The effects of sex, nation, ethnicity, age and self-reported pubertal development on participant-measured right-left 2D:4D (Dr-l) in the BBC internet study.

Digit ratio (2D:4D) - a proxy for prenatal sex steroids - shows sex, nationality and ethnic differences and is linked to pubertal onset. It is unclear whether right-left 2D:4D (Dr-l) also correlates with prenatal sex steroids, as evidence of these differences has been less conclusive. The present study examined the effects of sex, nation, ethnicity, age and self-reported pubertal development (i.e. the rate of physical development and age at menarche [females] or first shave [males]) on Dr-l in a large online study (the BBC internet study). Digit lengths were self-measured in 201,865 adults (110,955 males) and the sample of nations included 41 countries. Participants reported the self-perceived rate of physical pubertal development on a five-point scale (from very slow to very fast) and provided information on the age at menarche or first shave. Adult (>17 years) males had lower Dr-l than females with weak effect size across 41 nations (males-females; d = -.065, p < .0001). There were sex and ethnicity effects on Dr-l across seven ethnic groups with males < females and lower Dr-l in Whites and Middle/Near Eastern participants compared to Asian, Black and Chinese respondents. Considering age effects, the authors focused on participants >12 years; there were stable sex differences and a weak positive effect of age on Dr-l. Dr-l showed a positive relationship with the rate of physical development and a negative relationship with age at menarche or first shave. Relationships were present in males and females with stronger effects in the latter. It is concluded that Dr-l shows a weak sex difference (males < females) independent of nation, ethnicity and age, and suggest that Dr-l is a proxy for prenatal sex steroids.

Parental income inequality and children's digit ratio (2D:4D): a 'Trivers-Willard' effect on prenatal androgenization?

Income inequality is associated positively with disease prevalence and mortality. Digit ratio (2D:4D) - a negative proxy for prenatal testosterone and a positive correlate of prenatal oestrogen - is related to several diseases. This study examined the association of income inequality (operationalized as relative parental income) and children's 2D:4D. Participants self-measured finger lengths (2D=index finger, and 4D=ring finger) in a large online survey conducted in July 2005 (the BBC Internet Study) and reported their parents' income. Children of parents of above-average income had low 2D:4D (high prenatal testosterone, low prenatal oestrogen) while the children of parents of below-average income had high 2D:4D (low prenatal testosterone, high prenatal oestrogen). The effects were significant in the total sample, present among Whites (the largest group in the sample), in the two largest national samples (UK and USA) and were greater for males than females. The findings suggest a Trivers-Willard effect, such that high-income women may prenatally masculinize their sons at the expense of the fitness of their daughters. Women with low income may prenatally feminize their daughters at the fitness expense of their sons. The effect could, in part, explain associations between low income, high 2D:4D (low prenatal testosterone) and some major causes of mortality such as cardiovascular disease.

Digit ratio (2D:4D) and body mass index in the BBC Internet Study: prenatal sex steroids and a Trivers-Willard effect on body composition.

Digit ratio - a putative measure of prenatal sex steroids - may be related to body mass index (BMI). However, reports of correlations between 2D:4D and BMI have yielded mixed results with some studies showing no relationship while others have reported positive associations in men or women only. This study considers associations between self-reported 2D:4D and BMI in a large online survey (i.e. the BBC Internet Study). At the individual level, there was a weak positive association between 2D:4D and BMI in both sexes with greater effect sizes in women. Body mass index was positively related to age and negatively related to parental income; however, the relationship between 2D:4D and BMI was independent of both variables. At the national level, mean 2D:4D per country showed positive associations with mean national BMI but those correlations were restricted to females. It is concluded that BMI is positively related to low prenatal testosterone and high prenatal oestrogen. Parental income inequality may influence both prenatal sex steroids (through a 'Trivers-Willard' effect) and BMI such that increases in inequality result in reductions in prenatal testosterone and increases in BMI at the individual and national level.

Temperature response to cold challenge and mobile phone thermography as outcome measures for systemic sclerosis-related Raynaud's phenomenon.

Objectives: Objective outcome measures of systemic sclerosis (SSc)-related Raynaud's phenomenon (RP) are badly needed. Our objectives were to validate the thermographic response to a standard hand cold challenge as an outcome measure by assessing sensitivity to change, and to explore mobile phone thermography as a feasible, ambulatory tool.Method: Twelve patients with an SSc-spectrum disorder admitted for intravenous iloprost infusions underwent a standard cold challenge before and after one infusion. Thermographic measurements included area under the rewarming curve (AUC) and maximum rewarming temperature (MAX). Before and during another infusion, each patient underwent monitoring of finger skin temperature by two methods: continuous thermocouple recording (standard method) and mobile phone thermography.Results: All cold challenge summary measures, including AUC and MAX, increased after iloprost (most not significantly). However, when the response curves were modelled after averaging across fingers (linear mixed models, three versions), significant change was detected. For example, with Model 1 (no interaction between period and time), temperature was on average 1.67ºC [95% confidence interval (CI) 1.49-1.85, p < 0.001] higher post-iloprost. Mobile phone and thermocouple temperature measurements showed a strong estimated latent correlation (0.88, 95% CI 0.81-0.92). The estimated increases/hour were 0.25ºC (95% CI 0.05-0.45) for the thermocouple and 0.36ºC (95% CI 0.13-0.60) for mobile phone thermography.Conclusion: Our pilot study suggests that the thermographic response to a cold challenge is sensitive to change and mobile phone thermography could bring feasibility to thermographic parameters as outcome measures in later-phase, large-scale, community-based clinical trials of RP.

Imaging digital arteries in systemic sclerosis by tomographic 3-dimensional ultrasound.

Objective methods are needed to quantify digital artery disease in systemic sclerosis (SSc) for clinical trials of vascular therapies. Our primary aim was to examine feasibility of a novel tomographic three-dimensional-(3-D) ultrasound (tUS) with high-frequency ultrasound (HFUS) or ultra-high-frequency ultrasound (UHFUS) to assess the digital arteries in patients with SSc compared to healthy controls. A secondary objective was to compare the total wall volume (TWV) as a measure of intimal/medial thickness. Eighteen patients with a confirmed diagnosis of SSc were studied by tUS HFUS (17.5 MHz, n = 10) or tUS UHFUS (48 and 70 MHz, n = 8) with equal numbers of healthy controls of similar age and gender. The majority of patients had limited cutaneous SSc and were representative of a spectrum of digital vasculopathy, with over half (n = 6 HFUS and n = 5 UHFUS) having previous digital ulceration. Over half were receiving oral vasodilatory therapy. TWV was measured in both digital arteries of the middle finger bilaterally. At least, two digital arteries could be identified at 17.5 MHz in all patients and healthy controls. Whereas, at least two digital arteries could be identified in relatively fewer patients compared to healthy controls using 48 MHz (n = 6 and 10) and especially 70 MHz (n = 4 and 10) UHFUS. The median difference in TWV between patients and healthy controls was -6.49 mm3 using 17.5 MHz, 1.9 mm3 at 48 MHz, and -0.4 mm3 at 70 MHz. tUS using UHFUS is a feasible method to measure TWV of digital arteries in SSc. Transducer frequency plays an important factor in successful digital artery measurement, with 48 MHz being the optimal frequency.

Impact and associates of digital pitting in patients with systemic sclerosis: a pilot study.

Objective: Despite being a cardinal clinical sign of systemic sclerosis (SSc), digital pitting has been little studied. Our objective was to test, in a pilot study, the hypothesis that pitting is painful and associated with digital vascular disease severity.Method: Fifty patients with SSc were recruited: 25 with and 25 without digital pitting. Fingertip pain was assessed on a 0-10 scale. Thermography of both hands assessed surface temperature, allowing calculation of the distal-dorsal difference (temperature gradient) for each finger. Nailfold capillaroscopy was performed in each finger using a dermatoscope, and graded on a 0-3 scale (0 = normal; 3 = grossly abnormal).Results: In the 25 patients with digital pitting, 65 fingers in total were affected (mainly the index and middle fingers). Pain scores were higher in 'pitting' patients [median 4 (interquartile range 3-8) vs 0 (0-2), p < 0.001], and pitting patients reported that pitting impacted on activities of everyday living. Temperature gradients along the fingers did not differ significantly between patients with and without pitting (p = 0.248). Pitting patients were more likely to have 'grossly abnormal' capillaries than those without pitting, and less likely to have 'no/mild' nailfold capillary changes.Conclusions: Digital pitting is painful and impacts on hand function. Capillaroscopy findings provide further support for an association between pitting and severity of digital vascular change. Larger, more comprehensive studies are required to examine the pathophysiology of pitting and to pave the way to therapeutic intervention, ideally including preventive strategies.

Influence of psoas muscle area on mortality following elective abdominal aortic aneurysm repair.

BACKGROUND: The effect of sarcopenia based on the total psoas muscle area (TPMA) on CT is inconclusive in patients undergoing abdominal aortic aneurysm (AAA) intervention. The aim of this prospective cohort study was to evaluate morphometric sarcopenia as a method of risk stratification in patients undergoing elective AAA intervention. METHODS: TPMA was measured on preintervention CT images of patients undergoing elective endovascular aneurysm repair (EVAR) or open aneurysm repair. Mortality was assessed in relation to preintervention TPMA using Cox regression analysis, with calculation of hazard ratios at 30 days, 1 year and 4 years. Postintervention morbidity was evaluated in terms of postintervention care, duration of hospital stay and 30-day readmission. Changes in TPMA on surveillance EVAR imaging were also evaluated. RESULTS: In total, 382 patient images acquired between March 2008 and December 2016 were analysed. There were no significant intraobserver and interobserver differences in measurements of TPMA. Preintervention TPMA failed to predict morbidity and mortality at all time points. The mean(s.d.) interval between preintervention and surveillance imaging was 361·3(111·2) days. A significant reduction in TPMA was observed in men on surveillance imaging after EVAR (mean reduction 0·63(1·43) cm2 per m2 ; P < 0·001). However, this was not associated with mortality (adjusted hazard ratio 1·00, 95 per cent c.i. 0·99 to 1·01; P = 0·935). CONCLUSION: TPMA is not a suitable risk stratification tool for patients undergoing effective intervention for AAA.

Changes in disability and their relationship with skin thickening, in diffuse and limited cutaneous systemic sclerosis: a retrospective cohort study.

OBJECTIVE: The burden of disability associated with systemic sclerosis (SSc) is being increasingly recognized. Our aim was to test the hypothesis that changes in functional ability over time differ between patients with limited (lcSSc) and diffuse cutaneous (dcSSc) subtypes, and that in dcSSc (but not lcSSc) these changes correlate with skin thickening. METHOD: This was a retrospective analysis of data collected prospectively between 2005 and 2016 at a single centre. Data recorded at annual review visits included modified Rodnan skin score (mRSS) and Health Assessment Questionnaire Disability Index (HAQ-DI). Yearly rates of mRSS and HAQ-DI change were assessed by individual linear regressions, and those gradients were compared between disease groups (lcSSc/dcSSc) for each of early/late disease (less/greater than 5 years' duration). RESULTS: The study included 402 patients (110 dcSSc, 292 lcSSc), with mean length of follow-up of 5.5 years (sd 3.5). Mean baseline HAQ-DI was 1.4 in dcSSc and 1.2 in lcSSc. In dcSSc, increased mRSS was associated with worsening disability (ρ = 0.36, p = 0.004) during early but not late disease (ρ = 0.12, p = 0.331). In lcSSc, changes in mRSS were not associated with changes in disability for early (ρ = -0.15, p = 0.173) or late disease (ρ = 0.10, p = 0.137). CONCLUSION: These findings confirm high disability in patients with SSc. A relationship between HAQ-DI and mRSS (worsening mRSS associated with increasing disability) was found only in patients with early dcSSc, suggesting that in other patient subgroups other factors play the major role.

Reduced perfusion in systemic sclerosis digital ulcers (both fingertip and extensor) can be increased by topical application of glyceryl trinitrate.

OBJECTIVES: In patients with systemic sclerosis (SSc), fingertip digital ulcers (DUs) are believed to be ischaemic, and extensor surface DUs a result of mechanical factors/microtrauma. Our aim was to assess blood flow response to topical glyceryl trinitrate (GTN) compared to placebo in SSc DUs, looking for differences in pathophysiology between fingertip and extensor lesions. METHOD: This was a double-blind, randomised, crossover, placebo-controlled study. Sixteen (6 fingertip, 10 extensor) DUs were each studied twice (one day apart): once with GTN and once with placebo ointment. Perfusion at the DU centre ('DUCore') and periphery ('DUPeriphery'), as measured by laser Doppler imaging was performed before and immediately after ointment application, then every 10min, up to 90min post-application. We calculated the area under the response curve (AUC) and the ratio of peak perfusion to baseline, then compared these between GTN and placebo. RESULTS: Perfusion was lower in the DUCore compared to the DUPeriphery (ratio of 0.52). The microvessels of the DUCore were responsive to GTN, with an increase in perfusion, with a similar effect in both fingertip and extensor DUs. The AUC and peak/baseline perfusion difference in means (ratio, 95% confidence interval) between GTN and placebo at the DUCore were 1.2 (1.0-1.6) and 1.2 (1.0-1.5) respectively, and at the DUPeriphery were 1.1 (0.8-1.6) and 1.0 (0.9-1.2) respectively. CONCLUSION: DUs (both fingertip and extensor) were responsive to topical GTN, with an increase in perfusion to the ischaemic DU centre. If both fingertip and extensor DUs have a (potentially reversible) ischaemic aetiology, this has important treatment implications.

Sweet complementarity: the functional pairing of glycans with lectins.

Carbohydrates establish the third alphabet of life. As part of cellular glycoconjugates, the glycans generate a multitude of signals in a minimum of space. The presence of distinct glycotopes and the glycome diversity are mapped by sugar receptors (antibodies and lectins). Endogenous (tissue) lectins can read the sugar-encoded information and translate it into functional aspects of cell sociology. Illustrated by instructive examples, each glycan has its own ligand properties. Lectins with different folds can converge to target the same epitope, while intrafamily diversification enables functional cooperation and antagonism. The emerging evidence for the concept of a network calls for a detailed fingerprinting. Due to the high degree of plasticity and dynamics of the display of genes for lectins the validity of extrapolations between different organisms of the phylogenetic tree yet is inevitably limited.

Decision-making and future planning for children with life-limiting conditions: a qualitative systematic review and thematic synthesis.

BACKGROUND: In the last decade, the number of children with life-limiting and life-threatening conditions in England has almost doubled, and it is estimated that worldwide, there are 1.2 million children with palliative care needs. Families and professionals caring for children with life-limiting conditions are likely to face a number of difficult treatment decisions and develop plans for future care over the course of the child's life, but little is known about the process by which these decisions and plans are made. METHODS: The purpose of this review is to synthesize findings from qualitative research that has investigated decision-making and future planning for children with life-limiting conditions. A systematic search of six online databases was conducted and identified 887 papers for review; five papers were selected for inclusion, using predefined criteria. Reference list searching and contacting authors identified a further four papers for inclusion. RESULTS: Results sections of the papers were coded and synthesized into themes. Nineteen descriptive themes were identified, and these were further synthesized into four analytical themes. Analytical themes were 'decision factors', 'family factors', 'relational factors' and 'system factors'. CONCLUSIONS: Review findings indicate that decision-making and future planning is difficult and needs to be individualized for each family. However, deficits in understanding the dynamic, relational and contextual aspects of decision-making remain and require further research.

History of surgical debridement, anticentromere antibody, and disease duration are associated with calcinosis in patients with systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc)-related calcinosis is often painful and disabling. Our aim was to examine its clinical and serological associates, and whether it is possible to build a model to predict the presence of calcinosis. METHOD: This was a retrospective cross-sectional study. Clinical and demographic variables examined were: age, gender, disease subtype, SSc duration, previous intravenous prostanoid infusions, surgical debridement and/or amputation, autoantibody status (anticentromere and antitopoisomerase), pulmonary fibrosis, and pulmonary hypertension. Univariable logistic regression was used to investigate associations between demographic and clinical factors and the odds of clinical calcinosis, then multivariable regression to obtain adjusted odds ratios (ORs) and confidence intervals (CIs). RESULTS: A total of 317 patients (86% female, median age 60 years) were included: 94 (30%) had clinically apparent calcinosis. Age and gender were similar in those with and without calcinosis. Only surgical debridement (OR 3.55, 95% CI 1.71-7.53), anticentromere status (OR 2.32, 95% CI 1.27-4.32), and disease duration (OR 1.08, 95% CI 1.04-1.11) remained significant predictors after adjusting for other variables. In combination, the selected variables explained approximately 18% of the variation in the outcome but did not grant sufficient predictive power to discriminate between those with and without calcinosis [Nagelkerke's R(2) = 0.18, area under the receiver operating characteristic curve (AuROC) = 0.51, both adjusted for optimism]. CONCLUSIONS: History of surgical debridement, positive anticentromere antibody, and disease duration were independently associated with calcinosis. However, the low explanatory and discriminatory power of a multiple logistic regression model suggests there are other important predictors of calcinosis unaccounted for in this analysis.

Calcinosis preferentially affects the thumb compared to other fingers in patients with systemic sclerosis.

OBJECTIVES: Although Raynaud's phenomenon often spares the thumb, clinical experience suggests conversely that, in patients with systemic sclerosis (SSc), the thumb is frequently affected by calcinosis (as is demonstrated on plain radiographs). Our aim was to investigate the hypothesis that, in patients with SSc, thumbs are more commonly affected by calcinosis than other digits. METHOD: Sixty-eight hand radiographs with at least one area of calcinosis were identified. Each digit on both hands of each patient was assigned a severity score on a scale from 0 to 3 (0 = no calcinosis, 3 = most severe). The scoring was completed twice, including and excluding the metacarpals. RESULTS: Right hands were found to be associated with slightly higher scores than left hands [estimate 0.14, 95% confidence interval (CI) 0.03-0.26]. Scores were lower for other fingers compared to thumbs. There was strong evidence (p < 0.0001) of a trend of decreasing severity moving from the thumb to the little finger. There was no evidence that the pattern of severity across the fingers was different on left and right hands (p = 0.77). The results were similar whether or not metacarpals were included. CONCLUSIONS: The thumb is affected by calcinosis more than other digits, followed by the index finger. This observation provides insight into the pathogenesis of SSc-related calcinosis, which may relate more to repetitive trauma than to ischaemia.

Pathways Mediating Activity-Induced Enhancement of Recovery From Peripheral Nerve Injury.

This article outlines the novel hypothesis that exercise promotes axon regeneration after peripheral nerve injury through neuronal brain-derived neurotrophic factor (BDNF), and there are three required means of promoting BDNF expression: 1) increased signaling through androgen receptors, 2) increased cAMP-responsive element-binding protein expression, and 3) increased expression of the transcription factor SRY-box containing gene 11.

A red tide of Alexandrium fundyense in the Gulf of Maine.

In early July 2009, an unusually high concentration of the toxic dinoflagellate Alexandrium fundyense occurred in the western Gulf of Maine, causing surface waters to appear reddish brown to the human eye. The discolored water appeared to be the southern terminus of a large-scale event that caused shellfish toxicity along the entire coast of Maine to the Canadian border. Rapid-response shipboard sampling efforts together with satellite data suggest the water discoloration in the western Gulf of Maine was a highly ephemeral feature of less than two weeks in duration. Flow cytometric analysis of surface samples from the red water indicated the population was undergoing sexual reproduction. Cyst fluxes downstream of the discolored water were the highest ever measured in the Gulf of Maine, and a large deposit of new cysts was observed that fall. Although the mechanisms causing this event remain unknown, its timing coincided with an anomalous period of downwelling-favorable winds that could have played a role in aggregating upward-swimming cells. Regardless of the underlying causes, this event highlights the importance of short-term episodic phenomena on regional population dynamics of A. fundyense.

SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity.

Hepatocellular carcinoma (HCC) is a major cause of cancer death, but the molecular mechanism for its development beyond its initiation has not been well characterized. Suppressor of cytokine signaling (SOCS-1; also known as JAB and SSI-1) switches cytokine signaling 'off' by means of its direct interaction with Janus kinase (JAK). We identified aberrant methylation in the CpG island of SOCS-1 that correlated with its transcription silencing in HCC cell lines. The incidence of aberrant methylation was 65% in the 26 human primary HCC tumor samples analyzed. Moreover, the restoration of SOCS-1 suppressed both growth rate and anchorage-independent growth of cells in which SOCS-1 was methylation-silenced and JAK2 was constitutively activated. This growth suppression was caused by apoptosis and was reproduced by AG490, a specific, chemical JAK2 inhibitor that reversed constitutive phosphorylation of STAT3 in SOCS-1 inactivated cells. The high prevalence of the aberrant SOCS-1 methylation and its growth suppression activity demonstrated the importance of the constitutive activation of the JAK/STAT pathway in the development of HCC. Our results also indicate therapeutic strategies for the treatment of HCC including use of SOCS-1 in gene therapy and inhibition of JAK2 by small molecules, such as AG490.

Digit ratio (2D:4D) and its relationship to foetal and maternal sex steroids: A mini-review.

The challenges of terrestrial existence may mean that the early development of tetrapod limb traits is linked to the development of the urogenital system and sex steroids. One such limb trait is the sex-dependent ratio of the lengths of the 2nd and 4th digits (2D:4D). Direct evidence for the association between early sex steroids and offspring 2D:4D can be obtained by manipulating foetal sex hormones. However, this is not ethically permissible in humans. It is widely accepted that 2D:4D is a biomarker for early foetal sex hormones in tetrapods but the link in humans remains controversial. Here we review the evidence that (i) manipulation of sex steroids in early development leads to sex-dependent changes in 2D:4D throughout the tetrapods, and (ii) maternal sex steroids cross the placenta and thus are associated with offspring 2D:4D in both non-human and human animals. We suggest a research focus on associations between human maternal sex steroids and offspring 2D:4D to clarify the link between 2D:4D and early sex steroids. A protocol is proposed to examine the correlation between 1st-trimester maternal sex steroids and offspring 2D:4D. Such an association may explain the existence and medium effect size of the human sex difference in 2D:4D.

Expression of NEDD4L and ENaC in Urinary Extracellular Vesicles in Pre-eclampsia.

OBJECTIVE: To assess changes in expression of renal epithelial sodium channel (ENaC) and NEDD4L, a ubiquitin ligase, in urinary extracellular vesicles (UEV) of pre-eclamptic women compared to normal pregnant controls. METHODS: Urine was collected from pre-eclamptic women (PE, n = 20) or during normal pregnancy (NP, n = 20). UEV were separated by differential ultracentrifugation. NEDD4L, α-ENaC and γ-ENaC were identified by immunoblotting. RESULTS: There was no difference in the expression of NEDD4L (p = 0.17) and α-ENaC (p = 0.10). PE subjects showed increased expression of γ-ENaC by 6.9-fold compared to NP (p < 0.0001). CONCLUSION: ENaC expression is upregulated in UEV of pre-eclamptic subjects but was not associated with changes in NEDD4L.

Chondroitinase ABC reduces time to muscle reinnervation and improves functional recovery after sciatic nerve transection in rats.

Application of chondroitinase ABC (ChABC) to injured peripheral nerves improves axon regeneration, but it is not known whether functional recovery is also improved. Recordings of EMG activity [soleus (Sol) M response and H reflexes] evoked by nerve stimulation and of Sol and tibialis anterior (TA) EMG activity and hindlimb and foot kinematics during slope walking were made to determine whether ChABC treatment of the sciatic nerve at the time of transection improves functional recovery. Recovery of evoked EMG responses began as multiple small responses with a wide range of latencies that eventually coalesced into one or two more distinctive and consistent responses (the putative M response and the putative H reflex) in both groups. Both the initial evoked responses and the time course of their maturation returned sooner in the ChABC group than in the untreated (UT) group. The reinnervated Sol and TA were coactivated during treadmill locomotion during downslope, level, and upslope walking throughout the study period in both UT and ChABC-treated rats. By 10 wk after nerve transection and repair, locomotor activity in Sol, but not TA, had returned to its pretransection pattern. There was an increased reliance on central control of Sol activation across slopes for both groups as interpreted from elevated prestance Sol EMG activity that was no longer modulated with slope. Limb length and orientation during locomotion were similar to those observed prior to nerve injury during upslope walking only in the ChABC-treated rats. Thus treatment of cut nerves with ChABC leads to improvements in functional recovery.