. Several care pathways have been developed to lower the risk of negative outcomes but most pathways are limited to only one aspect of care. The aim of this study was therefore to develop a comprehensive care pathway for older persons with a hip fracture and to conduct a preliminary analysis of its effect.
A comprehensive multidisciplinary care pathway for patients aged 60 years or older with a hip fracture was developed by a multidisciplinary team. The new care pathway was evaluated in a clinical trial with historical controls. The data of the intervention group were collected prospectively. The intervention group included all patients with a hip fracture who were admitted to University Medical Center Groningen between 1 July 2009 and 1 July 2011. The data of the control group were collected retrospectively. The control group comprised all patients with a hip fracture who were admitted between 1 January 2006 and 1 January 2008. The groups were compared with the independent sample t-test, the Mann–Whitney U-test or the Chi-squared test (Phi test). The effect of the intervention on fasting time and length of stay was adjusted by linear regression analysis for differences between the intervention and control group.
The intervention group included 256 persons (women, 68%; mean age (SD), 78 (9) years) and the control group 145 persons (women, 72%; mean age (SD), 80 (10) years). Median preoperative fasting time and median length of hospital stay were significantly lower in the intervention group: 9 vs. 17 hours (p < 0.001), and 7 vs. 11 days (p < 0.001), respectively. A similar result was found after adjustment for age, gender, living condition and American Society of Anesthesiologists (ASA) classification. In-hospital mortality was also lower in the intervention group: 2% vs. 6% (p < 0.05). There were no statistically significant differences in other outcome measures.
The new comprehensive care pathway was associated with a significant decrease in preoperative fasting time and length of hospital stay.
PMCID: PMC4053577  PMID: 24885674
Care pathway; Elderly; Hip fracture; Fasting time; Length of stay
15.  A window on the past: male ornamental plumage reveals the quality of their early-life environment 
It is well established that the expression of many ornamental traits is dependent on the current condition of the bearer. However, conditions experienced in early life are also known to be important for an individual's subsequent fitness and therefore, directly or indirectly, for the fitness of their mate. Specifically, a recent hypothesis suggests that sexually selected traits might be sensitive to conditions experienced during early-life development and thereby function as honest indicators of developmental history. Whether this applies to colourful male plumage, however, is largely unknown. We tested this idea with a field experiment by manipulating neonatal nutrition in a sexually dichromatic passerine, the hihi (Notymystis cincta). We found that carotenoid supplementation increased nestling plasma carotenoid concentration, which was in turn correlated with increased yellow saturation in male breeding plumage after moulting. We also found that the post-moult luminance (lightness) of the white ear-tufts tended to be reduced in males that had received an all-round nutritional supplement as nestlings. Black breeding plumage was not affected by neonatal nutritional treatment. Although the mechanisms that generate colourful plumage are evidently diverse, our results show that at least some parts of this display are accurate indicators of environmental conditions during development.
PMCID: PMC3574376  PMID: 23407833
hihi; developmental stress hypothesis; nutrition; carotenoid-based plumage; melanin-based plumage; structural colours
16.  The influence of computer-assisted surgery on rotational, coronal and sagittal alignment in revision total knee arthroplasty 
Despite good results of primary total knee arthroplasty (TKA), the number of revision total knee arthroplasties (rTKAs) is rising. Proper implant position is essential, since malposition leads to worse clinical outcome. In rTKA most anatomical landmarks have disappeared because of extensive bone loss, making it more difficult to adequately implant the knee prosthesis. In primary TKA, computer-assisted surgery (CAS) leads to better prosthetic alignment than mechanical navigation guides. Literature about the use of CAS in rTKA is scarce though, and the effect on rotational prosthetic alignment has not been investigated yet. Hence the primary objective of this study is to compare rotational prosthetic alignment when using CAS in rTKA compared to a mechanical navigation guide. Secondary objectives are to compare prosthetic alignment in the coronal and sagittal planes. It is hypothesized that CAS leads to better rotational, coronal and sagittal prosthetic alignment when used during rTKA.
A prospective clinical intervention study with use of a historical control group will be conducted. Forty-four patients with a minimum age of 18 to be admitted for CAS-rTKA between September 2012 and September 2015 will be included in the intervention group. Forty-four patients with a minimum age of 18 who underwent rTKA with the use of a mechanical navigation guide between January 2002 and April 2012 will form the historical control group. Both groups will be matched according to gender and type of revision prosthesis. Rotational prosthesis alignment will be evaluated using a CT-scan of the knee joint.
Proper implant position is essential, since malposition leads to worse clinical outcome. Several studies show a significantly positive influence of CAS on prosthetic alignment in primary TKA, but literature about the use of CAS in rTKA is limited. The purpose of this study is thus to investigate the influence of CAS during rTKA on postoperative prosthetic alignment, compared to mechanical navigation guides.
Trial registration
Netherlands National Trial Register NTR3512
PMCID: PMC3995112  PMID: 24646028
17.  Poorer survival after a primary implant during revision total knee arthroplasty 
International Orthopaedics  2012;37(3):415-419.
Revision total knee arthroplasty (rTKA) is a complex procedure. Depending on the degree of ligament and bone damage, either primary or revision implants are used. The purpose of this study was to compare survival rates of primary implants with revision implants when used during rTKA.
A retrospective comparative study was conducted between 1998 and 2009 during which 69 rTKAs were performed on 65 patients. Most common indications for revision were infection (30 %), aseptic loosening (25 %) and wear/osteolysis (25 %). During rTKA, a primary implant was used in nine knees and a revision implant in 60.
Survival of primary implants was 100 % at one year, 73 % [95 % confidence interval (CI) 41–100] at two years and 44 % (95 % CI 7–81) at five years. Survival of revision implants was 95 % (95 % CI 89–100) at one year, 92 % (95 % CI 84–99) at two years and 92 % (95 % CI 84–99) at five years. Primary implants had a significantly worse survival rate than revision implants when implanted during rTKA [P = 0.039 (hazard ratio = 4.56, 95 % CI 1.08–19.27)].
Based on these results, it has to be considered whether primary implants are even an option during rTKA.
PMCID: PMC3580082  PMID: 23263508
18.  Cardiac autonomic neuropathy in patients with diabetes mellitus 
World Journal of Diabetes  2014;5(1):17-39.
Cardiac autonomic neuropathy (CAN) is an often overlooked and common complication of diabetes mellitus. CAN is associated with increased cardiovascular morbidity and mortality. The pathogenesis of CAN is complex and involves a cascade of pathways activated by hyperglycaemia resulting in neuronal ischaemia and cellular death. In addition, autoimmune and genetic factors are involved in the development of CAN. CAN might be subclinical for several years until the patient develops resting tachycardia, exercise intolerance, postural hypotension, cardiac dysfunction and diabetic cardiomyopathy. During its sub-clinical phase, heart rate variability that is influenced by the balance between parasympathetic and sympathetic tones can help in detecting CAN before the disease is symptomatic. Newer imaging techniques (such as scintigraphy) have allowed earlier detection of CAN in the pre-clinical phase and allowed better assessment of the sympathetic nervous system. One of the main difficulties in CAN research is the lack of a universally accepted definition of CAN; however, the Toronto Consensus Panel on Diabetic Neuropathy has recently issued guidance for the diagnosis and staging of CAN, and also proposed screening for CAN in patients with diabetes mellitus. A major challenge, however, is the lack of specific treatment to slow the progression or prevent the development of CAN. Lifestyle changes, improved metabolic control might prevent or slow the progression of CAN. Reversal will require combination of these treatments with new targeted therapeutic approaches. The aim of this article is to review the latest evidence regarding the epidemiology, pathogenesis, manifestations, diagnosis and treatment for CAN.
PMCID: PMC3932425  PMID: 24567799
Diabetes mellitus; Cardiac; Cardiovascular; Autonomic; Neuropathy; Dysfunction; Cardiac autonomic neuropathy; Sympathetic; Parasympathetic; Heart rate variability; Spectral analysis; Diabetic cardiomyopathy; Postural hypotension
19.  Disruptive ecological selection on a mating cue 
Adaptation to divergent ecological niches can result in speciation. Traits subject to disruptive selection that also contribute to non-random mating will facilitate speciation with gene flow. Such ‘magic’ or ‘multiple-effect’ traits may be widespread and important for generating biodiversity, but strong empirical evidence is still lacking. Although there is evidence that putative ecological traits are indeed involved in assortative mating, evidence that these same traits are under divergent selection is considerably weaker. Heliconius butterfly wing patterns are subject to positive frequency-dependent selection by predators, owing to aposematism and Müllerian mimicry, and divergent colour patterns are used by closely related species to recognize potential mates. The amenability of colour patterns to experimental manipulation, independent of other traits, presents an excellent opportunity to test their role during speciation. We conducted field experiments with artificial butterflies, designed to match natural butterflies with respect to avian vision. These were complemented with enclosure trials with live birds and real butterflies. Our experiments showed that hybrid colour-pattern phenotypes are attacked more frequently than parental forms. For the first time, we demonstrate disruptive ecological selection on a trait that also acts as a mating cue.
PMCID: PMC3497240  PMID: 23075843
ecological speciation; Heliconius; magic trait; avian vision; mimicry; natural selection
20.  Evaluation of the effect of a comprehensive multidisciplinary care pathway for hip fractures: design of a controlled study 
Hip fractures constitute an economic burden on healthcare resources. Most persons with a hip fracture undergo surgery. As morbidity and mortality rates are high, perioperative care leaves room for improvement. Improvement can be achieved if it is organized in comprehensive care pathways, but the effectiveness of these pathways is not yet clear. Hence the objective of this study is to compare the clinical effectiveness of a comprehensive care pathway with care as usual on self-reported limitations in Activities of Daily Living.
A controlled trial will be conducted in which the comprehensive care pathway of University Medical Center Groningen will be compared with care as usual in two other, nonacademic, hospitals. In this trial, propensity scores will be used to adjust for differences at baseline between the intervention and control group. Propensity scores can be used in intervention studies where a classical randomized controlled trial is not feasible. Patients aged 60 years and older will be included. The hypothesis is that 15% more patients at University Medical Center Groningen compared with patients in the care-as-usual condition will have recovered at least as well at 6 months follow-up to pre-fracture levels for Activities of Daily Living.
This study will yield new knowledge with respect to the clinical effectiveness of a comprehensive care pathway for the treatment of hip fractures. This is relevant because of the growing incidence of hip fractures and the consequent massive burden on the healthcare system. Additionally, this study will contribute to the growing knowledge of the application of propensity scores, a relatively novel statistical technique to simulate a randomized controlled trial in studies where it is not possible or difficult to execute this kind of design.
Trial registration
Nederlands Trial Register NTR3171
PMCID: PMC3815070  PMID: 24119130
Hip fracture; Care pathway; Propensity score; Elderly; Physical functioning
21.  Defeating Crypsis: Detection and Learning of Camouflage Strategies 
PLoS ONE  2013;8(9):e73733.
Camouflage is perhaps the most widespread defence against predators in nature and an active area of interdisciplinary research. Recent work has aimed to understand what camouflage types exist (e.g. background matching, disruptive, and distractive patterns) and their effectiveness. However, work has almost exclusively focused on the efficacy of these strategies in preventing initial detection, despite the fact that predators often encounter the same prey phenotype repeatedly, affording them opportunities to learn to find those prey more effectively. The overall value of a camouflage strategy may, therefore, reflect both its ability to prevent detection by predators and resist predator learning. We conducted four experiments with humans searching for hidden targets of different camouflage types (disruptive, distractive, and background matching of various contrast levels) over a series of touch screen trials. As with previous work, disruptive coloration was the most successful method of concealment overall, especially with relatively high contrast patterns, whereas potentially distractive markings were either neutral or costly. However, high contrast patterns incurred faster decreases in detection times over trials compared to other stimuli. In addition, potentially distractive markings were sometimes learnt more slowly than background matching markings, despite being found more readily overall. Finally, learning effects were highly dependent upon the experimental paradigm, including the number of prey types seen and whether subjects encountered targets simultaneously or sequentially. Our results show that the survival advantage of camouflage strategies reflects both their ability to avoid initial detection (sensory mechanisms) and predator learning (perceptual mechanisms).
PMCID: PMC3769369  PMID: 24040046
22.  Cutaneous Structural and Biochemical Correlates of Foot Complications in High-Risk Diabetes 
Diabetes Care  2012;35(9):1913-1918.
Impairment of skin quality may contribute to diabetic foot ulceration (DFU). Our goal was to determine whether high-risk patients exhibited specific skin structural and metabolic deficits that could predispose to foot complications.
A total of 46 patients comprising 9 diabetic control subjects, 16 with diabetic peripheral neuropathy (DPN) alone, and 21 with recurrent DFUs (including 9 with Charcot neuroarthropathy [CNA]) were recruited and compared with 14 nondiabetic control (NDC) subjects. DPN was assessed using the Michigan Neuropathy Screening Instrument (MNSI). Skin punch biopsies (3 mm) were performed on upper and lower leg skin for measurements of intraepidermal nerve fiber density (IENFD), structural analysis, type 1 procollagen abundance, tissue degrading matrix metalloproteinases (MMPs), and poly(ADP-ribose) (PAR) immunoreactivity.
MNSI scores were comparable across DPN groups. IENFD was decreased by diabetes and DPN but did not differ between neuropathic groups. Skin structural deficit scores were elevated in all neuropathic subjects, particularly in the DFU group. Type 1 procollagen abundance was reduced in DFU subjects 387 ± 256 units (mean ± 1 SD) compared with NDC subjects (715 ± 100, P < 0.001). MMP-1 and MMP-2 were activated by diabetes. PAR immunoreactivity was increased in DFU (particularly in the CNA group; P < 0.01) compared with other DPN subjects.
Increased PAR, reduced type 1 procollagen abundance, and impaired skin structure are associated with foot complications in diabetes. The potential of therapies that improve skin quality to reduce DFU needs to be investigated.
PMCID: PMC3424985  PMID: 22751961
23.  Reliability and validity of the Dutch version of the foot and ankle outcome score (FAOS) 
The Foot and Ankle Outcome Score (FAOS) is a patient-reported questionnaire measuring symptoms and functional limitations of the foot and ankle. Aim is to translate and culturally adapt the Dutch version of the FAOS and to investigate internal consistency, validity, repeatability and responsiveness.
According to the Cross Cultural Adaptation of Self-Report Measures guideline, the FAOS was translated into Dutch. Eighty-nine patients who had undergone an ankle arthroscopy, ankle arthrodesis, ankle ligament reconstruction or hallux valgus correction completed the FAOS, FFI, WOMAC and SF-36 questionnaires and were included in the validity study. Sixty-five of them completed the FAOS a second time to determine repeatability. Responsiveness was analysed in an additional 15 patients who were being treated for foot or ankle problems.
Internal consistency of the FAOS is high (Cronbach’s alphas varying between 0.90 and 0.96). Repeatability can be considered good, with ICC’s ranging from 0.90 to 0.96. Construct validity can be classified as good with moderate-to-high correlations between the FAOS subscales and subscales of the FFI (0.55 to 0.90), WOMAC (0.57 to 0.92) and SF-36 subscales physical functioning, pain, social functioning and role-physical (0.33 to 0.81). Low standard response means were found for responsiveness (0.0 to 0.4).
The results of this study show that the Dutch version of the FAOS is a reliable and valid questionnaire to assess symptoms and functional limitations of the foot and ankle.
PMCID: PMC3681600  PMID: 23758917
Foot; Ankle; Questionnaire; FAOS; Dutch; Reliability; Validity; Orthopaedics
24.  Obstructive Sleep Apnea and Diabetic Neuropathy 
Rationale: Diabetic peripheral neuropathy is common and causes significant morbidity. Obstructive sleep apnea (OSA) is also common in patients with type 2 diabetes. Because OSA is associated with inflammation and oxidative stress, we hypothesized that OSA is associated with peripheral neuropathy in type 2 diabetes.
Objectives: To assess the relationship between OSA and peripheral neuropathy in patients with type 2 diabetes.
Methods: A cross-sectional study of adults with type 2 diabetes recruited randomly from the diabetes clinic of two UK hospitals.
Measurements and Main Results: Peripheral neuropathy was diagnosed using the Michigan Neuropathy Screening Instrument. OSA (apnea-hypopnea index ≥ 5 events/h) was assessed using home-based, multichannel respiratory monitoring. Serum nitrotyrosine was measured by ELISA, lipid peroxide by spectrophotometer, and microvascular function by laser speckle contrast imaging. Two hundred thirty-four patients (mean [SD] age, 57 [12] yr) were analyzed. OSA prevalence was 65% (median apnea-hypopnea index, 7.2; range, 0–93), 40% of which were moderate to severe. Neuropathy prevalence was higher in patients with OSA than those without (60% vs. 27%, P < 0.001). After adjustment for possible confounders, OSA remained independently associated with diabetic neuropathy (odds ratio, 2.82; 95% confidence interval, 1.44–5.52; P = 0.0034). Nitrotyrosine and lipid peroxide levels (n = 102, 74 with OSA) were higher in OSA and correlated with hypoxemia severity. Cutaneous microvascular function (n = 71, 47 with OSA) was impaired in OSA.
Conclusions: We describe a novel independent association between diabetic peripheral neuropathy and OSA. We identified increased nitrosative/oxidative stress and impaired microvascular regulation as potential mechanisms. Prospective and interventional studies are needed to assess the impact of OSA and its treatment on peripheral neuropathy development and progression in patients with type 2 diabetes.
PMCID: PMC3443800  PMID: 22723291
obstructive sleep apnea; diabetic neuropathy; nitrosative stress; microvascular function; laser speckle contrast imaging
25.  Linking the evolution and form of warning coloration in nature 
Many animals are toxic or unpalatable and signal this to predators with warning signals (aposematism). Aposematic appearance has long been a classical system to study predator–prey interactions, communication and signalling, and animal behaviour and learning. The area has received considerable empirical and theoretical investigation. However, most research has centred on understanding the initial evolution of aposematism, despite the fact that these studies often tell us little about the form and diversity of real warning signals in nature. In contrast, less attention has been given to the mechanistic basis of aposematic markings; that is, ‘what makes an effective warning signal?’, and the efficacy of warning signals has been neglected. Furthermore, unlike other areas of adaptive coloration research (such as camouflage and mate choice), studies of warning coloration have often been slow to address predator vision and psychology. Here, we review the current understanding of warning signal form, with an aim to comprehend the diversity of warning signals in nature. We present hypotheses and suggestions for future work regarding our current understanding of several inter-related questions covering the form of warning signals and their relationship with predator vision, learning, and links to broader issues in evolutionary ecology such as mate choice and speciation.
PMCID: PMC3234570  PMID: 22113031
aposematism; predation; signal; defensive coloration; vision

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