Bone marrow–mesenchymal stromal cell infusion in patients with chronic kidney disease: A safety study with 18 months of follow-up

Background

Chronic kidney disease (CKD) is a progressive loss of kidney function and structure that affects approximately 13% of the population worldwide. A recent meta-analysis revealed that cell-based therapies improve impaired renal function and structure in preclinical models of CKD. We assessed the safety and tolerability of bone marrow–mesenchymal stromal cell (MSC) infusion in patients with CKD.

Addressing the theoretical and clinical advantages of combination therapy with inhibitors of the renin–angiotensin–aldosterone system: Antihypertensive effects and benefits beyond BP control

AimsThis article reviews the importance of the renin–angiotensin–aldosterone system (RAAS) in the cardiometabolic continuum; presents the pros and cons of dual RAAS blockade with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs); and examines the theoretical and practical benefits supporting the use of direct renin inhibitors (DRIs) in combination with ACEIs or ARBs.Main methodsThe author reviewed the literature for key publications related to the biochemical physiology of the RAAS and the pharmacodynamic effects of ACEIs, ARBs, and DRIs, with a particular focus on dual RAAS blockade with these drug classes.Key findingsAlthough ACEI/ARB combination therapy produces modest improvement in BP, it has not resulted in the major improvements predicted given the importance of the RAAS across the cardiorenal disease continuum. This may reflect the fact that RAAS blockade with ACEIs and/or ARBs leads to exacerbated renin release through loss of negative-feedback inhibition, as well as ACE/aldosterone escape through RAAS and non-RAAS-mediated mechanisms. Plasma renin activity (PRA) is an independent predictor of morbidity and mortality, even for patients receiving ACEIs and ARBs. When used alone or in combination with ACEIs and ARBs, the DRI aliskiren effectively reduces PRA. Reductions in BP are greater with these combinations, relative to the individual components alone.SignificanceIt is possible that aliskiren plus either an ACEI or ARB may provide greater RAAS blockade than monotherapy with ACEIs or ARBs, and lead to additive improvement in BP and clinically important outcomes.     

The King–Devick test as a predictor of cognitive effects after chronic partial sleep restriction: a pilot study

Sleep and Biological Rhythms - The King–Devick test (K–D) is sensitive to the effects of acute sleep deprivation. It remains unclear whether the K–D is sensitive to the effects of...     

Exploration of disease mechanism in acute kidney injury using a multiplex bead array assay: a nested case–control pilot study

Background: Acute kidney injury (AKI) following cardiac surgery with cardiopulmonary bypass (CPB) causes increased morbidity and mortality.

Objective: To evaluate the plasma profile of biomarkers potentially involved in AKI development following CPB.

Methods: In a nested case–control study, plasma levels of 27 biomarkers in 11 AKI cases were compared with 25 controls.

Results: Pre-CPB, plasma levels of epidermal growth factor and macrophage inflammatory protein-1β, 2?h following CPB, soluble vascular cell adhesion molecule-1 (sVCAM-1), fractalkine and macrophage inflammatory protein-1α, and at later time points, sVCAM-1 and interleukin-6 were associated with AKI.

Conclusion: Biomarkers associated with AKI following CPB may merit further study.     

Combination of urinary kidney injury molecule-1 and interleukin-18 as early biomarker for the diagnosis and progressive assessment of acute kidney injury following cardiopulmonary bypass surgery: a prospective nested case–control study

The aim of this nested case–control study was to assess the combined use of urinary kidney injury molecule (KIM)-1 and interleukin (IL)-18 for acute kidney injury (AKI) after cardiopulmonary bypass surgery (CPB). From a cohort of 122 subjects who underwent CPB, serial urinary KIM-1 and IL-18 concentrations were determined in 30 AKI and 92 non-AKI patients. An increased level of urinary KIM-1 was associated with the occurrence of AKI, whereas an increased level of IL-18 was related to progressive AKI. The combination of these two biomarkers facilitates the early diagnosis and assessment of the likely progression of AKI after CPB.     

Cascading effects of soil organic and inorganic fertilizers on tri-trophic interactions: Plant–aphid–parasitoid wasp as a study system

Understanding the mechanisms underlying tri-trophic interactions between insect herbivores, their host plants and natural enemies is an important aim in ecology. In the present study, the effect of urea fertilizer and vermicompost on a tri-trophic level cascade, comprising safflower, Carthamus tinctorius, safflower aphid, Uroleucon carthami and its primary parasitoid wasp, Praon yomenae, was investigated. Vermicompost increased the number of leaves, leaf area, fresh weight, dry weight, the total number of aphids and reduced the number of winged aphids and aphid load (Aphid load = number of aphids / plant fresh weight). Only two variables, plant phenol content and relative water content, were not significantly affected by vermicompost. Urea fertilizer had no impact on all variables except a significant effect on plant height. In another experiment, the effect of urea fertilizer and vermicompost on the wasp parasitoid was studied. The number of parasitoid mummies, mummification time, developmental time, the number of emerged adults, sex ratio, percentage of parasitism and hind tibia length was measured. Vermicompost had no significant effect on any of the measured parameters, but urea fertilizer increased the hind tibia length of the parasitoid. Vermicompost increased plant growth parameters and had an indirect and inhibiting effect on the safflower aphid itself. There was evidence of a bottom-up cascade to the third trophic level by adding fertilizers in this system: Urea fertilizer enhanced plant height but seemingly had no impact on the attacking herbivore. It is interesting that the effect of urea can be transferred to the third trophic level, that is parasitoid. This suggests that vermicompost could be used simultaneously with urea fertilizer, because urea fertilizer had a positive impact on the parasitoid and vermicompost had a positive impact on plant growth as well as the ability to reduce aphid load.     

Tacrine–propargylamine derivatives with improved acetylcholinesterase inhibitory activity and lower hepatotoxicity as a potential lead compound for the treatment of Alzheimer’s disease

Abstract

A series of tacrine–propargylamine derivatives were synthesised and evaluated as possible anti-Alzheimer’s disease (AD) agents. Among these derivatives, compounds 3a and 3b exhibited superior activities and a favourable balance of AChE and BuChE activities (3a: IC₅₀ values of 51.3 and 77.6?nM; 3b: IC₅₀ values of 11.2 and 83.5?nM). Compounds 3a and 3b also exhibited increased hAChE inhibitory activity compared with tacrine by approximately 5- and 28-fold, respectively, and low neurotoxicity. Importantly, these compounds also had lower hepatotoxicity than tacrine. Based on these results, compounds 3a and 3b could be considered as potential lead compounds for the treatment of AD and other AChE related diseases, such as schizophrenia, glaucoma and myasthenia gravis.     

Clinical variables predicting the risk of a hospital stay for longer than 7 days in patients with severe acute exacerbations of chronic obstructive pulmonary disease: a prospective study

Background

Chronic obstructive pulmonary disease (COPD) patients may experience an acute exacerbation (AECOPD) that requires hospitalisation. The length of hospital stay (LHS) has a great economic impact on the health-care system. Knowing the predictors of prolonged LHS could help to identify possible interventions.

Methods

We performed a prospective study to identify the clinical predictors of prolonged LHS in patients hospitalised for AECOPD. We divided the study sample by LHS into normal (≤7?days) and prolonged LHS (>?7?days) groups. Outcomes were the need for non-invasive and invasive mechanical ventilation (NIMV and IMV), intensive care unit (ICU) admission, and the 3-year mortality.

Results

We enrolled 437 patients, of which 213 and 224 had normal LHS and prolonged LHS, respectively. Patients with a prolonged LHS had more prior hospitalisations for AECOPD, a worse mMRC (modified Medical Research Council) dyspnoea score, a higher prevalence of long-term oxygen therapy and a higher rate of congestive heart disease. During the current admission, this group also tended to require NIMV, IMV and ICU admission and the mortality risks at 6?months, 1?year and 3?years were higher. In the multivariate regression analysis, an mMRC dyspnoea score?≥?2 (odds ratio-OR 2.24; 95% confidence interval-CI 1.34 to 3.74; p?=?0.002) and the presence of acute respiratory acidosis (OR 2.75; 95% CI 1.49 to 5.05; p?=?0.001) predicted a prolonged LHS at admission.

Conclusions

The presence of an mMRC ≥2 and acute respiratory acidosis at admission independently increased the risk of a prolonged LHS for AECOPD.

     

“As du Coeur” study: a randomized controlled trial on quality of life impact and cost effectiveness of a physical activity program in patients with cardiovascular disease

Background

Physical activity programs (PAP) in patients with cardiovascular disease require evidence of cost-utility. To assess improvement in health-related quality of life (QoL) and reduction of health care consumption of patients following PAP, a randomized trial was used.

Methods

Patients from a health insurance company who had experienced coronary artery disease or moderate heart failure were invited to participate (N?=?1891). Positive responders (N?=?50) were randomly assigned to a progressively autonomous physical activity (PAPA) program or to a standard supervised physical activity (SPA) program. The SPA group had two supervised sessions per week over 5?months. PAPA group had one session per week and support to aid habit formation (written tips, exercise program, phone call). To measure health-related quality of life EQ-5D utility score were used, before intervention, 6?months (T6) and 1 year later. Health care costs were provided from reimbursement databases.

Results

Mobility, usual activities and discomfort improved significantly in both group (T6). One year later, EQ-5D utility score was improved in the PAPA group only. Total health care consumption in the intervention group decreased, from a mean of 4097 euros per year before intervention to 2877 euros per year after (p?=?0.05), compared to a health care consumption of 4087 euros and 4180 euros per year, in the total population of patients (N?=?1891) from the health insurance company. The incremental cost effectiveness ratio was 10,928 euros per QALYs.

Conclusion

A physical activity program is cost-effective in providing a better quality of life and reducing health care consumption in cardiovascular patients.

Trial registration

ISRCTN77313697, retrospectively registered on 20 November 2015.

     

Discovery and structure–activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis

A series of phenoxy benzoxaboroles were synthesized and screened for their inhibitory activity against PDE4 and cytokine release. 5-(4-Cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2728) showed potent activity both in vitro and in vivo. This compound is now in clinical development for the topical treatment of psoriasis and being pursued for the topical treatment of atopic dermatitis.     

The potential of micromorphology for interpreting sedimentation processes in wetland sites: a case study of a Late Bronze–early Iron Age lakeshore settlement at Lake Luokesa (Lithuania)

Lake Luokesa lies in the eastern part of Lithuania and is part of a region of lakes formed by the Scandinavian ice-sheet and its melt waters during the last glaciation. During the Late Bronze–Early Iron Age transition, between 625 and 535 cal BC, a lakeside settlement with an onshore palisade was built on the platform of a carbonate bank. A total of five profiles, each comprising an organic occupation layer and lake sediments at its bottom and top, were examined micromorphologically. In this paper, natural and anthropogenic processes that led to the formation of the individual layers are presented; their possible origins are reconstructed and then discussed and compared to lakeside settlements of the circum-alpine region. This includes the emergence of lake marl, accumulation of organic layers in the settlement area as well as their decomposition, erosion and trampling features and inwash of sand through runoff from the hinterland. Due to the accumulation of the up to 60 cm thick culture layers in waterlogged environments, indications of seasonal deposition cycles could be identified.     

Analysis of the sphingomyelin phosphodiesterase 1 gene (SMPD1) in Turkish Niemann–Pick disease patients: Mutation profile and description of a novel mutation

Niemann–Pick disease (NPD) is a lysosomal storage disorder that results from the deficiency of a lysosomal enzyme, acid sphingomyelinase. Niemann–Pick disease type A and B is caused by mutations in the sphingomyelin phosphodiesterase gene (SMPD1) coding for ASM. The aim of this study was to evaluate the spectrum of SMPD1 gene mutations in Turkish NPD patients and to study genotype–phenotype associations. We present a molecular analysis of 10 Turkish NPD type A/B patients. Four of the patients had type A and six had type B NPD. All mutant SMPD1 alleles were identified, including 5 different mutations, 1 of which was novel. These mutations included three missense mutations: c.409T>C (p.L137P), c.1262 A>G (p.H421R) and c.1552T>C (p.L549P), a common frameshift mutation in codon 189, identified in three patients, is caused by the deletion of the 567T, introducing a stop codon 65 amino acids downstream (p.P189fsX65), and a novel frameshift mutation c.1755delC (p.P585PfsX24) which was not reported previously.     

Design,synthesis and preliminary structure–activity relationship investigation of nitrogen-containing chalcone derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors: a further study based on Flavokawain B Mannich base derivatives

In order to study the structure–activity relationship of Flavokawain B Mannich-based derivatives as acetylcholinesterase (AChE) inhibitors in our recent investigation, 20 new nitrogen-containing chalcone derivatives (4?a–8d) were designed, synthesized, and evaluated for AChE inhibitory activity in vitro. The results suggested that amino alkyl side chain of chalcone dramatically influenced the inhibitory activity against AChE. Among them, compound 6c revealed the strongest AChE inhibitory activity (IC₅₀ value: 0.85?μmol/L) and the highest selectivity against AChE over BuChE (ratio: 35.79). Enzyme kinetic study showed that the inhibition mechanism of compound 6c against AChE was a mixed-type inhibition. The molecular docking assay showed that this compound can both bind with the catalytic site and the peripheral site of AChE.     

Efficacy of cascade-primed cell infusion as an adjuvant immunotherapy with concurrent chemotherapy for patients with non–small-cell lung cancer: A retrospective observational study with a 5-year follow-up

BackgroundClinical studies have shown the efficacy of combination therapy for various malignancies. In this study, the characteristics, safety and feasibility of use of cascade-primed (CAPRI) cells for the combination treatment of non–small-cell lung cancer (NSCLC) were evaluated both in vitro and in vivo.MethodsSixty-five patients with stage II–IV NSCLC were recruited. Of these patients, 31 patients received CAPRI cell therapy combined with chemotherapy (CAPRI group), and the other 34 patients constituted the control group and received chemotherapy alone. This study primarily aimed to evaluate the overall survival (OS), progression-free survival (PFS), short-term responses and treatment efficacy.ResultsCD83, CD1a, CD80 and CD86 marker levels were significantly upregulated in CAPRI cells. Interferon-γ expression levels were highest in CD3⁺CD8⁺ cells (33.77% ± 4.40%). Furthermore, interleukin-2 levels were highest in CD3⁺CD56⁺ cells (26.73% ± 6.63%), whereas perforin expression levels were similar in CD3⁺CD8⁺ and CD3⁺CD56⁺ cells. Furthermore, CAPRI cells had a better anti-tumor potential in CD3⁺CD56⁺ cells and displayed the highest expression levels of CD107a to H460 and A549 cell lines. The 5-year OS was significantly greater in the CAPRI group than in the control group (P = 0.008), and the PFS of two groups exhibited a significant difference (P = 0.007). Median OS (48 versus 31.6 months; P = 0.004) and PFS (48 versus 36.4 months; P = 0.016) differed between these two groups. Moreover, treatment-associated toxicities were mild and well-tolerated by patients with NSCLC.ConclusionCAPRI cell therapy potentially prolongs the survival of patients with NSCLC when combined with chemotherapy.     

Use of “Cold Spell” indices to quantify excess chronic obstructive pulmonary disease (COPD) morbidity during winter (November to March 2000–2007): case study in Porto

The aim of this study was to examine the relationship between the occurrence of cold episodes and excess hospital admissions for chronic obstructive pulmonary disease (COPD) in Porto, Portugal, in order to further understand the effects of cold weather on health in milder climates. Excess COPD winter morbidity was calculated from admissions for November to March (2000–2007) in the Greater Porto Metropolitan Area (GPMA). Cold spells were identified using several indices (Díaz, World Meteorological Organization, Cold Spell Duration Index, Australian Index and Ondas’ Project Index) for the same period. Excess admissions in the periods before and after the occurrence of cold spells were calculated and related to the cold spells identified. The COPD seasonal variation admission coefficient (CVSA) showed excess winter admissions of 59 %, relative to other months. The effect of cold spell on the aggravation of COPD occurs with a lag of at least 2 weeks and differs according to the index used. This study indicates the important role of the persistence of cold periods of at least 2 weeks duration in the increase in COPD admissions. The persistence of moderate temperatures (Tmin ≤5 °C) for a week can be more significant for increasing COPD admissions than very low temperatures (Tmin?≤?1.6 °C) for just a few days. The Ondas projects’ index provides the most accurate detection of the negative impacts of cold persistency on health, while the Diaz index is better at evaluating the consequences of short extreme cold events.     

The Berger–Parker index as an effective tool for monitoring the biodiversity of disturbed soils: a case study on Mediterranean oribatid (Acari: Oribatida) assemblages

Recent data on oribatid mites (Acari: Oribatida) indicates that Mediterranean soil communities tend to show uneven patterns of species abundance distribution (SAD) that are well fitted by a simple model such as the geometric series. In the case of linear distributions, the fraction of total sampled individuals that is contributed by the most abundant species, known as the Berger–Parker index, synthetically describes the SAD of disturbed communities. This study assessed the bioindicator potential of the Berger–Parker index by comparing its variations among Mediterranean oribatid assemblages under different types of soil disturbance. The index significantly changes between undisturbed and disturbed soils reaching the highest values in areas with strong physical disturbance due to agricultural management. The Berger–Parker index is therefore a practical and effective tool for monitoring biodiversity impairment linked to human disturbance in soil ecosystems.     

Pure manganese(III) 5,10,15,20-tetrakis(4-benzoic acid)porphyrin (MnTBAP) is not a superoxide dismutase mimic in aqueous systems: a case of structure–activity relationship as a watchdog mechanism in experimental therapeutics and biology

Superoxide is involved in a plethora of pathological and physiological processes via oxidative stress and/or signal transduction pathways. Superoxide dismutase (SOD) mimics have, thus, been actively sought for clinical and mechanistic purposes. Manganese(III) 5,10,15,20-tetrakis(4-benzoic acid)porphyrin (MnTBAP) is one of the most intensely explored "SOD mimics" in biology and medicine. However, we show here that this claimed SOD activity of MnTBAP in aqueous media is not corroborated by comprehensive structure-activity relationship studies for a wide set of Mn porphyrins and that MnTBAP from usual commercial sources contains different amounts of noninnocent trace impurities (Mn clusters), which inhibited xanthine oxidase and had SOD activity in their own right. In addition, the preparation and thorough characterization of a high-purity MnTBAP is presented for the first time and confirmed that pure MnTBAP has no SOD activity in aqueous medium. These findings call for an assessment of the relevance and suitability of using MnTBAP (or its impurities) as a mechanistic probe and antioxidant therapeutic; conclusions on the physiological and pathological role of superoxide derived from studies using MnTBAP of uncertain purity should be examined judiciously. An unequivocal distinction between the biological effects due to MnTBAP and that of its impurities can only be unambiguously made if a pure sample is/was used. This work also illustrates the contribution of fundamental structure-activity relationship studies not only for drug design and optimization, but also as a "watchdog" mechanism for checking/spotting eventual incongruence of drug activity in chemical and biological settings.