Deciphering Tacrolimus-Induced Toxicity in Pancreatic ß Cells.

ß Cell transcription factors such as forkhead box protein O1 (FoxO1), v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), pancreatic and duodenal homeobox 1, and neuronal differentiation 1, are dysfunctional in type 2 diabetes mellitus (T2DM). Posttransplant diabetes mellitus resembles T2DM and reflects interaction between pretransplant insulin resistance and immunosuppressants, mainly calcineurin inhibitors (CNIs). We evaluated the effect of tacrolimus (TAC), cyclosporine A (CsA), and metabolic stressors (glucose plus palmitate) on insulinoma ß cells in vitro and in pancreata of obese and lean Zucker rats. Cells were cultured for 5 days with 100 µM palmitate and 22 mM glucose; CsA (250 ng/mL) or TAC (15 ng/mL) were added in the last 48 h. Glucose plus palmitate increased nuclear FoxO1 and decreased nuclear MafA. TAC in addition to glucose plus palmitate magnified these changes in nuclear factors, whereas CsA did not. In addition to glucose plus palmitate, both drugs reduced insulin content, and TAC also affected insulin secretion. TAC withdrawal or conversion to CsA restored these changes. Similar results were observed in pancreata of obese animals on CNIs. TAC and CsA, in addition to glucose plus palmitate, induced comparable inhibition of calcineurin and nuclear factor of activated T cells (NFAT); therefore, TAC potentiates glucolipotoxicity in ß cells, possibly by sharing common pathways of ß cell dysfunction. TAC-induced ß cell dysfunction is potentially reversible. Inhibition of the calcineurin-NFAT pathway may contribute to the diabetogenic effect of CNIs but does not explain the stronger effect of TAC compared with CsA.

Enhancing dendritic cell immunotherapy for melanoma using a simple mathematical model.

BACKGROUND: The immunotherapy using dendritic cells (DCs) against different varieties of cancer is an approach that has been previously explored which induces a specific immune response. This work presents a mathematical model of DCs immunotherapy for melanoma in mice based on work by Experimental Immunotherapy Laboratory of the Medicine Faculty in the Universidad Autonoma de Mexico (UNAM). METHOD: The model is a five delay differential equation (DDEs) which represents a simplified view of the immunotherapy mechanisms. The mathematical model takes into account the interactions between tumor cells, dendritic cells, naive cytotoxic T lymphocytes cells (inactivated cytotoxic cells), effector cells (cytotoxic T activated cytotoxic cells) and transforming growth factor ß cytokine (T G F-ß). The model is validated comparing the computer simulation results with biological trial results of the immunotherapy developed by the research group of UNAM. RESULTS: The results of the growth of tumor cells obtained by the control immunotherapy simulation show a similar amount of tumor cell population than the biological data of the control immunotherapy. Moreover, comparing the increase of tumor cells obtained from the immunotherapy simulation and the biological data of the immunotherapy applied by the UNAM researchers obtained errors of approximately 10 %. This allowed us to use the model as a framework to test hypothetical treatments. The numerical simulations suggest that by using more doses of DCs and changing the infusion time, the tumor growth decays compared with the current immunotherapy. In addition, a local sensitivity analysis is performed; the results show that the delay in time " τ", the maximal growth rate of tumor "r" and the maximal efficiency of tumor cytotoxic cells rate "aT" are the most sensitive model parameters. CONCLUSION: By using this mathematical model it is possible to simulate the growth of the tumor cells with or without immunotherapy using the infusion protocol of the UNAM researchers, to obtain a good approximation of the biological trials data. It is worth mentioning that by manipulating the different parameters of the model the effectiveness of the immunotherapy may increase. This last suggests that different protocols could be implemented by the Immunotherapy Laboratory of UNAM in order to improve their results.

The higher diabetogenic risk of tacrolimus depends on pre-existing insulin resistance. A study in obese and lean Zucker rats.

Insulin resistance may interact with calcineurin inhibitors, enhancing the diabetogenic effect of tacrolimus compared with cyclosporine-A. We studied both drugs in insulin-resistant animals: obese Zucker rats (n = 45), and insulin-sensitive animals: lean Zucker rats (n = 21). During 11 days, animals received saline-buffer, cyclosporine-A (2.5 mg/kg/day) or tacrolimus (0.3 mg/kg/day). At Days 0 and 12 animals underwent intraperitoneal glucose tolerance test (0-30-60-120 min). Islet morphometry, beta-cell proliferation, apoptosis and Ins2 gene expression were analyzed. By Day 12, no lean animal had developed diabetes, while all obese animals on tacrolimus and 40% on cyclosporine-A had. In obese animals, tacrolimus reduced beta-cell proliferation and Ins2 gene expression compared with cyclosporine-A. Five days after treatment discontinuation, partial recovery was observed, with only 10% and 60% of the animals on cyclosporine and tacrolimus remaining diabetic respectively. Beta-cell proliferation increased in animals on tacrolimus while Ins2 gene expression remained unaltered. In conclusion, insulin resistance exacerbated the diabetogenic effect of tacrolimus compared with cyclosporine-A. This may be explained by greater inhibition of Ins2 gene and beta-cell proliferation by tacrolimus in the insulin resistant state. Discontinuation of the drugs may allow the recovery of the metabolic alterations.

Identification of a novel recurrent gain on 20q13 in chronic lymphocytic leukemia by array CGH and gene expression profiling.

BACKGROUND: The presence of genetic changes is a hallmark of chronic lymphocytic leukemia (CLL). The most common cytogenetic abnormalities with independent prognostic significance in CLL are 13q14, ATM and TP53 deletions and trisomy 12. However, CLL displays a great genetic and biological heterogeneity. The aim of this study was to analyze the genomic imbalances in CLL cytogenetic subsets from both genomic and gene expression perspectives to identify new recurrent alterations. PATIENTS AND METHODS: The genomic imbalances and expression levels of 67 patients were analyzed. The novel recurrent abnormalities detected with bacterial artificial chromosome array were confirmed by FISH and oligonucleotide microarrays. In all cases, gene expression profiling was assessed. RESULTS: Copy number alterations were identified in 75% of cases. Overall, the results confirmed FISH studies for the regions frequently involved in CLL and also defined a new recurrent gain on chromosome 20q13.12, in 19% (13/67) of the CLL patients. Oligonucleotide expression correlated with the regions of loss or gain of genomic material, suggesting that the changes in gene expression are related to alterations in copy number. CONCLUSION: Our study demonstrates the presence of a recurrent gain in 20q13.12 associated with overexpression of the genes located in this region, in CLL cytogenetic subgroups.

Role of late maternal thyroid hormones in cerebral cortex development: an experimental model for human prematurity.

Hypothyroxinemia affects 35-50% of neonates born prematurely (12% of births) and increases their risk of suffering neurodevelopmental alterations. We have developed an animal model to study the role of maternal thyroid hormones (THs) at the end of gestation on offspring's cerebral maturation. Pregnant rats were surgically thyroidectomized at embryonic day (E) 16 and infused with calcitonin and parathormone (late maternal hypothyroidism [LMH] rats). After birth, pups were nursed by normal rats. Pups born to LMH dams, thyroxine treated from E17 to postnatal day (P) 0, were also studied. In developing LMH pups, the cortical lamination was abnormal. At P40, heterotopic neurons were found in the subcortical white matter and in the hippocampal stratum oriens and alveus. The Zn-positive area of the stratum oriens of hippocampal CA3 was decreased by 41.5% showing altered mossy fibers' organization. LMH pups showed delayed learning in parallel to decreased phosphorylated cAMP response element-binding protein (pCREB) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) expression in the hippocampus. Thyroxine treatment of LMH dams reverted abnormalities. In conclusion, maternal THs are still essential for normal offspring's neurodevelopment even after onset of fetal thyroid function. Our data suggest that thyroxine treatment of premature neonates should be attempted to compensate for the interruption of the maternal supply.

Influence of multi-walled carbon nanotubes on the physico-chemical and biological responses of chitosan-based hybrid hydrogels.

Photoresponsive membranes were successfully obtained by combining chitosan (CS), poly(vinyl alcohol) (PVA) crosslinked with genipin (GEN) and filled with multi-walled carbon nanotubes (MWCNTs). It was demonstrated that adding a small quantity (0.01% w/v) of MWCNTs conferred to those nanocomposite hybrid hydrogels an outstanding photomechanical response under infrared irradiation. Moreover, it was observed that MWCNTs enhanced the crystallinity, increased the elastic modulus but did not contribute to the thermal stability of the nanocomposite hybrid hydrogels. The swelling capacity and contact angle values of these materials were modified through the addition of MWCNTs, and the offered free OH and NH2 functional groups in their current chemical structures. These functional groups - on hybrid hydrogels' surfaces - also enhanced the adhesion and proliferation of human dermal fibroblast cells, showing typical morphologies and sizes. Additionally, non-cytotoxic effects were observed for these nanocomposite hybrid hydrogels, suggesting their potential use in tissue engineering and biomedical applications. Chemical compounds studied in this article: Chitosan (PubChem CID: 71853); Polyvinyl alcohol (PubChem CID: 11199); Genipin (PubChem CID: 442424).

Identification of novel vaccine candidates against cryptosporidiosis of neonatal bovines by reverse vaccinology.

The apicomplexan protozoan Cryptosporidium parvum is an important causative agent of diarrhea of neonatal bovines. Vaccination has been proposed as an advantageous strategy against cryptosporidiosis of calves since besides protection against disease it has also the potential to prevent dissemination of infective oocysts into the environment. Antigens anchored to the parasite surface via glycosylphosphatidylinositol (GPI) are implicated in host cell attachment and invasion and represent promising vaccine candidates. A reverse vaccinology approach was employed to (i) identify the GPI-anchored proteome of C. parvum using available web-based bioinformatic tools and (ii) characterize previously unrecognized novel vaccine antigens. Altogether, 14 putative GPI-anchored proteins could be determined of which CpH1 and CpSUB2 as well as GP60 were further characterized. Sequencing and comparison of GP60, CpH1, and CpSUB1 alleles amplified from different geographic isolates showed a high degree of conservation. All three antigens were recombinant expressed and immunoblotted using sera of 12 Cryptosporidium-infected calves sampled at age periods 1-11 and 12-28 days after birth. Specific antibody reactions against the studied antigens were detected in all analyzed calves, demonstrating their immunreactivity and expression, and recognition in vivo at an early stage of host infection. Besides the acknowledged GP60 vaccinogen, the presented reverse vaccinology approach reveals the additional vaccine candidates CpH1 and CpSUB1 for inclusion into a subunit vaccine formulation.

Endogenous endophthalmitis by Propionibacterium acnes associated with leflunomide and adalimumab therapy.

PURPOSE: To report a case of unusual endogenous endophthalmitis associated with the use of leflunomide and adalimumab. METHODS: A 48-year-old woman on treatment with leflunomide and adalimumab for rheumatoid arthritis developed an endogenous endophthalmitis caused by Propionibacterium acnes. Diagnosis was confirmed by polymerase chain reaction and positive cultures. The patient underwent surgical treatment and intravitreal vancomycin, but the eye developed retinal fibrosis and untreatable retinal detachment. RESULTS: This report of endogenous endophthalmitis associated with the use of anti-tumor necrosis factor alpha (anti -TNF-a) drugs is consistent with those in the literature. P. acnes may induce pathologic reactions in compromised patients and cause endophthalmitis, but only after ocular surgery or in intravenous drug users. The Naranjo probability scale indicated a probable relationship between the drugs and the infection. CONCLUSIONS: Awareness of atypical infectious conditions in patients on anti-TNF-a drugs is critical for early diagnosis and good outcome.

[Chronic blepharitis and Demodex]. / Demodex y blefaritis crónica.

PURPOSE: Demodex is a mite commonly found in eyelash hair follicles and sebaceous glands of healthy people. Due to the fact this mite has also been reported in many chronic cases of blepharitis, we aimed to investigate the incidence of infestation with this mite in healthy people and in patients with chronic blepharitis, in addition to evaluating the response to the different treatments used for blepharitis. METHODS: 105 subjects without blepharitis were selected as a control group and 20 subjects diagnosed as having chronic blepharitis were selected as patients. Epilated eyelashes were observed under microscope in both groups of patients. Those with overpopulation of mites were treated with ether lid and eyelash scrubs and 2% mercury oxide ointment. RESULTS: The incidence of Demodex infestation in the control group was 0.08 mites per eyelash, whereas in the patients with chronic blepharitis the incidence was 0.69 mites per eyelash; this difference was statistically significant (p=0.006). All the mites found were Demodex folliculorum except in one patient where the mite was identified as Demodex brevis. After 3-8 weeks of specific treatment the number of mites per eyelash decreased dramatically (0.03, with p=0.001). Two patients were intolerant of the therapy. CONCLUSIONS: In this study the incidence of Demodex in patients with blepharitis was very high, when compared with normal subjects, showing a clear association between blepharitis and Demodex infestation. Treatment with mercury oxide ointment was satisfactory in controlling the infection, despite difficulty in its application and occasional toxicity.

Second versus first generation DES in multiple vessel disease and unprotected left main stenosis: insights from ERACI IV Study.

Recent data from randomized clinical trials (RCT) between PCI with first generation drug-eluting stent (DES) versus coronary artery bypass graft (CABG) showed a lack of benefit in the incidence of death and myocardial infarction (MI) with PCI. However in the last years a large improvement in the DES platforms was seen and was translated to a significant increase in safety and efficacy observed in RCT and observational studies. However, at present time little is known about the role of second generation DES in patients with complex multiple vessel coronary artery disease (CAD). ERACI IV registry is a multicenter, prospective and controlled open label study that evaluates a second generation DES, for the treatment of patients with multiple vessel CAD including unprotected left main. End point was to compare major adverse cardiovascular events (MACCE) and each component of them with previous arms of ERACI III study, first generation DES and CABG. ERACI IV compared to ERACI III DES arm, had greater number of diabetics (p = 0.02), at rest unstable angina (P = 0.01), 3 vessels plus left main (P = 0.02) and also more stent length per patient (P = 0.03).In ERACI IV 66.2% of patients had intermediate or high Syntax score. At one year, patients treated with 2nd generation compared to 1st generation DES had lower incidence of death (0.4% vs. 3.1% 4 P = 0.03), death/MI/stroke (0.9 vs. 6.7% P = 0.001), unplanned revascularization (1.8% vs. 8.9%, P = 0.001) and MACCE (2.2% vs. 12% P ≤ 0.001). Advantages was also observed in diabetics, MI (0% vs. 8.5 P = 0.05), death/MI/stroke (0% vs. 12.8%, P = 0.009), unplanned revascularization (1.4% vs. 14.9%, P = 0.01) and MACCE (1.4% vs. 21.3%, P < 0.001). In ERACI IV diabetic and non-diabetics had similar MACCE (1.4% vs. 2.6 %, P = 0.97). In conclusion, at one-year follow-up patients treated with second generation DES showed a remarkable low incidence of MACCE and any component of them; benefit was also seen in diabetics.

Coronary stenting in patients undergoing percutaneous transluminal coronary angioplasty during acute myocardial infarction.

Although coronary stenting has been useful in the treatment of patients with suboptimal results, abrupt closure, and threatening occlusion after percutaneous transluminal coronary angioplasty (PTCA), its use in patients with acute myocardial infarction (AMI) is controversial because of the presence of intracoronary thrombus. In this study intracoronary stenting was used to treat suboptimal results and complications in 30 patients (35 lesions) undergoing PTCA during AMI. There were 28 men and 2 women, mean age 58 +/- 12 years. Thirteen patients (43%) had undergone rescue PTCA because of unsuccessful thrombolysis. Four patients had Killip's grade IV, 5 Killip's grade III, and 21 Killip's grade < or = 2 heart failure. Stents were placed in the 35 lesions because of suboptimal result (n = 19), early loss (n = 9), abrupt closure (n = 2), and coronary dissection with threatening occlusion (n = 5). All stents were deployed successfully. In-hospital complications included 1 in-hospital death (3.0%); no patient required emergency coronary artery bypass graft surgery. One patient (3.0%) developed abrupt closure and was successfully treated with PTCA and intracoronary thrombolysis. Vascular complications requiring blood transfusion developed in 3 of 30 patients (10%). At 11.8 months (range 4 to 24) follow-up, there were no deaths or myocardial infarction. One patient underwent coronary artery bypass grafting. The remaining patients were free of angina at follow-up. Thus, intracoronary stents can be used successfully to treat both suboptimal results and complications occurring in patients undergoing PTCA during AMI.

Time course and mechanism of early luminal diameter loss after percutaneous transluminal coronary angioplasty.

To assess the time course and mechanism of early minimal luminal diameter (MLD) loss, serial angiographic observations were performed. Seventy-four patients (with 74 severe narrowings [ > or = 70%]) with acute ischemic syndromes who had an early loss in MLD of > 0.3 mm at 24 hours after percutaneous transluminal coronary angioplasty (PTCA) also underwent 1 hour post-PTCA angiography. In 12 consecutive patients with early loss 1 hour after PTCA, angioscopy was also performed to assess the mechanism of early loss. The percent diameter stenosis for the 74 lesions was 16.8 +/- 8.4% immediately after PTCA, 35.1 +/- 14.2% 1 hour after PTCA (p < 0.002 vs immediately after), and 41.4 +/- 13.2% at 24 hours (p < 0.10 vs 1 hour after). The MLD also showed similar differences: 2.6 +/- 0.3 mm immediately after to 2.0 +/- 0.4 mm 1 hour after(p < 0.002) to 1.8 +/- 0.4 mm 24 hours after PTCA (p < 0.10 vs 1 hour). In 60 patients (81%), the > 0.3 mm loss was detected 1 hour after PTCA. These 60 patients had no further decreases in MLD at 24 hours (1.9 +/- 0.4 vs 1.8 +/- 0.4 mm at 1 and 24 hours, respectively, p = NS). Adequate angioscopic images available in 11 patients showed that red thrombus was present in 1, minor or multiple dissection in 5, and neither thrombus nor dissection in 5 other patients (consistent with early wall recoil). Thus, in narrowings demonstrating early loss in MLD at 24 hours, 81% showed that the early loss occurred within 1 hour after PTCA. Early loss is not related to thrombus but usually to dissection or recoil.

ATPase and MHC class II molecules co-expression in Rana pipiens dendritic cells.

Mammalian Langerhans cells are antigen-presenting cells located in different epithelia. These cells have a characteristic ultrastructural pattern, present a plasmatic membrane ATPase activity and constitutively express class II molecules of the major histocompatibility complex. ATPase-positive dendritic cells that are morphologically similar to Langerhans cells have also been found in amphibian epidermis. In order to demonstrate that ATPase-positive dendritic cells of amphibian epidermis express class II molecules and are present in other stratified epithelia, histochemical and immunohistochemical as well as ultrastructural analysis were performed. ATPase-positive dendritic cells and class II-positive dendritic cells were observed in epidermis, nictitant membrane and cornea. In epidermis the number of ATPase-positive dendritic cells was 656+/-186/mm2 while class II-positive dendritic cells was 119+/-45/mm2. Some ATPase-positive dendritic cells showed co-expression of class II molecules. These results suggest the existence of dendritic cell subsets in amphibians as is clearly demonstrated in mammals.

K-edge digital subtraction imaging based on a dichromatic and compact x-ray source.

This work proposes a compact dichromatic imaging system for the application of the K-edge digital subtraction technique based on a conventional x-ray tube and a monochromator system. A quasi-monochromatic x-ray beam at the energy of iodine K-edge is produced by Bragg diffraction on a mosaic crystal. Two thin adjacent beams with energies that bracket the K-edge discontinuity are obtained from the diffracted beam by means of a proper collimation system. They are then detected using an array of Si detectors. A home-made phantom is used to study the image quality as a function of iodine concentration. Signal and signal-to-noise ratio analysis has also been performed. The results are compared with theoretical expectations.

[The usefulness of the application of nonlinear dynamics in the analysis of electrocardiograms in Chagas' disease patients]. / Utilidad de la aplicación de técnicas de modelado no lineal en el análisis de electrocardiogramas de pacientes con infección chagásica.

INTRODUCTION AND OBJECTIVES: The application of nonlinear techniques allows the definition of early risk markers in patients with Chagas infection and without any evidence of cardiac involvement evaluated by standard diagnostic test. Nonlinear modeling techniques have proved to be effective in cardiac rhythm analysis, thereby justifying its use in Chagas' disease. PATIENTS AND METHOD: The routine noninvasive test and heart rate variability analysis were performed in Chagas' disease patients and in a group of healthy subjects. In a second phase we used nonlinear analysis in the evaluation of patients with Chagas infection and no evidence of heart disease, Chagasic patients with minimal electrocardiographic abnormalities and healthy controls. RESULTS: Twenty-four-hour electrocardiographic ambulatory monitoring and heart rate variability allowed us to establish differences between the healthy subjects and patients with Chagas infection without evidence of cardiac disease (p c 0.05 and p <0.005). In sharp contrast nonlinear analysis characterized 4 subgroups in Chagasic patients without cardiac involvement (sensitivity and specificity of 1 00%). CONCLUSIONS: Our findings suggest that nonlinear modeling techniques have a high sensitivity and specificity in the early detection of cardiac involvement and very early autonomic disturbance. We recommend that these techniques be applied to patients with high risk of cardiac disease other than Chagasic myocarditis. Our findings should be corroborated with studies in larger populations. We are currently developing a prospective study to this end.

[Primary-care morbidity and true morbidity due to acute respiratory infections]. / Morbilidad asistida y morbilidad real por infecciones respiratorias agudas.

The present work presents the study of morbidity due to acute respiratory infections (ARI) in areas of the town of Lisa in Ciudad Habana, and Isla Juventud (Cuba), to characterize different aspects of morbidity measured by health care attendance and to measure true morbidity. About 90% of consultations for ARI were first-time consultations, while their ratio to further consultations was 5.3. True morbidity rates (TMR), obtained trough active research, ranged from 110.4 to 163.4 cases per 1000 inhabitants, considerably higher than morbidity rates measured by primary care consultations (MRPCC) in the same time period. The true morbidity index (TMI), as measured by the ratio of the two previous rates, ranged from 5 to 15. A high proportion (47.6%) of cases reported no medical care attendance. These results provide approximate estimates of true morbidity in the study area, and allow the establishment of a new control program, also improving epidemiologic surveillance within primary care activities.

Cell death and survival through the endoplasmic reticulum-mitochondrial axis.

The endoplasmic reticulum has a central role in biosynthesis of a variety of proteins and lipids. Mitochondria generate ATP, synthesize and process numerous metabolites, and are key regulators of cell death. The architectures of endoplasmic reticulum and mitochondria change continually via the process of membrane fusion, fission, elongation, degradation, and renewal. These structural changes correlate with important changes in organellar function. Both organelles are capable of moving along the cytoskeleton, thus changing their cellular distribution. Numerous studies have demonstrated coordination and communication between mitochondria and endoplasmic reticulum. A focal point for these interactions is a zone of close contact between them known as the mitochondrial-associated endoplasmic reticulum membrane (MAM), which serves as a signaling juncture that facilitates calcium and lipid transfer between organelles. Here we review the emerging data on how communication between endoplasmic reticulum and mitochondria can modulate organelle function and determine cellular fate.

Role of oral rapamycin to prevent restenosis in patients with de novo lesions undergoing coronary stenting: results of the Argentina single centre study (ORAR trial).

OBJECTIVE: To assess the role of oral rapamycin in the prevention of coronary restenosis in patients undergoing coronary stenting. METHODS: From December 2001 through February 2003, 76 patients with 103 de novo lesions treated percutaneously with bare stents received a loading dose of oral rapamycin 6 mg followed by a daily dose of 2 mg during 28 days in phase I (49 arteries in 34 patients) and 2 mg/day plus 180 mg/day of diltiazem in phase II (54 arteries in 42 patients). Rapamycin blood concentrations were measured in all patients. A six month follow up angiogram was performed in 82.5% (85 of 103 arteries). Follow up angiographic binary restenosis (> 50%), target vessel revascularisation, late loss, treatment compliance, and major adverse cardiovascular events were analysed and correlated with rapamycin concentrations. RESULTS: Rapamycin was well tolerated and only three patients discontinued the treatment for mild side effects. Angiographic restenosis was found in 15% of the arteries with angiographic restudy (13 of 85). The target vessel had been revascularised at follow up in 13.6% of the 103 vessels initially treated (14 of 103) and in 18.4% of the 76 patients (14 of 76). In-stent restenosis in phase I was 19% compared with 6.2% in phase II (p = 0.06). Angiographic in-stent restenosis in lesions of patients with rapamycin blood concentrations > or = 8 ng/ml was 6.2% and with rapamycin concentrations < 8 ng/ml was 22% (p = 0.041). Late loss was also significantly lower when rapamycin concentrations were > or = 8 ng/ml (0.6 mm v 1.1 mm, p = 0.031). A Pearson test showed a linear correlation between follow up late loss and rapamycin blood concentration (r = -0.826, p = 0.008). CONCLUSION: Oral rapamycin administered for one month after percutaneous coronary intervention was safe and with few minor side effects. High rapamycin blood concentrations were associated with significantly lower late loss and angiographic in-stent restenosis.