Mesenchymal Stromal Cell Characteristics and Regenerative Potential in Cardiovascular Disease: Implications for Cellular Therapy.

Administration of mesenchymal stromal cells (MSCs) is a promising strategy to treat cardiovascular disease (CVD). As progenitor cells may be negatively affected by both age and comorbidity, characterization of MSC function is important to guide decisions regarding use of allogeneic or autologous cells. Definitive answers on which factors affect MSC function can also aid in selecting which MSC donors would yield the most therapeutically efficacious MSCs. Here we provide a narrative review of MSC function in CVD based on a systematic search. A total of 41 studies examining CVD-related MSC (dys)function were identified. These data show that MSC characteristics and regenerative potential are often affected by CVD. However, studies presented conflicting results, and directed assessment of MSC parameters relevant to regenerative medicine applications was lacking in many studies. The predictive ability of in vitro assays for in vivo efficacy was rarely assessed. There was no correlation between quality of study reporting and study findings. Age mismatch was also not associated with study findings or effect size. Future research should focus on assays that assess regenerative potential in MSCs and parameters that relate to clinical success.

Detecting Proximal Secondary Caries Lesions: A Cost-effectiveness Analysis.

When choosing detection methods for secondary caries lesions, dentists need to weigh sensitivity, allowing early initiation of retreatments to avoid lesion progression, against specificity, aiming to reduce risks of false-positive diagnoses and invasive overtreatments. We assessed the cost-effectiveness of different detection methods for proximal secondary lesions using Monte Carlo microsimulations. A vital permanent molar with an occlusal-proximal restoration was simulated over the lifetime of an initially 20-y-old. Three methods were compared: biannual tactile detection, radiographic detection every 2 y, and biannual laser fluorescence detection. Methods were employed either on their own or in pairwise combinations at sensitive and specific thresholds estimated with systematically collected data. A mixed public-private payer perspective in the context of German health care was applied. Effectiveness was calculated as years of tooth retention. Net-benefit analyses were used to evaluate cost-effectiveness acceptability at different willingness-to-pay thresholds. Radiographic detection verified by tactile assessment (both at specific thresholds) was least costly (mean, 1,060 euros) but had limited effectiveness (mean retention time, 50 y). The most effective but also more costly combination was laser fluorescence detection verified by radiography, again at specific thresholds (1157 euros, 53 y, acceptable if willingness to pay >32 euro/y). In the majority of simulations, not combining detection methods or applying them at sensitive thresholds was less effective and more costly. Net benefits were not greatly altered by applying different discounting rates or using different baseline prevalence of secondary lesions. Current detection methods for secondary lesions should best be used in combination, not on their own, at specific thresholds to avoid false-positive diagnoses leading to costly and invasive overtreatment. The relevant characteristics, such as predictive value, of different methods should be assessed in longitudinal clinical studies.

Detecting Secondary Caries Lesions: A Systematic Review and Meta-analysis.

Secondary caries lesions are the main late complication of dental restorations, limiting their life span and generating costs by repeated reinterventions. Accurate detection of secondary lesions is crucial for estimating the true burden of the disease and allocating appropriate treatments. We aimed to assess the accuracy of detection methods for secondary caries lesions. Clinical or in vitro studies were included that investigated the accuracy of 5 detection methods--visual, tactile, radiography, laser fluorescence, quantitative light-induced fluorescence--of natural or artificially induced secondary lesions, as verified against an established reference test. Sensitivity, specificity, positive and negative likelihood ratios, as well as diagnostic odds ratios were calculated and publication bias assessed. From 1,179 screened studies, 23 were included. Most studies were performed in vitro, on permanent posterior teeth, and had high risk of bias or applicability concerns. Lesions were on proximal (14 studies) or other surfaces and adjacent to amalgam (16 studies) or tooth-colored materials. Visual (n = 11), radiographic (n = 13), and laser fluorescence detection (n = 8) had similar sensitivities (0.50 to 0.59) and specificities (0.78 to 0.83), with visual and laser fluorescence assessment being more accurate on nonproximal surfaces and adjacent to composites, respectively. Tactile assessment (n = 7) had low accuracy. Light-induced fluorescence (n = 3) was sensitive on nonproximal surfaces but had low specificities. Most analyses seemed to suffer from publication bias. Despite being a significant clinical and dental public health problem, detection of secondary caries lesions has been assessed by only a few studies with limited validity and applicability. Visual, radiographic and laser-fluorescence detection might be useful to detect secondary lesions. The validity of tactile assessment and quantitative light-induced fluorescence remains unclear at present.

[The 'Soarchmjitter'. The use of a Frisian lingual measurement instrument in care of the elderly]. / De 'Soarchmjitter'. Het gebruik van een Friestalig meetinstrument in de ouderenzorg.

In this article a research has been described funded by the province Fryslân. The aim of this research project is bipartite. First, to determine the reliability and the validity of the instrument and, secondly, to inquire the involved residents living in old people's homes after the valuation of the use of the Frisian language in the care. The research is conducted among 73 residents living in nine old people's homes in the province Fryslân. On two moments in time residents of the old people's homes are asked to fill in a questionnaire with regard to their own care (in)dependency and once with regard to the use of the Frisian language in the care. Reliability analysis shows with regard to internal consistency high Cronbach's alpha values. Test-retest reliability (Cohen's kappa and Spearman Correlation) reveals fair to moderate values. Factor analysis (principal components analysis) results in a one-factor solution. According to the residents, the 'Soarchmjitter' gives a good picture of their care dependency and its questions and answers join their needs. It can be concluded that the 'Soarchmjitter' is a useful instrument to communicate in the own spoken language of the resident and to come in this way to an agreement with nurses about their care demands.

Voluntary arrangements to cope with diffuse pollution from agriculture and their role in European water policy.

A limited number of Member States in the EU have gained experience with establishing co-operative agreements between agriculture and the water sector. Their main aim is to reduce or prevent water pollution caused by intensive farming practices. The research has shown that significant changes in farming practices have been achieved as a result of negotiation between farmers and water suppliers. Consequently, in many catchment areas improvements in water quality can be observed. Co-operative agreements have the important advantage that the measures taken can be tailored to the different local conditions in catchment areas. Reducing diffuse pollution resulting from intensive agriculture is one of the main issues of the EU Water Framework Directive. The current paper builds on the results of a EU-wide research project which examines the role co-operative agreements can play in water policy and the Common Agricultural Policy.

Noradrenaline-induced relaxation of rat oesophageal muscularis mucosae: mediation solely by innervated beta 3-adrenoceptors.

We investigated the effects of cocaine and corticosterone on the noradrenaline-induced relaxation of rat oesophageal smooth muscle in the absence and presence of the selective beta2-antagonist, ICI 111,551. It was found that the concentration-response curve (CRC) of noradrenaline was not shifted by ICI 118,551 at 1 microM, whereas a clear shift to the right was observed at 100 microM of the antagonist. In the presence of corticosterone (10 microM), CRC's were clearly shifted to the left; with cocaine (10 microM) additionally present, a further leftward shift was observed, indicating the involvement of both neuronal and extraneuronal uptake sites. It was concluded that the relaxation of rat oesophageal muscularis mucosae by noradrenaline is solely mediated by beta3-adrenoceptors which are sympathetically innervated.

Thoracic electrical bioimpedance: suitable for monitoring stroke volume during pregnancy?

To obtain normal values for maternal stroke volume and cardiac output during pregnancy, a non-invasive, accurate and reproducible method is required. The thoracic electrical bioimpedance (TEB) method may be suitable. However, this method is as yet only qualified for short-term trend recordings, since it assumes that body dimensions such as height, weight and thoracic circumference remain constant during the study. This may not be the case in long-term studies, especially during pregnancy. In this paper it is argued that changes in stroke volume (SV) during pregnancy are reflected most strongly when using the formula: SV = P VET (dZ/dt)max/Z0, where P is a personal factor to be determined at the beginning of pregnancy; VET the ventricular ejection time; (dZ/dt)max the maximum of the first derivative of the thoracic impedance during the cardiac cycle and Z0 the time average of this impedance during the cardiac cycle. Indexed parameters should not be used as this reduces sensitivity. Commercial equipment, based upon other algorithms, can be used by feeding the right parameters for each series of measurements. This enables calculation, trends in stroke volume and cardiac output for longitudinal studies for instance during pregnancy.

Sustained prejunctional facilitation of noradrenergic neurotransmission by adrenaline as a co-transmitter in the portal vein of freely moving rats.

1. The duration of the facilitatory effect of adrenaline on the electrically evoked overflow of noradrenaline was studied in the portal vein of permanently adreno-demedullated freely moving rats. 2. Rats were infused with adrenaline (20 or 100 ng min-1) for 2 h. After an interval of 1 h, when plasma adrenaline had returned to undetectable levels, electrical stimulation resulted in an enhanced catecholamine overflow amounting to 219% (noradrenaline) and 241% (noradrenaline plus adrenaline) of control (saline infusion), respectively. 3. When stimulation was applied again, in the same animal, at 24, 48 and 72 h after the first stimulation episode, the evoked noradrenaline overflow was 150, 111 and 102% (after 20 ng ml-1 adrenaline) and 158, 134 and 105% (after 100 ng min-1 adrenaline) of control. 4. The beta 2-adrenoceptor antagonist, ICI 118,551 (0.3 mg kg-1), blocked the facilitatory effect obtained after the 100 ng min-1 adrenaline infusion on all days. 5. The results show that adrenaline, after being taken up by and released from sympathetic nerve terminals, is able to facilitate the evoked noradrenaline overflow through activation of prejunctional beta 2-adrenoceptors for at least 48 h after administration.

Strong activation of vascular prejunctional beta 2-adrenoceptors in freely moving rats by adrenaline released as a co-transmitter.

The effect of adrenaline on the electrically evoked noradrenaline overflow in the portal vein of adrenal demedullated freely moving rats was studied. Adrenaline (100 ng/min) was infused for 2 h into the portal vein. After a 1-h interval when plasma adrenaline had returned to pre-infusion undetectable levels, the portal vein nervus plexus was electrically stimulated. During stimulation (2 Hz, 3 ms, 5 mA) adrenaline and noradrenaline were released. The stimulus-evoked noradrenaline overflow was facilitated to 194% of the control-evoked overflow (infusion of saline). Total catecholamine overflow (noradrenaline plus adrenaline) was enhanced to 258%. The facilitation of the evoked overflow of both noradrenaline and adrenaline was blocked by the selective beta 2-adrenoceptor antagonist, ICI 118,551 (0.3 mg/kg). Cocaine (2.5 mg/kg plus 0.05 mg/kg per min) infused together with adrenaline prevented the evoked release of adrenaline and no facilitation of the stimulus-induced noradrenaline overflow occurred. Inhibition of prejunctional inhibitory alpha 2-adrenoceptors with yohimbine (0.5 mg/kg) further enhanced, to 577%, the electrically evoked catecholamine overflow after adrenaline infusion. The results demonstrate that adrenaline can be taken up by sympathetic nerve endings through cocaine-sensitive uptake carriers, and is released from these nerves during electrical stimulation of the portal vein nervus plexus. Neuronally released adrenaline can strongly facilitate electrically evoked neurotransmitter overflow through activation of prejunctional beta 2-adrenoceptors.

The beta-adrenoceptors mediating relaxation of rat oesophageal muscularis mucosae are predominantly of the beta 3-, but also of the beta 2-subtype.

1. beta-Adrenoceptor-mediated relaxation of rat oesophageal smooth muscle was investigated by studying the effects of beta 1- and beta 2-selective antagonists on the relaxation induced by (-)-isoprenaline, the beta 2-selective agonists fenoterol and clenbuterol and the beta 3-agonist, BRL 37344. 2. The highly beta 1-selective antagonist CGP 20721A did not antagonize (-)-isoprenaline- or BRL 37344-induced relaxations in concentrations up to 10 microM. Only at 100 microM of CGP 20712A were clear rightward shifts of the agonist concentration-response curves (CRCs) observed, with pA2 values of 4.70 and 4.97 against (-)-isoprenaline and BRL 37344, respectively. 3. ICI 118,551, a potent and selective beta 2-antagonist, at 100 nM caused moderate rightward shifts of the CRCs of (-)-isoprenaline, fenoterol and clenbuterol; with fenoterol and clenbuterol, this was accompanied by a clear steepening of the curve. Only at the highest concentration (100 microM ICI 118,551) did the shifts to the right further increase substantially. Resulting Schild-plots were clearly biphasic. BRL 37344-induced relaxations were only antagonized at 100 microM ICI 118,551, yielding a pA2 value of 5.48. 4. These results clearly demonstrate that the BRL 37344-induced relaxation of rat oesophageal muscularis mucosae is mediated solely through beta 3-adrenoceptors, whereas (-)-isoprenaline-, fenoterol- and clenbuterol-induced relaxations were shown to involve both beta 2- and, predominantly, beta 3-adrenoceptors.

Comparison of effects of dopamine hydrochloride and dopexamine hydrochloride on abdominal and femoral hemodynamics in anesthetized dogs.

The effects of dopamine and dopexamine administered in graded intravenous bolus injections (0.1-51.2 micrograms.kg-1) were compared in the renal and femoral, and in a number of splanchnic vessels at the organ level simultaneously in anesthetized dogs. Hemodynamic data are presented for each artery as conductance, which was obtained by dividing mean flow by mean arterial pressure. The data were analyzed in two different ways: 1) by responses at intervals of 3 sec to 12.8 micrograms dopamine or dopexamine during 1 min, and 2) by dose-response curves. Additionally, urine volume was measured during dopamine and dopexamine administration. During a period of 1 min after an injection of dopamine, early and late effects could be distinguished, while heart rate was unaltered. In the superior mesenteric, inferior mesenteric, splenic, common hepatic, renal, and femoral arteries, an early (at 18-21 sec) reduction in conductance was seen. The early reduction was often followed by an increase above the preinjection level. After dopexamine, the early reduction in conductance was not seen, except in the left gastric artery. In contrast to the effect of dopamine, dopexamine induced a more pronounced increase during the late phase. Contrary to dopamine, dopexamine increased the conductance in the common hepatic artery bed. It remains questionable whether dopaminergic receptors are present in this vascular bed. Dopamine raised blood pressure and urine production dose-dependently. Dopexamine decreased aortic pressure. Low dosages of dopexamine increased urine production, without raising renal blood flow. An advantage of dopexamine over dopamine could be that dopexamine does not stimulate alpha-adrenergic receptors.

A novel method to assess airway function parameters in chronically instrumented, unrestrained guinea-pigs.

A new method has been developed to measure airway functions in unanaesthetized, unrestrained guinea-pigs. The technique utilizes a specially designed pneumotachograph that is placed inside the trachea, and a saline-filled balloon, placed inside the pleural cavity. The pneumotachograph consists of a stainless steel cylinder with coaxial and perpendicular tubes attached to it, measuring the total pressure and the lateral pressure in the trachea, respectively. Via air-filled silicon conducting tubes, subcutaneously driven and permanently attached to the neck of the animal, the pressures are fed into a differential pressure transducer, yielding a pressure difference proportional to the airflow in the trachea. Via a saline-filled tubing, the pleural balloon is similarly attached to the neck of the animal, and pleural pressure (Ppl) is measured using a second pressure transducer. These data permit calculation of airway functions in conscious, unstressed animals. Control values for airway resistance (RAW), Ppl, tidal volume and respiratory frequency are all in the range of results reported previously for this species. A very significant correlation between RAW and Ppl (P < 0.001) was observed, indicating that sole Ppl-measurement can be used as a relatively simple and sensitive method to assess bronchial obstructive reactions in unrestrained guinea-pigs. Using a specially designed provocation cage, which allowed the animals to remain in a stress-free, unrestrained condition, the method has been successfully applied for the assessment of the dose-dependent bronchoconstrictor sensitivity to histamine as well as to allergen-induced early and late phase airway reactions.(ABSTRACT TRUNCATED AT 250 WORDS)

IgG- and IgE-mediated histamine release from superfused guinea-pig airway tissues.

Anaphylactic histamine release and the inhibition by the beta-adrenoceptor agonist fenoterol has been investigated using lung and tracheal tissues from two groups of guinea-pigs, differently sensitized to respond with IgG or IgE antibodies, respectively. A superfusion method was introduced and compared with classical batch incubation. The difference between IgG- and IgE-mediated histamine release during superfusion of both tissues was much greater than the difference obtained during batch-incubations. Fenoterol inhibited IgG-mediated histamine release during superfusion at lower concentrations and to a larger extent than the release from IgE-sensitized tissues. The inhibition by fenoterol was less pronounced after batch-wise incubations, preincubation at 0 degrees C abolished the quantitative difference of IgG- and IgE-mediated histamine release from lung slices as well as the difference in beta-adrenergic inhibition. It is concluded that the new superfusion procedure for airway tissues enhances the sensitivity of antigen-induced histamine release for pharmacological modulation, compared with batch-wise incubation. In addition, the effects of 0 degrees C pretreatment show that cooled transport and storage of airway tissue should be considered with care.

Differences in functional cyclic AMP compartments mediating lipolysis by isoprenaline and BRL 37344 in four adipocyte types.

Triglyceride mobilization and adenylyl cyclase activation in adipocytes from Wistar rats, lean Zucker (Fa/?) rats, obese Zucker (fa/fa) rats and humans were investigated in concentration-response studies with (-)-isoprenaline and the atypical beta 3-adrenoceptor selective agonist BRL 37344. Maximum FFA production by both agonists was identical in Wistar rat and lean Zucker rat adipocytes, while obese Zucker rat adipocytes and human adipocytes produced significantly less FFA, especially with BRL 37344. Maximum adenylyl cyclase activation by (-)-isoprenaline was similar for all types of adipocyte ghosts, whereas BRL 37344 was a partial agonist in all cases with the lowest intrinsic activity in human adipocytes. For (-)-isoprenaline the relationship between cAMP and lipolysis was steepest with Wistar rat adipocytes, followed by human and lean Zucker rat adipocytes, while obese Zucker rat cells showed a shallow relationship. For BRL 37344, the relationship was very steep and similar for all four adipocyte types, despite the marked differences in maximal lipolysis and cyclic AMP production. The results strongly argue in favour of cyclic AMP compartmentalization, the activity ratio between the functional and the non-functional compartment being least favourable in obese Zucker rat adipocytes. The atypical beta 3-adrenoceptor agonist BRL 37344 very efficiently directs the generated cyclic AMP into the functional compartment in all four adipocytes types investigated.

Relationship between lipolysis and cyclic AMP generation mediated by atypical beta-adrenoceptors in rat adipocytes.

1. The nature of the beta-adrenoceptor(s) mediating adenylyl cyclase activation in rat adipocyte ghosts by (-)-isoprenaline and the lipolytically selective beta-adrenoceptor agonist, BRL 37344, was investigated by use of the beta 1-selective antagonist, CGP 20712A. The results were compared with lipolysis in adipocytes. 2. While in lipolysis BRL 37344 was a full and 10 times more potent agonist than (-)-isoprenaline, in adenylyl cyclase activation similar pD2 values for both agonists were found. BRL 37344 was only a partial agonist on rat adipocyte adenylyl cyclase, with an intrinsic activity of 0.62. 3. With CGP 20712A small rightward shifts of the (-)-isoprenaline concentration-response curve (CRC) were observed at concentrations up to 10 microM, while at 100 microM and 1 mM clear rightward shifts occurred. The BRL 37344 CRC was not shifted with antagonist concentrations up to 10 microM. Only at 100 microM and 1 mM CGP 20712A were rightward shifts observed. 4. CGP 20712A concentrations of 10 microM and 100 microM depressed the maximum of the (-)-isoprenaline CRC to 89 and 60%, while the BRL 37344 CRCs retained the control maximum effect (62% of (-)-isoprenaline). Only at 1 mM CGP 20712A, was the CRC of BRL 37344 depressed, while the (-)-isoprenaline maximum was diminished further. 5. It was concluded that as with lipolysis, (-)-isoprenaline acts both through typical beta 1- and atypical beta 3-adrenoceptors for activation of adenylyl cyclase, while BRL 37344 acts solely through atypical beta 3-adrenoceptors. 6. The results also demonstrate that the relationship between adenosine 3':5'-cyclic monophosphate (cyclic AMP) and lipolysis is different for BRL 37344 and (-)-isoprenaline. Although the maximum activation of adenylyl cyclase by BRL 37344 is only 62% of that by (-)-isoprenaline, the distance between the lipolysis and adenylyl cyclase CRCs is much larger in the case of BRL 37344, indicating a larger transduction reserve for this agonist.

Role of phosphoinositide metabolism in human bronchial smooth muscle contraction and in functional antagonism by beta-adrenoceptor agonists.

The aim of the present investigation was to study in human bronchial smooth muscle (1) the relationship between methacholine and histamine-induced inositol phosphate (IP) production and contraction, (2) the influence of increasing concentrations of methacholine and histamine on the relaxation (pD2 and Emax) by isoproterenol (functional antagonism), and (3) the relation between IP production by methacholine and histamine and the changes of pD2 and Emax values of isoproterenol-induced relaxation. Methacholine and histamine were full agonists in contracting human bronchial smooth muscle, with pD2 values of 6.01 +/- 0.18 and 6.07 +/- 0.04, respectively. With IP production, however, pD2 values of 4.90 +/- 0.06 for methacholine and 5.15 +/- 0.16 for histamine were obtained, indicating a considerable reserve of PI metabolism for contraction. With increasing concentrations of histamine and methacholine (to 1 and 0.1 mM, respectively), subsequently performed dose-relaxation curves with isoproterenol showed decreasing values of pD2 (from 8.25 +/- 0.20 to 7.28 +/- 0.28) and Emax (from 100% to 56.7 +/- 12.4%). No differences were observed between methacholine and histamine in this respect. A significant correlation was found between IP production induced by the various concentrations of methacholine and histamine and the reduction of isoproterenol pD2 and Emax values. The results strongly suggest that PI metabolism may play an important role in the reduced efficacy of beta-adrenoceptor agonists to induce bronchodilation during active and severe asthma.

Muscarinic receptors in human airway smooth muscle are coupled to phosphoinositide metabolism.

In the present study we investigated whether muscarinic receptors in human airway smooth muscle are coupled to phosphoinositide metabolism as a possible transduction mechanism of contraction. Using isolated bronchial smooth muscle preparations, we found that the muscarinic agonist methacholine caused a time- and concentration-dependent accumulation of inositol phosphates in the presence of lithium, an effect which could be inhibited by atropine. Apart from its physiological significance, this finding may have great relevance for the biochemical investigation of cholinergic hyperresponsiveness in the airways of asthmatic patients.

Role of phosphoinositide metabolism in functional antagonism of airway smooth muscle contraction by beta-adrenoceptor agonists.

Histamine and the muscarinic agonists, methacholine, oxotremorine, and McN-A-343, were used to contract guinea-pig tracheal smooth muscle preparations. Cumulative dose-relaxation curves with isoprenaline were performed subsequently. In addition, the concentration-dependent induction of phosphoinositide metabolism by the contractile agonists was measured in bovine tracheal smooth muscle. All agonists were found to induce a decrease of the apparent affinity of isoprenaline and a loss of relaxation, depending on the concentration and type of contractile agonist used. The differential effects of the contractile agonists, especially at higher and supramaximal concentrations, on these beta-adrenergic parameters could be explained by differences in phosphoinositide metabolism.