Implantable device recalls: are we throwing away the baby with the bath water?

Over the past year, there has been a sharp increase in the number of recalls, or `field safety corrective actions'' concerning implantable defibrillators. This may be due to an actual rise in device or component-related problems (for which there is some evidence), overzealous reporting of potential problems (which is apparent), or most probably a combination of the two. In this day and age of increasing numbers of ICD implantations, it is essential that all concerned realise that ICDs are no more infallible than other man-made devices and that the incidence of complications is therefore likely to increase commensurately. It is also important to weigh the procedural risk of replacing the device against the risk not only of device failure, but more importantly related harm to the patient. Odds actually favour replacement in very few cases. Above all this demands critical attention to communication between stakeholders, medical, industry, patients and press. This article attempts to place a number of these issues in some perspective, and offer future directions for management of ICD recalls and safety actions.     

Statin-Associated Polymyalgia Rheumatica. An Analysis Using WHO Global Individual Case Safety Database: A Case/Non-Case Approach

Objective

To assess whether there is an association between statin use and the occurrence of polymyalgia rheumatic (PMR) in the spontaneous reporting database of the World Health Organisation (WHO).

Methods

We conducted a case/non-case study based on individual case safety reports (ICSR) in the WHO global ICSR database (VigiBase). Case reports containing the adverse event term polymyalgia rheumatica (WHOART or MedDRA Preferred Term) were defined as cases. Non-cases were all case reports containing other adverse event terms. Each case was matched to five non-cases by age, gender, and time of reporting. Case reports regarding a statin as suspected or concomitant drug were identified using the Anatomical Therapeutic Chemical (ATC) classification. Multivariate logistic regression was used to calculate reporting odds ratios (RORs) with 95% confidence intervals (CI).

Results

We identified 327 reports of PMR as cases and 1635 reports of other ADRs as non-cases. Among cases, statins were more frequently reported as suspected agent (29.4%) compared to non-cases (2.9%). After adjustment for several covariates, statins were significantly associated with reports of PMR (ROR 14.21; 95% CI 9.89–20.85).

Conclusion

The results of this study lends support to previous anecdotal case reports in the literature suggesting that the use of a statin may be associated with the occurrence of PMR. Further studies are needed to study the strength of the association in more detail and to elucidate the underlying mechanism.     

Distribution of rod- and cone-specific phosducins in retinas of non-mammalian vertebrates

In mammalian retinas, it has been believed that just one kind of phosducin (PD) commonly exists in both rods and cones. However, we have previously reported that there are rod- and cone-specific PDs (OlPD-R and OlPD-C) in medaka (Oryzias latipes) retina [FEBS Lett., 502, 117-121, 2001]. To clarify the distribution and evolution of these photoreceptor type-specific PDs, we investigated PDs of another teleost and a reptile. Immunohistochemical and Western blot analyses using anti-medaka PD antisera demonstrated that two kinds of PDs are expressed in zebrafish (Danio rerio) photoreceptor cells. Our study is suggestive that teleosts generally possess rod- and cone-specific PDs. We isolated a cDNA encoding putative PD (PmlPD) of a diurnal gecko (Phelsuma madagascariensis longinsulae). Because diurnal gecko possesses a pure-cone retina, it was expected that PmlPD would be expressed in cones. Molecular phylogenetic analysis demonstrated that PmlPD was more closely related to mammalian PDs than teleost cone-specific PDs, suggesting that the rod- and cone-specific subtype of teleost PDs have arisen after the teleost-tetrapod divergence.     

Acute Impact of Selected Pyridoindole Derivatives on Fos Expression in Different Structures of the Rat Brain

The impacts of three pyridoindole derivatives (PDs), designated as PD144, PD143, and PD104, which have previously been shown to have antidepressant (PD144) and anxiolytic (PD143, PD104) properties, were investigated on the Fos expressions in 11 different rat brain areas, including the medial prefrontal cortex, striatum, septum, accumbens nucleus (shell, core), bed nucleus of the stria terminalis, hypothalamic paraventricular nucleus, central amygdala, locus coeruleus, dorsal raphe nucleus, and the solitary tract nucleus. Control rats received vehicle, while the other three groups the PDs in a dose of 25 mg/kg/b.w. The animals were transcardially perfused with a fixative 90 min after the treatments. Coronal sections of 40-µm thickness were processed for Fos-immunostaining by avidin–biotin-peroxidase complex and visualized by nickel-intensified diaminobenzidine complex. Fos-labeled sections were counterstained with neuropeptides including corticoliberine (CRH), oxytocin (OXY), vasopressin (AVP), and vasoactive intestinal polypeptide (VIP) and processed for immunofluorescence staining using Alexa Fluor 555 dye. In all the three groups of animals, the upregulation of PDs-induced Fos expression only in 2 of 11 brain areas was investigated, namely, in the hypothalamic paraventricular nucleus (PVN) and the central amygdaloid nucleus (CeA). The other brain structures studied were devoid of Fos expression. Counterstaining of the Fos-labeled CeA-containing sections with VIP antibody revealed that the Fos expression stimulated by the PDs was upregulated in all the CeA subdivisions (lateral, ventral, capsular), except the medial one. Dual immunoprocessings showed Fos/CRH-labeling in both the PVN and the amygdala and Fos/OXY in the PVN. No Fos/AVP colocalizations were seen in the PVN. The obtained data provide the first view on the intracerebral effects of three new PDs derivatives, which effects were restricted only to the PVN and CeA areas. The present data may help to improve our understanding of the impact of the selected PDs on the brain and to anticipate possible behavioral and neuroendocrine consequences.     

Season-associated modifications in symplasmic organization of the cambium in Populus nigra

Background and Aims

Alterations of plasmodesma (PD) connectivity are likely to be very important for plant development. Here, the repetitive division pattern of cambial initials in Populus nigra ‘italica’ was studied to follow the development of the PD network during maturation. Furthermore, seasonal changes were investigated in order to trace indications for developmental and functional adaptations.

Methods

Cambium samples of P. nigra twigs, collected in summer, autumn and spring, were chemically fixed for transmission electron microscopy. The parameters, PD density (number of PDs per square micrometre cell-wall area) and PD frequency (total number of PDs per average cell-wall area), were determined for radial and tangential cell interfaces deposited in chronological order.

Key Results

Data sets, presented in plasmodesmograms, show a strong variability in the PD network throughout the year. In summer, high PD numbers occur at the division wall which, after PD doubling by longitudinal fission, decline with further development both at the xylem and the phloem side. In autumn, the number of PDs at the division wall is low as they are in subsequent tangential interfaces. In spring, the first cell division coincides with a massive increase in PD numbers, in particular at the division wall. Only the radial walls between initials maintain their PD equipment throughout the year. This feature can be exploited for identification of the initial layer.

Conclusions

PD networks in the cambium go through a strict developmental programme depending on the season, which is associated with changing functional requirements. For instance, PD numbers correlate with proliferative activity and potential pathways for intercellular signalling. Increases in PD numbers are ascribed to longitudinal fission as a major mechanism, whereas the decline in older derivatives is ascribed to PD degradation.     

The behavior of pollination drop secretion in Ginkgo biloba L.

Pollination drop (PD) secretion plays a critical role in wind pollination in many gymnosperms. We conducted detailed investigations on PD secretion in Ginkgo biloba, and found that PDs could not form when the micropyle was removed, but were able to form after removal of the shoot, leaves, ovular stalk, or ovular collar. The duration and volume of the PD increased under high relative humidity, but addition of salt or sugar did not affect PD secretion, its size, or its duration. Morphological and anatomical observations showed that many secretion cells at the nucellus tip contributed to secreting the PD after the formation of pollen chamber. Under laboratory conditions, the PD persisted for approximately 10 d if not pollinated, and re-formed five times after it was removed, with the total volume of PDs reaching approximately 0.4 μL. These results suggested that PDs can be continuously secreted by the tip of the nucellus cells during the pollination stage to increase the chance of capturing pollen from the air. Importantly, PD secretion is an independent behavior of the ovule and PDs were produced apoplastically.     

Do symplasmic networks in cambial zones correspond with secondary growth patterns?

The plasmodesmal (PD) network in the cambial zone of Arabidopsis thaliana hypocotyls was analysed using electron microscopy and dye-coupling studies and compared to those of internodes of Populus nigra and Solanum lycopersicum. In all species, PD densities and frequencies undergo alterations in topologically successive cambial walls reflecting species-specific patterns of PD degradation and PD insertion during cell development. Longitudinal PD fission is responsible for an abrupt increment of PD numbers in specific walls of the youngest derivatives at the xylem and/or phloem side. Here, PDs seem to mediate positional signalling to control tissue fate and early cell determination. PD numbers at all cambial interfaces of A. thaliana correspond to those of the herbaceous tomato, but are higher with the woody poplar. This suggests a positive correlation between PD frequencies and the rapidity of cell division activity. Photoactivated green fluorescent protein (26 kDa) did not diffuse through cambial PDs of A. thaliana. This is in keeping with the common size exclusion limit (SEL) of 8–10 kDa observed for PDs at the youngest interfaces of tomato and poplar which may mediate diffusive exchange of developmental signals of equal molecular size. The regular growth patterns in internodal cambial zones of poplar and tomato result from synchronized cell division activity of neighbouring initials. A. thaliana hypocotyls have an irregular mode of secondary growth. Here, signalling through PDs in misaligned radial walls between non-homologous derivatives may control tissue development. The observed organizational differences between the cambia cast doubts on the suitability of A. thaliana as a model plant for cambial research.     

裸子植物传粉滴研究进展

传粉滴是裸子植物胚珠在传粉期所产生的一种分泌物, 在珠孔处聚集成液滴状。传粉滴的分泌和形成在裸子植物传粉、花粉萌发和受精等有性生殖过程中发挥重要作用。该文综合国内外裸子植物传粉滴的研究进展, 并结合作者近年来所取得的实验结果, 全面综述了传粉滴的产生、分泌规律、成分、收缩机制以及在有性生殖过程中的功能, 系统总结了传粉滴选择和识别花粉功能, 以及促进花粉萌发与花粉管生长和防御病菌侵染等方面的作用。此外, 文中还提出了传粉滴研究存在的一些问题, 并从生物化学和分子生物学层面进一步明确了传粉滴与花粉之间相互作用的分子机理。     

Redox regulation of intercellular transport

Plant cells communicate with each other via plasmodesmata (PDs) in order to orchestrate specific responses to environmental and developmental cues. At the same time, environmental signals regulate this communication by promoting changes in PD structure that modify symplastic permeability and, in extreme cases, isolate damaged cells. Reactive oxygen species (ROS) are key messengers in plant responses to a range of biotic and abiotic stresses. They are also generated during normal metabolism, and mediate signaling pathways that modulate plant growth and developmental transitions. Recent research has suggested the participation of ROS in the regulation of PD transport. The study of several developmental and stress-induced processes revealed a co-regulation of ROS and callose (a cell wall polymer that regulates molecular flux through PDs). The identification of Arabidopsis mutants simultaneously affected in cell redox homeostasis and PD transport, and the histological detection of hydrogen peroxide and peroxidases in the PDs of the tomato vascular cambium provide new information in support of this novel regulatory mechanism. Here, we describe the evidence that supports a role for ROS in the regulation of callose deposition and/or in the formation of secondary PD, and discuss the potential importance of this mechanism during plant growth or defense against environmental stresses.     

Plague management of prairie dog colonies: degree and duration of deltamethrin flea control

Plague is a flea‐borne disease of mammalian hosts. On the grasslands of western North America, plague stifles populations of Cynomys spp. prairie dogs (PDs). To manage plague, PD burrows are treated with 0.05% deltamethrin dust that can suppress flea numbers and plague transmission. Here, we evaluate the degree and duration of deltamethrin flea control with three PD species at six sites across four U.S. states. Data were simultaneously collected at paired plots. Burrows from one randomly assigned member of each pair were treated with deltamethrin; non‐treated plots served as experimental baselines. Flea control was strong ≤two months after treatment, remained moderate one year later, and was statistically detectable for up to two years at some sites. Flea abundance was lower in plots with higher rates of deltamethrin application. After burrow treatments, flea abundance increased over time, reaching >one per PD within 255 to 352 days. Nevertheless, annual treatments of burrows with deltamethrin provided PDs with substantial protection against plague. Even so, deltamethrin should be further evaluated and combined with other tools under an integrated approach to plague management. Integrated plague management should help to conserve PDs and species that associate with them, including the endangered black‐footed ferret (Mustela nigripes).     

Constant rate of evolution in the antigenicity of glucose 6-phosphate dehydrogenase revealed by the enzyme inhibition method

Rabbit and chicken antisera against pure and impure rat glucose 6-phosphate dehydrogenase (G6PD) samples were prepared, and their inhibition potencies (RIP) were measured against G6PDs from 26 vertebrate and invertebrate species. The results demonstrated that the -logRIP values of antisera against G6PDs from various test species neatly correlate with paleontologically estimated divergence times between rat and the test species. This suggests that the antigenicity of G6PD has evolved at a constant rate. The correlation coefficients were evidently greater with chicken antisera than with rabbit antisera, but did not markedly differ between chicken antisera elicited to pure and impure rat G6PD samples. Based on the data obtained with chicken antisera, it is estimated that lineages which separated 250-300 million years ago differ in their G6PDs by one unit of the -logRIP.     

Can Patient Safety Incident Reports Be Used to Compare Hospital Safety? Results from a Quantitative Analysis of the English National Reporting and Learning System Data

Background

The National Reporting and Learning System (NRLS) collects reports about patient safety incidents in England. Government regulators use NRLS data to assess the safety of hospitals. This study aims to examine whether annual hospital incident reporting rates can be used as a surrogate indicator of individual hospital safety. Secondly assesses which hospital characteristics are correlated with high incident reporting rates and whether a high reporting hospital is safer than those lower reporting hospitals. Finally, it assesses which health-care professionals report more incidents of patient harm, which report more near miss incidents and what hospital factors encourage reporting. These findings may suggest methods for increasing the utility of reporting systems.

Methods

This study used a mix methods approach for assessing NRLS data. The data were investigated using Pareto analysis and regression models to establish which patients are most vulnerable to reported harm. Hospital factors were correlated with institutional reporting rates over one year to examine what factors influenced reporting. Staff survey findings regarding hospital safety culture were correlated with reported rates of incidents causing harm; no harm and death to understand what barriers influence error disclosure.

Findings

5,879,954 incident reports were collected from acute hospitals over the decade. 70.3% of incidents produced no harm to the patient and 0.9% were judged by the reporter to have caused severe harm or death. Obstetrics and Gynaecology reported the most no harm events [OR 1.61(95%CI: 1.12 to 2.27), p<0.01] and pharmacy was the hospital location where most near-misses were captured [OR 3.03(95%CI: 2.04 to 4.55), p<0.01]. Clinicians were significantly more likely to report death than other staff [OR 3.04(95%CI: 2.43 to 3.80) p<0.01]. A higher ratio of clinicians to beds correlated with reduced rate of harm reported [RR = -1.78(95%Cl: -3.33 to -0.23), p = 0.03]. Litigation claims per bed were significantly negatively associated with incident reports. Patient satisfaction and mortality outcomes were not significantly associated with reporting rates. Staff survey responses revealed that keeping reports confidential, keeping staff informed about incidents and giving feedback on safety initiatives increased reporting rates [r = 0.26 (p<0.01), r = 0.17 (p = 0.04), r = 0.23 (p = 0.01), r = 0.20 (p = 0.02)].

Conclusion

The NRLS is the largest patient safety reporting system in the world. This study did not demonstrate many hospital characteristics to significantly influence overall reporting rate. There were no association between size of hospital, number of staff, mortality outcomes or patient satisfaction outcomes and incident reporting rate. The study did show that hospitals where staff reported more incidents had reduced litigation claims and when clinician staffing is increased fewer incidents reporting patient harm are reported, whilst near misses remain the same. Certain specialties report more near misses than others, and doctors report more harm incidents than near misses. Staff survey results showed that open environments and reduced fear of punitive response increases incident reporting. We suggest that reporting rates should not be used to assess hospital safety. Different healthcare professionals focus on different types of safety incidents and focusing on these areas whilst creating a responsive, confidential learning environment will increase staff engagement with error disclosure.     

Overexpressed alpha3beta1 and constitutively activated extracellular signal-regulated kinase modulate the angiogenic properties of ECV304 cells.

ECV304, a spontaneously transformed cell line derived from the human umbilical vein endothelial cell (HUVEC) (Takahashi et al., 1990), has been developed as an in vitro angiogenesis model. In the present study, we further characterized the angiogenic properties of this cell line. Compared to HUVEC, ECV304 cells showed distinct features including a higher activity of cellular adhesion, slower but reproducible progression of angiogenesis on Matrigel, and resistance to apoptosis. Thus, the expression of integrin and activation of extracellular-signal regulated kinase 1/2 (Erk1/2), a downstream effector of the integrin pathway, were examined. Flow cytometry revealed that alpha3beta1 integrin was markedly upregulated in ECV304 cells, while alpha(v)beta1 and alpha5beta1 integrins were slightly downregulated. Consistent with this, the binding activity to collagen type IV and laminin, major extracellular matrices of Matrigel, was increased 1.4- and 1.9-fold in ECV304 cells, respectively. This tight binding may retard the initial stage of sprouting and migration in the angiogenesis of ECV304 cells. It has been further demonstrated that Erk1/2 is constitutively active in ECV304 cells, rendering them resistent to the inhibitory effect of PD98059 on proliferation. However, migration of both HUVEC and ECV304 cells was inhibited to a similar extent by PD98059 in a dose-dependent manner. Up to 50 microM of PD98059, no significant changes in cell binding and tubulogenesis on Matrigel was observed in ECV304 cells. In contrast, the tubulogenesis of HUVEC was severely impaired by PD98059. Elevated Erk1/2 activity in ECV304 cells was suppressed by dominant negative H-Ras, but not by cytochalasin D. These results suggest that the overexpression of alpha3beta1 integrin and the constitutive activation of Erk1/2 play a key role in the alteration of the angiogenic properties of ECV304 cells.     

Identifying the Basal Ganglia Network Model Markers for Medication-Induced Impulsivity in Parkinson's Disease Patients

Impulsivity, i.e. irresistibility in the execution of actions, may be prominent in Parkinson''s disease (PD) patients who are treated with dopamine precursors or dopamine receptor agonists. In this study, we combine clinical investigations with computational modeling to explore whether impulsivity in PD patients on medication may arise as a result of abnormalities in risk, reward and punishment learning. In order to empirically assess learning outcomes involving risk, reward and punishment, four subject groups were examined: healthy controls, ON medication PD patients with impulse control disorder (PD-ON ICD) or without ICD (PD-ON non-ICD), and OFF medication PD patients (PD-OFF). A neural network model of the Basal Ganglia (BG) that has the capacity to predict the dysfunction of both the dopaminergic (DA) and the serotonergic (5HT) neuromodulator systems was developed and used to facilitate the interpretation of experimental results. In the model, the BG action selection dynamics were mimicked using a utility function based decision making framework, with DA controlling reward prediction and 5HT controlling punishment and risk predictions. The striatal model included three pools of Medium Spiny Neurons (MSNs), with D1 receptor (R) alone, D2R alone and co-expressing D1R-D2R. Empirical studies showed that reward optimality was increased in PD-ON ICD patients while punishment optimality was increased in PD-OFF patients. Empirical studies also revealed that PD-ON ICD subjects had lower reaction times (RT) compared to that of the PD-ON non-ICD patients. Computational modeling suggested that PD-OFF patients have higher punishment sensitivity, while healthy controls showed comparatively higher risk sensitivity. A significant decrease in sensitivity to punishment and risk was crucial for explaining behavioral changes observed in PD-ON ICD patients. Our results highlight the power of computational modelling for identifying neuronal circuitry implicated in learning, and its impairment in PD. The results presented here not only show that computational modelling can be used as a valuable tool for understanding and interpreting clinical data, but they also show that computational modeling has the potential to become an invaluable tool to predict the onset of behavioral changes during disease progression.     

Stabilization of cellular properties and differentiation mutilpotential of human mesenchymal stem cells transduced with hTERT gene in a long-term culture

Human bone marrow mesenchymal stem cells (hMSCs) are promising candidates for cell therapy and tissue engineering. The life span of hMSCs during in vitro culture is limited. Human telomerase catalytic subunit (hTERT) gene transduction can prolong the life span of hMSCs and maintain their potential of osteogenic differentiation. We established a line of hMSCs transduced with exogenous hTERT (hTERT-hMSCs) and investigated its sustaining cellular properties in a long-term culture. This line of hTERT-hMSCs was cultured for 290 population doublings (PDs) without loss of contact inhibition. Under adipogenic, chondrogenic and osteogenic induction, hTERT-hMSCs at PD 95 and PD 275 could differentiate respectively into adipocytes, chondrocytes, and osteocytes. hTERT-hMSCs at these PDs showed no transforming activity through both in vitro assay of cell growth in soft agar and in vivo assay of tumorigenicity in NOD-SCID mice. Karyotype analyses showed no significant chromosomal abnormalities in hTERT-hMSCs at these PDs. These results suggested that the hTERT-hMSCs at lower population doubling levels (PDLs) should be considered as a cell model for studies of cellular senescence, differentiation and in vitro tissue engineering experiment because of its prolonged life span and normal cellular properties.     

Effects of STN and GPi deep brain stimulation on impulse control disorders and dopamine dysregulation syndrome

Objective

Impulse control disorders (ICDs) and dopamine dysregulation syndrome (DDS) are important behavioral problems that affect a subpopulation of patients with Parkinson''s disease (PD) and typically result in markedly diminished quality of life for patients and their caregivers. We aimed to investigate the effects of subthalamic nucleus (STN) and internal globus pallidus (GPi) deep brain stimulation (DBS) on ICD/DDS frequency and dopaminergic medication usage.

Methods

A retrospective chart review was performed on 159 individuals who underwent unilateral or bilateral PD DBS surgery in either STN or GPi. According to published criteria, pre- and post-operative records were reviewed to categorize patients both pre- and post-operatively as having ICD, DDS, both ICD and DDS, or neither ICD nor DDS. Group differences in patient demographics, clinical presentations, levodopa equivalent dose (LED), and change in diagnosis following unilateral/bilateral by brain target (STN or GPi DBS placement) were examined.

Results

28 patients met diagnostic criteria for ICD or DDS pre- or post-operatively. ICD or DDS classification did not differ by GPi or STN target stimulation. There was no change in DDS diagnosis after unilateral or bilateral stimulation. For ICD, diagnosis resolved in 2 of 7 individuals after unilateral or bilateral DBS. Post-operative development of these syndromes was significant; 17 patients developed ICD diagnoses post-operatively with 2 patients with pre-operative ICD developing DDS post-operatively.

Conclusions

Unilateral or bilateral DBS did not significantly treat DDS or ICD in our sample, even though a few cases of ICD resolved post-operatively. Rather, our study provides preliminary evidence that DDS and ICD diagnoses may emerge following DBS surgery.     

东莞市预防接种不良反应监测和处理控制系统的建立及评价

为了解东莞市各种疫苗预防接种不良反应的发生情况,建立预防接种不良反应(AEFI)监测和处理控制系统,评价其运行状况,提高预防接种工作质量。根据WHO对AEFI的定义和分类方法,确定了东莞市AEFI报告范围,报告人、报告程序、报告制度以及调查内容和方法,并对该系统2005年收集的AEFI病例进行描述性分析。全市共登记预防接种不良反应560例,其中疫苗反应占了95.36%。男性多于女性。在所使用的26种疫苗中有18种出现不良反应,以Hib和百白破(DPT)的发生率最高,且百白破的报告数最多,占57.5%。在报告的预防接种不良反应中,发热、局部红肿疼痛以及皮疹等过敏性反应占了94.1%。结果认为该系统在评价疫苗的安全性,发现不良反应发生的危险因素,改善预防接种服务质量起着重要作用。     

Concentration‐mediated multicolor fluorescence polymer carbon dots

Polymer dots (PDs) showing concentration‐mediated multicolor fluorescence were first prepared from sulfuric acid‐treated dehydration of Pluronic® F‐127 in a single step. Pluronic‐based PDs (P‐PDs) showed high dispersion stability in solvent media and exhibited a fluorescence emission that was widely tunable from red to blue by adjusting both the excitation wavelengths and the P‐PD concentration in an aqueous solution. This unique fluorescence behavior of P‐PDs might be a result of cross‐talk in the fluorophores of the poly(propylene glycol)‐rich core inside the P‐PD through either energy transfer or charge transfer. Reconstruction of the surface energy traps of the P‐PDs mediated through aggregation may lead to a new generation of carbon‐based nanomaterials possessing a fluorescence emission and tunable by adjusting the concentration. These structures may be useful in the design of multifunctional carbon nanomaterials with tunable emission properties according to a variety of internal or external stimuli. Copyright © 2015 John Wiley & Sons, Ltd.     

Pharmacodynamics of T-cell function for monitoring immunosuppression

OBJECTIVES: Recent studies show that measuring pharmacodynamic (PD) effects offers a unique possibility to predict immunosuppression. Thus, in this study we have monitored the PD properties of immunosuppressants on diverse T-cell functions in heart transplant (HTx) recipients. MATERIALS: PDs and blood concentrations (PK) of three different basis-immunosuppressive drugs were studied: cyclosporin A (CsA); tacrolimus (TRL) and sirolimus (SRL). T-cell function was analysed by expression of proliferating cell nuclear antigen (PCNA) labelling, expression of cytokines (IL-2, IFN-gamma) and surface antigen (for example, CD25) by FACS analysis. RESULTS: In group I, at time points C0 and C2, increased CsA-PK significantly inhibited expression of IL-2, IFN-gamma, PCNA and CD25 (P < 0.05). Correlations (r(2)) at C2 between inhibition of T-cell functions (PD) with PK and with drug doses were: CsA-PK: 0.71-0.91 and CsA-dose: 0.73-0.87. In group II, increased TRL-PK over time did not further inhibit expression of CD25, but inhibited PCNA expression more on day 3, and IL-2 and IFN-gamma expression was significantly higher on days 2 and 3 compared to PD effects of CsA (P < 0.05). Blood SRL concentrations in C0 group III, increased on day 1 and remained stable at days 3 and 4. Expression of PCNA was not altered in the SRL-PK category, whereas expression of CD25 was higher and expression of cytokines was lower than PD effects of CsA. CONCLUSIONS: Our results show that PD effects on T-cell function can be used to monitor immunosuppression bringing potential to increase the efficacy and safety of immunosuppressive therapy after HTx.