Correction to: Bone metabolism in patients with anorexia nervosa and amenorrhoea.

Unfortunately, the sixth author name was incorrectly spelled as "S. Fassio" instead of "A. Fassio" in the original publication.

Bone metabolism in patients with anorexia nervosa and amenorrhoea.

PURPOSE: Aim of this study is focusing on bone metabolism in AN patients with amenorrhoea and related estrogen deficiency effects. METHODS: AN patients were compared both with healthy females and with postmenopausal women (reference model for estrogen deficiency). The study sample included 81 females with AN. Laboratory tests [25-OH vitamin D, bone turnover markers, intact parathyroid hormone, sclerostin (SOST) and dickkopf-related protein (DKK1)] and dual energy X-ray absorptiometry (DXA) were taken into account. RESULTS: AN patients had higher levels of C-terminal telopeptide of type I collagen (CTX) than both control groups. AN adolescents had CTX higher than AN young adults. In postmenopausal women, intact N-propeptide of type I collagen was higher if compared with each other group. In AN groups, Dickkopf-related protein 1 was significantly lower than the two control groups. No differences were found in sclerostin except in adolescents. In AN adolescents, DXA values at femoral sites were higher than in AN young adults and a positive correlation was found with body weight (p < 0.01) and with fat mass evaluated using DXA (p < 0.01). CONCLUSIONS: AN women with amenorrhoea have an increased bone resorption like postmenopausal women but bone formation is depressed. The consequent remodeling uncoupling is considerably more severe than that occurring after menopause.

Teriparatide and denosumab combination therapy and skeletal metabolism.

Several therapies are available for osteoporis. Understanding the bone turnover changes and their mutual realtionship gives an overall view and might lead to a target therapy INTRODUCTION: The aim of this study is to compare the changes in bone turnover markers in patients treated with either denosumab alone, teriparatide (TPTD) alone, or in a third therapeutic scheme, when TPTD was added to patients previously treated with denosumab. METHODS: Fifty-nine women over 65 years old with severe postmenopausal osteoporosis (evidence of at least two moderate-severe vertebral fractures) were enrolled in the study. Serum samples were collected every 3 months. They were assayed for intact N-propeptide of type I collagen (P1NP), C-terminal telopeptide of type I collagen (CTX), intact parathyroid hormone (PTH), 25 hydroxy-vitamin D (25 OHD), Sclerostin (SOST), and Dickkopf-related protein 1 (DKK1). Bone mass density was assessed by dual-energy X-ray absorptiometry at the lumbar spine and at the total hip. RESULTS: In the groups treated only with TPTD or with denosumab, bone turnover markers increased and decreased, respectively. In TPTD group, a later significant increase in DKK1 was observed, while in denosumab group, a progressive increase in SOST was associated with a progressive significant decrease in DKK1. In the group treated first with denosumab and in which TPTD was added 3 months later, both CTX and P1NP increased 3 months after the beginning of TPTD. The strong effect of denosumab on bone turnover seems to be reversed by TPTD treatment. CONCLUSIONS: In this study, we showed that TPTD is able to express its biological activity even when bone turnover is fully suppressed by denosumab treatment. The combination therapy is associated with significant increases in both DKK1 and SOST.

Large oesophageal epiphrenic diverticulum resected by transhiatal robotic-assisted approach -- case report.

INTRODUCTION: Epiphrenic diverticula (ED) represent about 20% of oesophageal diverticula. They are considered to be pulsion diverticula, characterized by out pouchings of the oesophageal mucosa originating in the distal 10 cm of the oesophagus and are frequently associated with spastic oesophageal dysmotility. The most frequent clinical manifestations of ED are dysphagia, regurgitations and chest pain. Only symptomatic diverticula should be treated by surgery. The surgical procedure can be performed minimally invasively by robotic approach and consists of diverticulectomy,hiatus calibration and an antireflux procedure, usually adding an esophagomiotomy as well. CASE-REPORT: We present the case of 43-year-old male patient who was admitted for a four-month history of epigastric pain, pyrosis and regurgitations. Preoperative investigation shave shown an epiphrenic diverticulum 6 cm large in diameter.A robotic-assisted transhiatal diverticulectomy with a linear endostapler, hiatal calibration and a Nissen-Rossetti fundoplication were performed using a three-arm da Vinci Robotic System. Operative time was 150 min. Postoperative course was uneventful and the patient was discharged on postoperative day 9, without complications. Ten days later,he came back and was readmitted under emergency status for right chest pain, dyspnoea and fetid breath, being diagnosed with a right empyema secondary to a delayed fistula of the oesophageal suture line. A right minimal pleurotomy and pleural drainage under local anaesthesia were performed and an intravenous antibiotherapy was started with complete remission of symptomatology, the patient remaining asymptomatic after 18 months of follow-up. CONCLUSIONS: Robotic approach is a feasible and safe minimally invasive surgical option in the treatment of selected cases of ED. We consider transhiatal abdominal robotic approach possible in almost all cases of ED, regardless of size,thus avoiding thoracic approach and its possible major complications.The most common serious complication after surgery of ED is post diverticulectomy suture line fistula, but if properly and rapidly diagnosed it could be conservatively treated with very good results.

Occult thyroid carcinoma in our experience -- should we reconsider total thyroidectomy for benign thyroid pathology?

BACKGROUND: The reported incidence rate of occult thyroid carcinoma in patients operated for benign thyroid pathology has been much higher than expected in the last years,especially for multinodular goitre, which raises the question about which should the proper surgical management for these cases be. AIM: To assess the incidence rate of OTC in a single medium volume surgical center and to establish the correct indication for initial surgical management, as well as to identify the benign thyroid pathology most frequently associated with OTC. We also reviewed the relevant scientific literature on this topic. MATERIAL AND METHOD: We conducted a retrospective study in the General Surgery Clinic of "Prof. dr. Agrippa Ionescu" Clinical Emergency Hospital, Bucharest, on a series of 145 patients who underwent surgical interventions for preoperatively diagnosed benign thyroid pathology over a ten year period, between 1st January 2002 - 31st December 2012. All cases of known thyroid cancer were excluded. RESULTS: Incidence rate of occult thyroid carcinoma in our series was 6.9 % (10 out of 145 patients), 80 % of them being diagnosed with multinodular goitre and two cases (20 %) with Hashimoto's lymphocytic thyroiditis. 6.8 % of all patients with multinodular goitre were found to present occult carcinoma,but this association was without statistical significance(p 0.05). Incidence rate of occult cancer among patients with Hashimoto thyroiditis was proved to be as high as 28.6%,statistically significant (p=0.020). The mean size of postoperatively diagnosed occult microcarcinoma was 7 mm, ranging between 3 mm and 14 mm, 90% of them being smaller than 1cm. Histologically, papillary microcarcinoma was found in all cases. The mean age of the patients diagnosed with occult microcarcinoma was 47.8 years with majority of the female gender. The most frequent operation performed was total thyroidectomy (70.8%). Overall morbidity in our series was 6.9% with a 0.7 % mortality rate (1 case). CONCLUSIONS: In our opinion, primary total thyroidectomy should be performed as the procedure of choice for the most part of preoperatively diagnosed benign thyroid pathology and particularly for multinodular goitre and Hashimoto thyroiditis,in order to radically resect all possible foci of aggressive thyroid microcarcinomas.Abbreviations and Acronyms: OTC (Occult Thyroid Carcinoma), PTMC (Papillary Thyroid Microcarcinoma); TT(Total Thyroidectomy), MNG (Multinodular Goitre), GD(Graves' disease), TNG (Toxic Nodular Goitre), FNAB(fine-needle aspiration biopsy).

Scavenging of NADPH oxidase-derived superoxide anions improves depressed baroreflex sensitivity in spontaneously hypertensive rats.

In pathological conditions, such as hypertension, there is impairment in the autonomic control of blood pressure resulting in changes in baroreflex sensitivity. In the present study we tested the hypothesis that acute superoxide scavenging would restore the depressed baroreflex sensitivity (BRS) in spontaneously hypertensive rats (SHR). Male 10-week-old SHR (n = 14) and their controls (Wistar-Kyoto (WKY) rats; n = 14) underwent femoral artery and vein catheterization for conscious blood pressure recording and drug administration. The BRS was obtained by the drug-induced method using phenylephrine (8 µg/kg, i.v.) and sodium nitroprusside (25 µg/kg, i.v.) before and after the administration of tiron (30 mg/kg, i.v.), a superoxide dismutase mimetic, or apocynin (30 µg/kg), an NADPH oxidase inhibitor. Spontaneously hypertensive rats was significantly hypertensive compared with WKY rats (160 ± 7 vs 105 ± 2 mmHg, respectively). However, there was no significant difference in heart rate between the two groups (388 ± 10 vs 370 ± 20 b.p.m.). In addition, SHR exhibited a diminished BRS compared with WKY rats (-1.34 ± 0.11 vs -2.91 ± 0.20 b.p.m./mmHg, respectively). Administration of tiron improved BRS in SHR (from -1.34 ± 0.11 to 2.26 ± 0.21 b.p.m./mmHg), as did apocynin (to -2.14 ± 0.23 b.p.m./mmHg). Serum samples from SHR (n = 20) and WKY rats (n = 20) were collected for thiobarbituric acid-reactive substances assays before and after tiron or apocynin to confirm the reduction in oxidative stress. There was considerably greater oxidative stress in SHR compared with WKY rats (36.2 ± 3.0 vs 13.3 ± 2.6 nmol/L, respectively). Both apocynin and tiron treatment reduced the oxidative stress in SHR (from 36.2 ± 3.0 to 21.5 ± 3.0 nmol/L and from 37.2 ± 3.9 to 21.9 ± 1.6 nmol/L, respectively). The data suggest that acute scavenging of NADPH oxidase-derived superoxide improves baroreflex sensitivity in SHR.

Different acquisition systems for heart rate variability analysis may lead to diverse outcomes.

Heart rate variability (HRV) is a relevant physiological variable for the estimation of cardiac autonomic function. Although the gold standard for HRV registration is the electrocardiogram (ECG), several applications (APPs) have been increasingly developed. The evaluation carried out by these devices must be compatible with ECG standards. The aim of this study was to compare the data obtained simultaneously with ECG and APP with chest heart rate transmitters. Fifty-six healthy individuals (28 men and 28 women) were evaluated at rest through a short simultaneous HRV measurement with both devices. Data from both acquisition systems were analyzed separately using their own analysis software and exported and analyzed using a validated software. Signal recordings were compatible between the two acquisition systems (Pearson r=0.99; P<0.0001). Although a high correlation was found for the HRV variables obtained in the time domain (Spearman r=0.99; P<0.0001), the correlation decreased in the frequency domain (Pearson r=0.85; P<0.0001) when two software programs were used. Comparison of the averages of spectral analysis parameters also showed differences when HRV data were analyzed separately in each device for low-frequency (LF) and high-frequency (HF) bands. Although the portability of these mobile devices allows for optimal HRV evaluation, the direct analysis obtained from these devices must be carefully evaluated with respect to frequency domain parameters.

'Super glue'.

Cell--cell adhesion is a significant mechanical component of cell and tissue structure. However, cell contacts are not just static mechanical structures: they are integrated into the cytoskeletal and signalling processes of the cell. The formation and remodelling of cell contacts are basic to both tissue morphogenesis and, after damage, wound repair. Loss of adhesion accompanies tumour metastasis. The interplay between these processes was a major theme of a recent joint meeting of the British Societies of Cell Biology and Developmental Biology on 'Cell and Tissue Morphogenesis' in Brighton, UK (3--6 April 2001).

Clinical characteristics and incidence of first fracture in a consecutive sample of post-menopausal women attending osteoporosis centers: The PROTEO-1 study.

BACKGROUND: Osteoporosis is a highly prevalent disease and fractures are a major cause of disability and morbidity. AIM: The purpose of this study was to characterize post-menopausal women attending osteoporosis centers in Italy, to evaluate physician management, and to determine the incidence of first osteoporotic fracture. SUBJECTS AND METHODS: PROTEO-1 was an observational longitudinal study with a 12-month follow-up. Data were collected from women attending osteoporosis centers. Women without prevalent fracture were eligible to enter the 1-yr follow-up phase: the clinical approach to patients according to their fracture risk profile and the incidence of fracture were recorded. RESULTS: 4269 patients were enrolled in 80 centers in the cross-sectional phase; 34.2% had an osteoporotic fracture at baseline. Patients with prevalent fractures were older and more likely to be treated compared with non-fractured patients. The incidence of vertebral or hip fracture after 1 yr was 3.84%, regardless of the calculated risk factor profile, and was significantly higher in patients with back pain at baseline (4.2%) compared with those without back pain (2.2%; p=0.023). Generally, physicians prescribed more blood exams and drugs to patients at higher risk of fracture. Among fractured patients only 24% were properly treated; the rate of non-responders to treatment was about 4%. CONCLUSIONS: In a large, unselected sample of post-menopausal women attending osteoporosis centers, those without previous fracture were at substantial risk of future fracture, regardless of their theoretical low 10-yr fracture risk. The presence of back pain in women without previous fracture warrants close attention.

[Risk factors for hip fracture in elderly persons]. / Fattori di rischio per frattura di femore in persone anziane.

OBJECTIVE: The aim of this observational study, promoted by the Health Authorities of the Regione Veneto (Italy), is to assess the prevalence of the most relevant environmental and individual risk factors in subjects with a recent hip fracture. METHODS: Patients aged more than 60 years of both genders with a recent hip fracture not associated with malignancies, were administered questionnaires on dietary habits, sun exposure, and disability score. A complete family, pharmacological and pathology history was collected together with information on previous falls, details of the fracture index, and anthropometric data. In all subjects, blood was taken for the measurement of serum 25 hydroxy-vitamin D (25OHD). RESULTS: The study included 704 patients (573 women and 131 men). Mean age was 81 ± 8 years (range 60-102). Severe pre-fracture disability was a common feature (58%) associated with multiple co-morbidities (84%), more frequently cardiovascular and neurological diseases, and specific medications. In a large proportion (86%) of the patients, environmental or individual risk factors for falling were found. Vitamin D insufficiency (serum 25OHD levels < 75 nmol/l) was quite common (70%), particularly in the regional Health Districts were strategies for preventing vitamin D deficiency were not implemented (91%). Only a small proportion (17%) of the study population had been evaluated and treated for osteoporosis. CONCLUSIONS: In senile patients with a recent hip fracture, pre-existing disability, multiple co-morbidities, high risk of falling and inadequate intake of calcium and vitamin D is relatively common. Community and case-finding interventions aimed at selecting subjects at high risk of osteoporosis, preventing vitamin D and dietary calcium deficiency, and increasing awareness on the environmental risks of falling are highly warranted.

Does Quorum Sensing play a role in microbial shifts along spontaneous fermentation of cocoa beans? An in silico perspective.

Cocoa fermentation is a spontaneous process shaped by a variable microbial ecosystem which is assembled due to cross-feeding relationship among yeasts and bacteria, resulting in a synchronized microbial succession started by yeasts, followed by lactic acid bacteria (LAB) and finalized by acetic acid bacteria (AAB). Several studies have indicated the effect of microbial interactions in food ecosystems highlighting the importance of quorum sensing (QS) in bacterial adaptation in harsh environments modulating several phenotypes such as biofilm formation, tolerance to acid stress, bacteriocin production, competence, morphological modifications, motility, among others. However, antagonic interactions also occur, and can be marked by Quorum Quenching (QQ) activity, negatively impacting QS regulated phenotypes. Our current knowledge regarding microbial cocoa composition and functioning is based on culture-based analysis and culture-independent PCR-based methods. Therefore, we set out to investigate the application of metagenomics analysis on a classical spontaneous cocoa fermentation in order to describe: (I) the microbial taxonomic composition; (II) the functional potential of the cocoa microbiome; (III) the microbiome putative QS potential; and (IV) the microbiome QQ potential. Both aims III and IV are related to the expression of effectors that may confer advantageous traits along fermentation which can explain their dominance in specific time zones during the entire process. We have observed a bacterial succession shaped by yeasts and filamentous fungi and then Enterobacteriaceales, LAB and AAB, as well as a diverse genetic metabolic potential related to proteins and carbohydrates metabolism associated to the yeast Saccharomyces cerevisiae and members of the Enterobacteriaceales order and LAB and AAB groups. In addition, in silico evidences of interspecific QS arsenal were found in members of the genera Enterobacter, Lactobacillus, Bacillus and Pantoea, while inferences of intraspecific QS potential were found in the members of the genera Bacillus, Enterobacter, Komagataeibacter, Lactobacillus and Pantoea. In addition, a QQ potential was detected in Lactobacillus and in AAB members. These findings indicate that QS and QQ may modulate bacterial dominance in different time points during fermentation, along with cross-feeding, being responsible for their maintenance in a large time range.

The small GTPases Rho and Rac are required for the establishment of cadherin-dependent cell-cell contacts.

Cadherins are calcium-dependent cell-cell adhesion molecules that require the interaction of the cytoplasmic tail with the actin cytoskeleton for adhesive activity. Because of the functional relationship between cadherin receptors and actin filament organization, we investigated whether members of the Rho family of small GTPases are necessary for cadherin adhesion. In fibroblasts, the Rho family members Rho and Rac regulate actin polymerization to produce stress fibers and lamellipodia, respectively. In epithelial cells, we demonstrate that Rho and Rac are required for the establishment of cadherin-mediated cell-cell adhesion and the actin reorganization necessary to stabilize the receptors at sites of intercellular junctions. Blocking endogenous Rho or Rac selectively removed cadherin complexes from junctions induced for up to 3 h, while desmosomes were not perturbed. In addition, withdrawal of cadherins from intercellular junctions temporally precedes the removal of CD44 and integrins, other microfilament-associated receptors. Our data showed that the concerted action of Rho and Rac modulate the establishment of cadherin adhesion: a constitutively active form of Rac was not sufficient to stabilize cadherindependent cell-cell contacts when endogenous Rho was inhibited. Upon induction of calcium-dependent intercellular adhesion, there was a rapid accumulation of actin at sites of cell-cell contacts, which was prevented by blocking cadherin function, Rho or Rac activity. However, if cadherin complexes are clustered by specific antibodies attached to beads, actin recruitment to the receptors was perturbed by inhibiting Rac but not Rho. Our results provide new insights into the role of the small GTPases in the cadherin-dependent cell- cell contact formation and the remodelling of actin filaments in epithelial cells.

H-Ras activation promotes cytoplasmic accumulation and phosphoinositide 3-OH kinase association of beta-catenin in epidermal keratinocytes.

The mechanisms underlying downregulation of the cadherin/catenin complexes and beta-catenin signaling during tumor progression are not fully understood. We have analyzed the effect of oncogenic H-Ras on E-cadherin/catenin complex formation/stabilization and beta-catenin distribution in epidermal keratinocytes. Microinjection or stable expression of V12Ras into keratinocytes promotes the loss of E-cadherin and alpha-catenin and relocalization of beta-catenin to the cytoplasm and nucleus. Moreover, these effects are dependent on PI3K (phosphoinositide 3-OH kinase) activity. Interestingly, a strong association of p85alpha and p110alpha subunits of PI3K with beta-catenin is induced in V12Ras-expressing keratinocytes, and in vitro binding assays show a direct interaction between beta-catenin and p85alpha. Overexpression of either V12Ras or constitutively active p110alpha induces metabolic stabilization of beta-catenin and promotes its accumulation in cytoplasmic and nuclear pools. In addition, the interaction of beta-catenin with the adenomatous polyposis coli protein is blocked in V12Ras and p110alpha transformants though no changes in glycogen synthase kinase 3 beta activity could be detected. Nevertheless, in V12Ras transformants the in vivo phosphorylation of beta-catenin in Ser residues is strongly decreased. These results indicate that H-Ras activation induces the relocalization and cytoplasmic stabilization of beta-catenin by a mechanism involving its interaction with PI3K.

Insights on the epigenetic mechanisms underlying pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH), characterized by localized increased arterial blood pressure in the lungs, is a slow developing long-term disease that can be fatal. PAH is characterized by inflammation, vascular tone imbalance, pathological pulmonary vascular remodeling, and right-sided heart failure. Current treatments for PAH are palliative and development of new therapies is necessary. Recent and relevant studies have demonstrated that epigenetic processes may exert key influences on the pathogenesis of PAH and may be promising therapeutic targets in the prevention and/or cure of this condition. The aim of the present mini-review is to summarize the occurrence of epigenetic-based mechanisms in the context of PAH physiopathology, focusing on the roles of DNA methylation, histone post-translational modifications and non-coding RNAs. We also discuss the potential of epigenetic-based therapies for PAH.

Caspase activation in the terminal differentiation of human epidermal keratinocytes.

The epidermis is a multilayered squamous epithelium in which dividing basal cells withdraw from the cell cycle and progressively differentiate as they are displaced toward the skin surface. Eventually, the cells lose their nucleus and other organelles to become flattened squames, which are finally shed from the surface as bags of cross-linked keratin filaments enclosed in a cornified envelope [1]. Although keratinocytes can undergo apoptosis when stimulated by a variety of agents [2], it is not known whether their normal differentiation programme uses any components of the apoptotic biochemical machinery to produce the cornified cell. Differentiating keratinocytes have been reported to share some features with apoptotic cells, such as DNA fragmentation, but these features have not been seen consistently [3]. Apoptosis involves an intracellular proteolytic cascade, mainly mediated by members of the caspase family of cysteine proteases, which cleave one another and various key intracellular target proteins to kill the cell neatly and quickly [4]. Here, we show for the first time that caspases are activated during normal human keratinocyte differentiation and that this activation is apparently required for the normal loss of the nucleus.

Regulation of cadherin function by Rho and Rac: modulation by junction maturation and cellular context.

Cadherins are cell-cell adhesion receptors whose adhesive function requires their association with the actin cytoskeleton via proteins called catenins. The small guanosine triphosphatases (GTPases), Rho and Rac, are intracellular proteins that regulate the formation of distinct actin structures in different cell types. In keratinocytes and in other epithelial cells, Rho and Rac activities are required for E-cadherin function. Here we show that the regulation of cadherin adhesiveness by the small GTPases is influenced by the maturation status of the junction and the cellular context. E-cadherin localization was disrupted in mature keratinocyte junctions after inhibition of Rho and Rac. However, an incubation of 2 h was required after GTPase inhibition, when compared with newly established E-cadherin contacts (30 min). Regarding other cadherin receptors, P-cadherin was effectively removed from mature keratinocytes junctions by blocking Rho or Rac. In contrast, VE-cadherin localization at endothelial junctions was independent of Rho/Rac activity. We demontrate that the insensitivity of VE-cadherin to inhibition of Rho and Rac was not due to the maturation status of endothelial junction, but rather the cellular background: when transfected into CHO cells, the localization of VE-cadherin was perturbed by inhibition of Rho proteins. Our results suggest that the same stimuli may have different activity in regulating the paracellular activity in endothelial and epithelial cells. In addition, we uncovered possible roles for the small GTPases during the establishment of E-cadherin-dependent contacts. In keratinocytes, Rac activation by itself cannot promote accumulation of actin at the cell periphery in the absence of cadherin-dependent contacts. Moreover, neither Rho nor Rac activation was sufficient to redistribute cadherin molecules to cell borders, indicating that redistribution results mostly from the homophilic binding of the receptors. Our results point out the complexity of the regulation of cadherin-mediated adhesion by the small GTPases, Rho and Rac.

Activation of the small GTPase Rac is sufficient to disrupt cadherin-dependent cell-cell adhesion in normal human keratinocytes.

To achieve strong adhesion to their neighbors and sustain stress and tension, epithelial cells develop many different specialized adhesive structures. Breakdown of these structures occurs during tumor progression, with the development of a fibroblastic morphology characteristic of metastatic cells. During Ras transformation, Rac-signaling pathways participate in the disruption of cadherin-dependent adhesion. We show that sustained Rac activation per se is sufficient to disassemble cadherin-mediated contacts in keratinocytes, in a concentration- and time-dependent manner. Cadherin receptors are removed from junctions before integrin receptors, suggesting that pathways activated by Rac can specifically interfere with cadherin function. We mapped an important region for disruption of junctions to the putative second effector domain of the Rac protein. Interestingly, although this region overlaps the domain necessary to induce lamellipodia, we demonstrate that the disassembly of cadherin complexes is a new Rac activity, distinct from Rac-dependent lamellipodia formation. Because Rac activity is also necessary for migration, Rac is a good candidate to coordinately regulate cell-cell and cell-substratum adhesion during tumorigenesis.

The scaffold protein Ajuba suppresses CdGAP activity in epithelia to maintain stable cell-cell contacts.

Levels of active Rac1 at epithelial junctions are partially modulated via interaction with Ajuba, an actin binding and scaffolding protein. Here we demonstrate that Ajuba interacts with the Cdc42 GTPase activating protein CdGAP, a GAP for Rac1 and Cdc42, at cell-cell contacts. CdGAP recruitment to junctions does not require Ajuba; rather Ajuba seems to control CdGAP residence at sites of cell-cell adhesion. CdGAP expression potently perturbs junctions and Ajuba binding inhibits CdGAP activity. Ajuba interacts with Rac1 and CdGAP via distinct domains and can potentially bring them in close proximity at junctions to facilitate activity regulation. Functionally, CdGAP-Ajuba interaction maintains junctional integrity in homeostasis and diseases: (i) gain-of-function CdGAP mutants found in Adams-Oliver Syndrome patients strongly destabilize cell-cell contacts and (ii) CdGAP mRNA levels are inversely correlated with E-cadherin protein expression in different cancers. We present conceptual insights on how Ajuba can integrate CdGAP binding and inactivation with the spatio-temporal regulation of Rac1 activity at junctions. Ajuba provides a novel mechanism due to its ability to bind to CdGAP and Rac1 via distinct domains and influence the activation status of both proteins. This functional interplay may contribute towards conserving the epithelial tissue architecture at steady-state and in different pathologies.

Different acquisition systems for heart rate variability analysis may lead to diverse outcomes

Heart rate variability (HRV) is a relevant physiological variable for the estimation of cardiac autonomic function. Although the gold standard for HRV registration is the electrocardiogram (ECG), several applications (APPs) have been increasingly developed. The evaluation carried out by these devices must be compatible with ECG standards. The aim of this study was to compare the data obtained simultaneously with ECG and APP with chest heart rate transmitters. Fifty-six healthy individuals (28 men and 28 women) were evaluated at rest through a short simultaneous HRV measurement with both devices. Data from both acquisition systems were analyzed separately using their own analysis software and exported and analyzed using a validated software. Signal recordings were compatible between the two acquisition systems (Pearson r=0.99; P<0.0001). Although a high correlation was found for the HRV variables obtained in the time domain (Spearman r=0.99; P<0.0001), the correlation decreased in the frequency domain (Pearson r=0.85; P<0.0001) when two software programs were used. Comparison of the averages of spectral analysis parameters also showed differences when HRV data were analyzed separately in each device for low-frequency (LF) and high-frequency (HF) bands. Although the portability of these mobile devices allows for optimal HRV evaluation, the direct analysis obtained from these devices must be carefully evaluated with respect to frequency domain parameters.