Functionally aligned total knee arthroplasty: A lateral flexion laxity up to 6 mm is safe!

PURPOSE: Loose flexion gaps are associated with poor functional outcomes and instability in total knee arthroplasty (TKA). The effect of a trapezoidal flexion gap in a functionally aligned TKA remains unknown. The aim of this study was to investigate the effect of a larger lateral flexion gap in a robotic-assisted (RA), functionally aligned (FA) and cruciate-retaining (CR) TKA on clinical outcomes. METHODS: Data from 527 TKA in 478 patients from 2018 to 2020 were collected. All patients underwent an RA (MAKO, Stryker), FA and CR TKA. Gap measurements were collected intraoperatively. Patient-reported outcome measures (PROMs), pain Visual analogue score (VAS) and range of motion were collected postoperatively. Patients were also asked about the ease of stair ascent and descent and kneeling on a 5-point scale. The minimum follow-up was 2 years. Patients were stratified into three groups based on lateral flexion laxity. RESULTS: At 2 years postoperatively, the group with a looser gap (3-6 mm) had higher mean PROMs when compared with the group with a gap of 2-3 mm. There were no differences detected in any other outcomes at 2 years. A total of 70.9% of patients in the group with a 3-6 mm gap reported being able to walk down a flight of stairs 'easily', compared with 56.7% in the 2-3 mm group and 54% in the <2 mm group (p = 0.04). CONCLUSION: The study shows that a loose lateral flexion gap in functionally aligned CR TKA does not adversely affect outcomes in the short term. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Inflammatory and Cardiovascular Biomarkers to Monitor Fabry Disease Progression.

Fabry disease is an invalidating multisystemic disorder affecting α-Galactosidase, a rate-limiting hydrolase dedicated to lipid catabolism. Non-metabolized substrates, such as Globotriaosylceramide and its derivatives trigger the direct or indirect activation of inflammatory events and endothelial dysfunction. In spite of the efficacy demonstrated by enzyme replacement therapy or pharmacological chaperones in delaying disease progression, few studies have analyzed whether these treatments can improve the pro-inflammatory state of FD patients. Therefore, the aim of this work was to assess cytokines and cardiovascular risk-related proteins detectable in plasma from FD patients, whether treated or not with ERT, to evaluate the reliability of these markers in monitoring disease stage and treatment effects. We identified inflammatory and endothelial dysfunction markers (ADAMTS-13, TNF-α, GDF-15, MIP-1ß, VEGFA, MPO, and MIC-1) that cooperate in a common pathway and are increased in FD patients' plasma samples. As shown by the assessment of these proteins over time, they can help to evaluate the risk of higher severity in FD, as well as ERT effects. Even though the analyzed proteins cannot be considered as proper biomarkers due to their non-specificity to FD, taken together they can provide a signature of reference molecules with prognostic value for early diagnosis, and evaluation of disease progression and treatment efficacy, using blood samples.

Peroral endoscopic myotomy as treatment for Zenker's diverticulum (Z-POEM): a multi-center international study.

BACKGROUND: Peroral endoscopic myotomy for the treatment of Zenker's diverticulum (Z-POEM) is a novel technique that has been described in several recent reports. This method utilizes the third space (submucosal layer) to create a tunnel to facilitate complete visualization of the septum and hence cutting it entirely. Conventional endoscopic septotomy carries the risk of recurrence due to incomplete visualization of the septum. While surgical correction is a risky and lengthy procedure in old comorbid patients with Zenker's diverticulum. The aim of this study is to assess the efficacy and safety of Z-POEM. METHODS: The study enrolled 24 patients diagnosed with Zenker's diverticulum (ZD) who underwent Z-POEM at seven independent endoscopy centers in five different countries. RESULTS: Mean patient age ± standard deviation (SD) was 74.3 ± 11 years. Most of the patients were males (n = 20, 83.3%); four (16.7%) were females. More than 50% of the patients (n = 14, 58.3%) had associated comorbidities. The mean size of the diverticula was 4 cm (range 2-7 cm). The Kothari-Haber Score was used to assess clinical symptoms; values ranged from 6 to 14 (median = 9). We achieved 100% technical success with a median procedure time of 61 min and no adverse events. Median hospital stay was 1 day (range 1-5 days). There is a significant reduction in the Kothari-Haber Score after Z-POEM (P < 0.0001). Technical success was achieved in 100% of the patients. Clinical success was achieved in 23/24 (95.8%) of the patients with a median follow-up of 10 months (range 6-24 months). CONCLUSION: Z-POEM is a safe and effective modality for managing ZD.

GladiaTOX: GLobal Assessment of Dose-IndicAtor in TOXicology.

SUMMARY: GladiaTOX R package is an open-source, flexible solution to high-content screening data processing and reporting in biomedical research. GladiaTOX takes advantage of the 'tcpl' core functionalities and provides a number of extensions: it provides a web-service solution to fetch raw data; it computes severity scores and exports ToxPi formatted files; furthermore it contains a suite of functionalities to generate PDF reports for quality control and data processing. AVAILABILITY AND IMPLEMENTATION: GladiaTOX R package (bioconductor). Also available via: git clone https://github.com/philipmorrisintl/GladiaTOX.git. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

In Vitro Systems Toxicology Assessment of a Candidate Modified Risk Tobacco Product Shows Reduced Toxicity Compared to That of a Conventional Cigarette.

Cigarette smoke increases the risk for respiratory and other diseases. Although smoking prevalence has declined over the years, millions of adults choose to continue to smoke. Modified risk tobacco products (MRTPs) are potentially valuable tools for adult smokers that are unwilling to quit their habit. Here, we investigated the biological impact of a candidate MRTP, the tobacco-heating system (THS) 2.2, compared to that of the 3R4F reference cigarette in normal primary human bronchial epithelial cells. Chemical characterization of the THS 2.2 aerosol showed reduced levels of harmful constituents compared to those of a combustible cigarette. Multiparametric indicators of cellular toxicity were measured via real-time cellular analysis and high-content screening. The study was complemented by a whole transcriptome analysis, followed by computational approaches to identify and quantify perturbed molecular pathways. Exposure of cells to 3R4F cigarette smoke resulted in a dose-dependent response in most toxicity end points. Moreover, we found a significant level of perturbation in multiple biological pathways, particularly in those related to cellular stress. By contrast, exposure to THS 2.2 resulted in an overall lower biological impact. At 3R4F doses, no toxic effects were observed. A toxic response was observed for THS 2.2 in some functional end points, but the responses occurred at doses between 3 and 15 times higher than those of 3R4F. The level of biological network perturbation was also significantly reduced following THS 2.2 aerosol exposure compared to that of 3R4F cigarette smoke. Taken together, the data suggest that THS 2.2 aerosol is less toxic than combustible cigarette smoke and thus may have the potential to reduce the risk for smoke-related diseases.

[Validation and adhesion to GESIDA quality indicators in patients with HIV infection]. / Validación y cumplimentación de los indicadores de calidad GESIDA en pacientes con infección por el VIH.

INTRODUCTION: The objective of the study is to validate the relevant GESIDA quality indicators for HIV infection, assessing the reliability, feasibility and adherence to them. METHODS: The reliability was evaluated using the reproducibility of 6 indicators in peer review, with the second observer being an outsider. The feasibility and measurement of the level of adherence to the 22 indicators was conducted with annual fragmented retrospective collection of information from specific databases or the clinical charts of the nine participating hospitals. RESULTS: Reliability was very high, with interobserver agreement levels higher than 95% in 5 of the 6 indicators. The median time to achieve the indicators ranged between 5 and 600minutes, but could be achieved progressively from specific databases, enabling obtaining them automatically. As regards adherence to the indicators related with the initial evaluation of the patients, instructions and suitability of the guidelines for ART, adherence to ART, follow-up in clinics, and achieve an undetectable HIV by PCR at week 48 of the ART. Indicators of quality related to the prevention of opportunistic infections and control of comorbidities, the standards set were not achieved, and significant heterogeneity was observed between hospitals. CONCLUSION: The GESIDA quality indicators of HIV infection enabled the relevant indicators to be feasibly and reliably measured, and should be collected in all the units that care for patients with HIV infection.

A framework for in vitro systems toxicology assessment of e-liquids.

Various electronic nicotine delivery systems (ENDS), of which electronic cigarettes (e-cigs) are the most recognized prototype, have been quickly gaining ground on conventional cigarettes because they are perceived as less harmful. Research assessing the potential effects of ENDS exposure in humans is currently limited and inconclusive. New products are emerging with numerous variations in designs and performance parameters within and across brands. Acknowledging these challenges, we present here a proposed framework for an in vitro systems toxicology assessment of e-liquids and their aerosols, intended to complement the battery of assays for standard toxicity assessments. The proposed framework utilizes high-throughput toxicity assessments of e-liquids and their aerosols, in which the device-to-device variability is minimized, and a systems-level investigation of the cellular mechanisms of toxicity is an integral part. An analytical chemistry investigation is also included as a part of the framework to provide accurate and reliable chemistry data solidifying the toxicological assessment. In its simplest form, the framework comprises of three main layers: (1) high-throughput toxicity screening of e-liquids using primary human cell culture systems; (2) toxicity-related mechanistic assessment of selected e-liquids, and (3) toxicity-related mechanistic assessment of their aerosols using organotypic air-liquid interface airway culture systems. A systems toxicology assessment approach is leveraged to enable in-depth analyses of the toxicity-related cellular mechanisms of e-liquids and their aerosols. We present example use cases to demonstrate the suitability of the framework for a robust in vitro assessment of e-liquids and their aerosols.

A new pathway that regulates 53BP1 stability implicates cathepsin L and vitamin D in DNA repair.

Genomic instability due to telomere dysfunction and defective repair of DNA double-strand breaks (DSBs) is an underlying cause of ageing-related diseases. 53BP1 is a key factor in DNA DSBs repair and its deficiency is associated with genomic instability and cancer progression. Here, we uncover a novel pathway regulating the stability of 53BP1. We demonstrate an unprecedented role for the cysteine protease Cathepsin L (CTSL) in the degradation of 53BP1. Overexpression of CTSL in wild-type fibroblasts leads to decreased 53BP1 protein levels and changes in its cellular distribution, resulting in defective repair of DNA DSBs. Importantly, we show that the defects in DNA repair associated with 53BP1 deficiency upon loss of A-type lamins are due to upregulation of CTSL. Furthermore, we demonstrate that treatment with vitamin D stabilizes 53BP1 and promotes DNA DSBs repair via inhibition of CTSL, providing an as yet unsuspected link between vitamin D action and DNA repair. Given that CTSL upregulation is a hallmark of cancer and progeria, regulation of this pathway could be of great therapeutic significance for these diseases.

Systems biology approach for evaluating the biological impact of environmental toxicants in vitro.

Exposure to cigarette smoke is a leading cause of lung diseases including chronic obstructive pulmonary disease and cancer. Cigarette smoke is a complex aerosol containing over 6000 chemicals and thus it is difficult to determine individual contributions to overall toxicity as well as the molecular mechanisms by which smoke constituents exert their effects. We selected three well-known harmful and potentially harmful constituents (HPHCs) in tobacco smoke, acrolein, formaldehyde and catechol, and established a high-content screening method using normal human bronchial epithelial cells, which are the first bronchial cells in contact with cigarette smoke. The impact of each HPHC was investigated using 13 indicators of cellular toxicity complemented with a microarray-based whole-transcriptome analysis followed by a computational approach leveraging mechanistic network models to identify and quantify perturbed molecular pathways. HPHCs were evaluated over a wide range of concentrations and at different exposure time points (4, 8, and 24 h). By high-content screening, the toxic effects of the three HPHCs could be observed only at the highest doses. Whole-genome transcriptomics unraveled toxicity mechanisms at lower doses and earlier time points. The most prevalent toxicity mechanisms observed were DNA damage/growth arrest, oxidative stress, mitochondrial stress, and apoptosis/necrosis. A combination of multiple toxicological end points with a systems-based impact assessment allows for a more robust scientific basis for the toxicological assessment of HPHCs, allowing insight into time- and dose-dependent molecular perturbations of specific biological pathways. This approach allowed us to establish an in vitro systems toxicology platform that can be applied to a broader selection of HPHCs and their mixtures and can serve more generally as the basis for testing the impact of other environmental toxicants on normal bronchial epithelial cells.

A framework for the systematic evaluation of a novel cigarette filter technology.

Any functional change in cigarette filter design warrants a rigorous assessment to ensure comparability to existing filter functionality. This study compares the functionality of a standard CA filter with a novel cellulose-based alternative using a combination of emissions, in silico approaches, pre-clinical assessments and behavioural studies. We assess the challenges faced with a significant filtration change, the substantiation of this change and the limitations of such assessments. We explore cigarette emission chemical profiles; assess the potential toxicological impacts (in vitro and statistical modelling) of the differing chemical profiles of cigarette smoke aerosol resulting from the respective filter types; and, finally investigate the behavioural aspects associated with use of the novel filter as compared to the traditional one. The aim of the study was to establish a weight of evidence assessment framework for the comprehensive evaluation of a novel cigarette filter design as part of robust stewardship approach. The data show comparability to a standard CA filter across all assessments and highlight potential areas of investigation for future novel filter product iterations. The approach demonstrates the applicability of a comprehensive step-wise assessment framework to identify any potential increased toxicant emissions and exposures associated with using the novel filter.

Novel roles for A-type lamins in telomere biology and the DNA damage response pathway.

A-type lamins are intermediate filament proteins that provide a scaffold for protein complexes regulating nuclear structure and function. Mutations in the LMNA gene are linked to a variety of degenerative disorders termed laminopathies, whereas changes in the expression of lamins are associated with tumourigenesis. The molecular pathways affected by alterations of A-type lamins and how they contribute to disease are poorly understood. Here, we show that A-type lamins have a key role in the maintenance of telomere structure, length and function, and in the stabilization of 53BP1, a component of the DNA damage response (DDR) pathway. Loss of A-type lamins alters the nuclear distribution of telomeres and results in telomere shortening, defects in telomeric heterochromatin, and increased genomic instability. In addition, A-type lamins are necessary for the processing of dysfunctional telomeres by non-homologous end joining, putatively through stabilization of 53BP1. This study shows new functions for A-type lamins in the maintenance of genomic integrity, and suggests that alterations of telomere biology and defects in DDR contribute to the pathogenesis of lamin-related diseases.

Crohn's-like disease in a patient with common variable immunodeficiency treated with azathioprine and adalimumab.

Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency. It is characterized by recurrent bacterial infections, and occurrence of autoimmune and neoplastic diseases is also frequent; there is also a high prevalence of gastrointestinal diseases. There are reports of inflammatory bowel disease in this entity, but incidence is low (2-4 %). We present the case of a patient with common variable immunodeficiency suffering a chronic diarrhea episode and who was diagnosed with ileocaecal Crohn s-like disease after performing intestinal transit, CT abdomen and colonoscopy with biopsy. It was first treated with prednisone but on showing cortisone dependency, treatment with azathioprine and adalimumab was started, with good results.

Behavioural intention of hand hygiene compliance in an average Ecuadorian hospital.

OBJECTIVE: This study aimed to characterize hand hygiene behavioural intention by hospital services clusters in a medium-sized hospital in an Ecuadorian city. METHODS: This is a cross-sectional study based on the World Health Organization Hand Hygiene Knowledge Questionnaire for Health-Care Workers. The responses on hand hygiene behavioural intention for the Five Moments for hand hygiene according to the World Health Organization were recorded in three categories: before patient contact, before and after sterile technique and management of body fluids, and after contact with the environment of the patient. The variables were the knowledge regarding the source of germs causing nosocomial infections, the optimal time to achieve disinfection with alcohol, hospital services clusters (clinical medicine, surgery, and therapeutic services), and history of previous formal hand hygiene training. The variables in each moment were analysed using a saturated log-linear model. RESULTS: The average age of participants was 34 years (Q1 32.1-Q3 36.4). Of them, 62% belonged to the clinic cluster and 87.6% had previous formal hand hygiene training. The incorrect response rates for before and after sterile technique and management of body fluids, before patient contact, and after contact with the environment of the patient were 30.2, 88.4, and 99.2%, respectively. In before patient contact, the incorrect responses for optimal time depended on the department (worse surgery cluster situation), and in before and after sterile technique and management of body fluids and after contact with the environment of the patient, the incorrect responses for source of germs depended on the previous formal hand hygiene training and the department (worse surgery and clinic clusters). CONCLUSION: The incorrect answer related to hand hygiene behavioural intention was high compared to other reports, and the worse situation was found in after contact with the environment of the patient and before patient contact. These data suggest the need of strengthening permanently the hand hygiene programme.

Twelve weeks of water-based circuit training exercise improves fitness, body fat and leg strength in people with stable coronary heart disease: a randomised trial.

QUESTION: In people with stable coronary heart disease, what are the effects of water-based circuit training exercise on aerobic capacity, strength and body composition? How do these effects compare with those of gym-based exercise? DESIGN: Parallel group, randomised controlled trial with concealed allocation and intention-to-treat analysis. PARTICIPANTS: Fifty-two participants with stable coronary heart disease. INTERVENTIONS: Twelve weeks of: three 1-hour sessions per week of moderate-intensity water-based circuit training exercise with alternating aerobic and resistance stations (WEX); three 1-hour sessions per week of moderate-intensity gym-based circuit training exercise (GEX); or continuing usual activities (control). OUTCOME MEASURES: Aerobic capacity (VO2peak), upper and lower limb one repetition maximum strength (biceps curl, latissimus dorsi pulldown, hamstring curl and leg press), anthropometry (weight, body mass index and girth) and dual energy x-ray absorptiometry. RESULTS: Forty-five participants completed the study (WEX n = 15, GEX n = 18, control n = 12). Both training groups significantly improved VO2peak compared with control: WEX by 2.5 ml/kg/min (95% CI 0.6 to 4.4) and GEX by 2.3 ml/kg/min (95% CI 0.6 to 4.0). WEX and GEX improved hamstring strength compared with control: WEX by 6.3 kg (95% CI 1.2 to 11.3) and GEX by 7.6 kg (95% CI 2.9 to 12.2). Compared with control, GEX increased leg press strength by 15.5 kg (95% CI 5.7 to 25.3), whereas the effect of WEX was less clear (MD 7.1 kg, 95% CI -3.5 to 17.7). Only GEX improved latissimus dorsi pulldown strength. Compared with control, total body fat was reduced with WEX (-1.1 kg, 95% CI -2.3 to 0.0) and GEX (-1.2 kg, 95% CI -2.3 to -0.1). There were negligible between-group differences in weight or waist circumference. CONCLUSION: WEX was well tolerated and improved aerobic capacity, leg strength and body fat to a similar degree as GEX in people with coronary heart disease. These findings suggest that WEX is an effective exercise training alternative to GEX for people with coronary heart disease. TRIAL REGISTRATION: ANZCTR12616000102471.

The role of RPA2 phosphorylation in homologous recombination in response to replication arrest.

Failure to reactivate stalled or collapsed DNA replication forks is a potential source of genomic instability. Homologous recombination (HR) is a major mechanism for repairing the DNA damage resulting from replication arrest. The single-strand DNA (ssDNA)-binding protein, replication protein A (RPA), plays a major role in multiple processes of DNA metabolism. However, the role of RPA2 hyperphosphorylation, which occurs in response to DNA damage, had been unclear. Here, we show that hyperphosphorylated RPA2 associates with ssDNA and recombinase protein Rad51 in response to replication arrest by hydroxyurea (HU) treatment. In addition, RPA2 hyperphosphorylation is critical for Rad51 recruitment and HR-mediated repair following HU. However, RPA2 hyperphosphorylation is not essential for both ionizing radiation (IR)-induced Rad51 foci formation and I-Sce-I endonuclease-stimulated HR. Moreover, we show that expression of a phosphorylation-deficient mutant of RPA2 leads to increased chromosomal aberrations following HU treatment but not after exposure to IR. Finally, we demonstrate that loss of RPA2 hyperphosphorylation results in a loss of viability when cells are confronted with replication stress whereas cells expressing hyperphosphorylation-defective RPA2 or wild-type RPA2 have a similar sensitivity to IR. Thus, our data suggest that RPA2 hyperphosphorylation plays a critical role in maintenance of genomic stability and cell survival after a DNA replication block via promotion of HR.

Serum levels of IGF-I, IGFBP-3 and colorectal cancer risk: results from the EPIC cohort, plus a meta-analysis of prospective studies.

Several prospective studies have shown a moderate positive association between increasing circulating insulin-like growth factor-I (IGF-I) levels and colorectal cancer risk. However, the associations were often statistically nonsignificant, and the relationship of cancer risk with IGF-I's major binding protein, IGFBP-3, showed major discrepancies between studies. We investigated the association of colorectal cancer risk with serum IGF-I, total and intact IGFBP-3, in a case-control study nested within the EPIC cohort (1,121 cases of colorectal cancer and 1,121 matched controls). Conditional logistic regression was used to adjust for possible confounders. Our present study results were combined in a meta-analysis with those from 9 previous prospective studies to examine the overall evidence for a relationship of prediagnostic serum IGF-I with colorectal cancer risk. In the EPIC study, serum concentrations of IGF-I and IGFBP-3 showed no associations with risk of colorectal cancer overall. Only in subgroup analyses did our study show moderate positive associations of IGF-I levels with risk, either among younger participants only (and only for colon cancer) or among participants whose milk intakes were in the lowest tertile of the population distribution (RR for an increase of 100 ng/ml = 1.43 [95% CI = 1.13-1.93]). Nevertheless, in the meta-analysis a modest positive association remained between serum IGF-I and colorectal cancer risk overall (RR = 1.07 [1.01-1.14] for 1 standard deviation increase in IGF-I). Overall, data from our present study and previous prospective studies combined indicate a relatively modest association of colorectal cancer risk with serum IGF-I.

Residue 826 in the calcium-sensing receptor is implicated in the response to calcium and to R-568 calcimimetic compound.

Within the extracellular loops of the seven-transmembrane domain of the calcium-sensing receptor (CaR) there is a region (I819-E837) relevant for calcimimetic activity. As the naturally occurring variant Ala826Thr is within this important region, it may be postulated that this change may influence the CaR response to calcium and R-568. Human embryonic kidney (HEK-293) cells transiently transfected with three different human CaRs (wild-type [A826], variant allele [T826], and artificial mutant [W826]) were used to test the ability of calcium alone or in combination with the calcimimetic R-568 to modulate CaR activity. CaR activation was detected by flow cytometry using a fluorescent probe. Intracellular calcium changes were measured in response to changes in extracellular calcium alone or with different R-568 concentrations. The change of the alanine in the 826 position (A826) for threonine (T826) worsened calcium sensitivity, increasing the EC(50) value from 2.34 +/- 0.48 mM (A826, wild-type) to 2.96 +/- 0.75 mM (T826) (P < 0.05). The T826 receptor reached a similar response with 1 muM R-568 compared with the wild-type receptor. On the contrary, the artificial introduction of a tryptophan in the same position (W826) did not affect calcium sensitivity (EC(50) = 2.64 +/- 0.81 mM) but reduced the ability of the receptor to respond to R-568. The results demonstrate the importance of the 826 residue in the CaR response to calcium and calcimimetics. Since the A826T change was described as a natural variant, the differences in the calcium and calcimimetic responses observed between the alleles could have potential clinical impact.

Lanthanum activates calcium-sensing receptor and enhances sensitivity to calcium.

BACKGROUND: The aim of this study was to investigate whether nanomolar concentrations of lanthanum could influence the calcium-sensing receptor (CaSR) response. METHODS: Embryonic kidney (HEK-293) cells transiently transfected with the human CaSR were used to test the ability of lanthanum to activate the CaSR, either alone or in combination with calcium. CaSR activation was measured by flow cytometry. Parathyroid glands from 4-month-old male Wistar rats with normal renal function (n = 60) were also cultured ex vivo with different concentrations of lanthanum to measure parathyroid hormone (PTH) secreted to the medium and PTH mRNA. RESULTS: The maximal CaSR activation induced by 1 muM lanthanum chloride (LaCl(3)) was similar to that induced by 16 mM calcium chloride (CaCl(2) 16 mM: 294 +/- 14%; LaCl(3) 1 muM: 303 +/- 11%). Lanthanum half effective concentration (EC(50)) was 77.28 nM, lower than the 2.30 mM obtained for calcium, supporting the concept that this metal is a strong agonist of the CaSR. Moreover, lanthanum was also able to enhance CaSR sensitivity to calcium. The presence of 1 nM LaCl(3) significantly left-shifted the CaSR response curve, changing the EC(50) value for calcium from 2.30 mM (calcium alone) to 1.26 mM (calcium + 1 nM lanthanum). The parathyroid glands cultured with lanthanum showed a trend to secrete less PTH compared to the control glands: 1.51 +/- 0.23 (control), 0.91 +/- 0.17 (La 100 nM) and 1.04 +/- 0.18 (La 400 nM) [(pg/h)/(pg/h), mean +/- SEM] (ANOVA P = 0.0145). A similar trend was also observed in PTH synthesis measured by PTH mRNA levels. CONCLUSIONS: These in vitro findings demonstrate that lanthanum, at nanomolar concentrations, is an agonist of the CaSR able to activate it in the absence of calcium. In addition, it can also enhance CaSR sensitivity to calcium, modulating PTH synthesis and secretion.

Physical Activity Is Higher in Patients with Left Ventricular Assist Device Compared with Chronic Heart Failure.

PURPOSE: Left ventricular assist devices (LVAD) are associated with an increased aerobic capacity in patients with chronic heart failure (CHF). However, studies evaluating the impact of LVAD implantation on physical activity (PA) are lacking. The aim of this study was to compare daily PA levels in participants with LVAD with well-matched CHF participants. METHODS: Sixteen participants with an LVAD (age, 59.1 ± 10.8 yr) were case-matched to 16 participants with advanced CHF (age, 58.3 ± 8.7 yr), who were listed or being considered for cardiac transplantation. Participants underwent a cardiopulmonary exercise test to determine peak oxygen consumption (V˙O2 peak). Physical activity was monitored continuously for seven consecutive days with an Actiheart monitor. RESULTS: V˙O2 peak in the CHF group (12.3 ± 3.5 mL·kg·min) was not significantly different to the LVAD group before LVAD implantation (10.4 ± 2.1 mL·kg·min), but was lower than in the LVAD group after implantation (15.8 ± 4.3 mL·kg·min; P < 0.05). Physical activity was higher in the LVAD (19.7 ± 6.4 kJ·kg·d) compared with the CHF group (11.6 ± 6.9 kJ·kg·d; P = 0.001). The LVAD participants spent more time performing moderate-intensity PA than their CHF counterparts (median, 26 min·d; interquartile range, 24-40 min·d vs median, 12 min·d; interquartile range, 9-16 min·d; P < 0.001). Physical activity was correlated with V˙O2 peak (r = 0.582; P = 0.001) across participants in the CHF and LVAD groups. CONCLUSIONS: Higher levels of PA were observed in participants with LVAD compared with patients with advanced CHF. This may be due to a higher V˙O2 peak, resulting in an improved capacity to perform activities of daily living with less symptoms.

Cerebral blood flow responses to exercise are enhanced in left ventricular assist device patients after an exercise rehabilitation program.

Cerebral blood flow during exercise is impaired in patients with heart failure implanted with left ventricular assist devices (LVADs). Our aim was to determine whether a 3-mo exercise training program could mitigate cerebrovascular dysfunction. Internal carotid artery (ICA) blood flow and intracranial middle (MCAv) and posterior cerebral (PCAv) artery velocities were measured continuously using Doppler ultrasound, alongside cardiorespiratory measures at rest and in response to an incremental cycle ergometer exercise protocol in 12 LVAD participants (5 female, 53.6 ± 11.8 yr; 84.2 ± 15.7 kg; 1.73 ± 0.08) pre- (PreTR) and post- (PostTR) completion of a 3-mo supervised exercise rehabilitation program. At rest, only PCAv was different PostTR (38.1 ± 10.4 cm/s) compared with PreTR (43.0 ± 10.8 cm/s; P < 0.05). PreTR, the reduction in PCAv observed from rest to exercise (5.2 ± 1.8%) was mitigated PostTR (P < 0.001). Similarly, exercise training enhanced ICA flow during submaximal exercise (~8.6 ± 13.7%), resulting in increased ICA flow PostTR compared with a reduced flow PreTR (P < 0.001). Although both end-tidal partial pressure of carbon dioxide and mean arterial pressure responses during incremental exercise were greater PostTR than PreTR, only the improved PETCO2 was related to the improved ICA flow (R2 = 0.14; P < 0.05). Our findings suggest that short-term exercise training improves cerebrovascular function during exercise in patients with LVADs. This finding should encourage future studies investigating long-term exercise training and cerebral and peripheral vascular adaptation.NEW & NOTEWORTHY Left ventricular assist devices, now used as destination therapy in end-stage heart failure, enable patients to undertake rehabilitative exercise training. We show, for the first time in humans, that training improves cerebrovascular function during exercise in patients with left ventricular assist devices. This finding may have implications for cerebrovascular health in patients with heart failure.