In vivo magnetic resonance spectrometry imaging demonstrates comparable adaptation of brain energy metabolism to metabolic stress induced by 72 h of fasting in depressed patients and healthy volunteers.

Major depressive disorder (MDD) is characterized by dysregulation of stress systems and by abnormalities in cerebral energy metabolism. Stress induction has been shown to impact neurometabolism in healthy individuals. Contrarily, neurometabolic changes in response to stress are insufficiently investigated in MDD patients. Metabolic stress was induced in MDD patients (MDD, N = 24) and in healthy individuals (CTRL, N = 22) by application of an established fasting protocol in which calorie intake was omitted for 72 h. Both study groups were comparable regarding age, gender distribution, and body mass index (BMI). Fasting-induced effects on brain high-energy phosphate levels and membrane phospholipid metabolism were assessed using phosphorus-31 magnetic resonance spectroscopy (31P-MRS). Two-way repeated measures ANOVAs did not reveal significant interaction effects (group x fasting) or group differences in adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi), phosphomonoesters (PME), phosphodiesters (PDE), or pH levels between MDD and CTRL. Fasting, independent of group, significantly increased ATP and decreased Pi levels and an overall increase in PME/PDE ratio as marker for membrane turnover was observed. Overall these results indicate reactive changes in cerebral energetics and in membrane phospholipid metabolism in response to fasting. The observed effects did not significantly differ between CTRL and MDD, indicating that neurometabolic adaptation to metabolic stress is preserved in MDD patients.

[Efficacy and safety of eltrombopag in aplastic anemia: A multi-center survey in China].

Objective: To evaluate the safety and efficacy of eltrombopag combined with immunosuppressive therapy in patients with aplastic anemia (AA) in China. Methods: We investigated and analyzed the clinical data of AA patients from 14 hematological treatment centers who were treated with oral eltrombopag for at least 3 mon. Results: We enrolled 56 AA patients, including 19 treatment-naïve patients and 37 IST-refractory patients. The median administration period for eltrombopag was 7 (3-31) months, and the median maximum stable dosage was 75 mg/d (50-150 mg/d) . The 3-month hematological response (HR) rate was 60%, and the complete response (CR) rate was 30% in 10 SAA patients who were treated with first-line eltrombopag and standard IST (ATG+CsA) . Eight of 9 eltrombopag and CsA ± androgen first-line treated SAA patients responded (8/9, 89%) and 4 (44%) gave CR. The overall HR and CR rates were 79% and 52.6%, respectively, among these 19 patients by the end of the follow-up period. Of the 19 AA patients who were refractory to CsA ± androgen, 11 achieved HR (57.9%) at 3 mon, and the best HR rate was 44% in standard IST (ATG+CsA) refractory 18 patients after eltrombopag treatment. Fifty-one percent of the patients experienced mild or moderate adverse events, and gastrointestinal discomfort was the most common adverse effect reported by the study subjects. Conclusion: Adding Eltrombopag in first-line IST can accelerate the acquisition and improve the quality of hematological responses in AA patients. AA with relatively more residual hematopoietic cells may be well treated with eltrombopag and non-ATG IST. Eltrombopag can be used as salvage therapy for CsA±androgen refractory patients. Eltrombopag was generally safe and well tolerated by AA patients in China.

Epidermal growth factor promotes intestinal secretory cell differentiation in weaning piglets via Wnt/ß-catenin signalling.

Small intestinal epithelium homeostasis involves four principal cell types: enterocytes, goblet, enteroendocrine and Paneth cells. Epidermal growth factor (EGF) has been shown to affect enterocyte differentiation. This study determined the effect of dietary EGF on goblet, enteroendocrine and Paneth cell differentiation in piglet small intestine and potential mechanisms. Forty-two weaned piglets were used in a 2 × 3 factorial design; the major factors were time post-weaning (days 7 and 14) and dietary treatment (0, 200 or 400 µg/kg EGF supplementation). The numbers of goblet and enteroendocrine cells were generally greater with the increase in time post-weaning. Moreover, the supplementation of 200 µg/kg EGF increased (P < 0.01) the number of goblet and enteroendocrine cells in villus and crypt of the piglet small intestine as compared with the control. Dietary supplementation with 200 µg/kg EGF enhanced (P < 0.05) abundances of differentiation-related genes atonal homologue 1, mucin 2 and intestinal trefoil factor 3 messenger RNA (mRNA) as compared with the control. Piglets fed 200 or 400 µg/kg EGF diet had increased (P < 0.05) abundances of growth factor-independent 1, SAM pointed domain containing ETS transcription factor and pancreatic and duodenal homeobox 1 mRNA, but decreased the abundance (P < 0.01) of E74 like ETS transcription factor 3 mRNA as compared with the control. Animals receiving 400 µg/kg EGF diets had enhanced (P < 0.05) abundances of neurogenin3 and SRY-box containing gene 9 mRNA as compared with the control. The mRNA abundance and protein expression of lysozyme, a marker of Paneth cell, were also increased (P < 0.05) in those animals. As compared with the control, dietary supplementation with 200 µg/kg EGF increased the abundance of EGF receptor mRNA and the ratio of non-phospho(p)-ß-catenin/ß-catenin (P < 0.05) in villus epithelial cells at days 7 and 14. This ratio in crypt epithelial cells was higher (P < 0.05) on the both 200 and 400 µg/kg EGF groups during the same period. Our results demonstrated that dietary EGF stimulated goblet, enteroendocrine and Paneth cell differentiation in piglets during the post-weaning period, partly through EGFR and Wnt/ß-catenin signalling.

Research on protective mechanism of ibuprofen in myocardial ischemia-reperfusion injury in rats through the PI3K/Akt/mTOR signaling pathway.

OBJECTIVE: To study the protective mechanism of ibuprofen (Ib) in myocardial ischemia-reperfusion (I/R) injury in rats, and to analyze its regulatory effect on the phosphatidylinositol 3-hydroxy kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway. MATERIALS AND METHODS: The rat model of myocardial I/R injury was established via ligation of the left main coronary artery (LCA) for 30 min and then reperfusion for 120 min. A total of 36 Sprague-Dawley (SD) rats were randomly divided into sham group (S group, n=12), model group (I/R group, n=12) and Ib group (n=12). The levels of serum creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) in each group were detected. The rats were executed, the heart was isolated and the area of myocardial infarction was determined via 2,3,5-triphenyltetrazolium chloride (TTC) staining. The expression levels of vascular endothelial growth factor (VEGF), hypoxia-inducible factor 1 (HIF-1) and apoptosis-related proteins in myocardial tissues in each group were detected via Western blotting. Moreover, the content of inflammatory factors in myocardial tissues in each group was detected using the enzyme-linked immunosorbent assay (ELISA) kit. The expression levels of related proteins in the PI3K/Akt/mTOR signaling pathway in myocardial tissues were further analyzed. RESULTS: Compared with those in S group, the levels of CK-MB and LDH were significantly increased (p<0.01), the area of myocardial infarction was significantly increased (p<0.01), the VEGF, HIF-1 and Cleaved caspase-3 protein levels in myocardial tissues were increased (p<0.01), while Bcl-2/Bax declined (p<0.01), the content of interleukin-1 (IL-1), IL-6 and tumor necrosis factor-α (TNF-α) in myocardial tissues was increased (p<0.01), while the content of IL-10 declined (p<0.01), and the expression levels of PI3K, p-Akt and p-mTOR proteins in myocardial tissues were significantly decreased (p<0.01) in I/R group. Compared with those in I/R group, the levels of CK-MB and LDH were significantly decreased (p<0.01), the area of myocardial infarction was significantly decreased (p<0.01), the VEGF, HIF-1 and Cleaved caspase-3 protein levels in myocardial tissues were decreased (p<0.01), while Bcl-2/Bax was increased (p<0.01), the content of IL-1, IL-6 and TNF-α in myocardial tissues declined (p<0.01), while the content of IL-10 was significantly increased (p<0.01), and the expression levels of PI3K, p-Akt and p-mTOR proteins in myocardial tissues were significantly increased (p<0.01) in Ib group. CONCLUSIONS: Ib can activate the PI3K/Akt/mTOR signaling pathway, reduce the release of inflammatory factors and apoptosis, and alleviate the myocardial I/R injury in myocardial cells in rats.

Interaction between bone marrow-derived dendritic cells and miR-21 of tubular renal epithelial cells under hypoxia.

OBJECTIVE: To investigate the intracellular response and role of microRNA 21 in the regulation of dendritic cell maturation and function. MATERIALS AND METHODS: Bone marrow-derived DCs (BMDCs) isolated from male C57BL/6J mice and primary renal tubular epithelial cells were used as primary cells to perform this study. Flow cytometry was used to determine BMDCs and analyze the apoptosis effect. Transmission electron microscopy was used for the identification of the diameter of exosomes. Reverse transcription-Polymerase Chain Reaction (RT-PCR) and Western blotting were used to detect the effect after cells were transfected with oligo. ELISA was used to determine the tumor necrosis factor-α (TNF-α), interleukin-12 (IL-12), and IL-1beta in DC supernatants. RESULTS: We found that the upregulation of microRNA 21 in dendritic cells induced by physical hypoxia contributed to decreased expressions of CD80 (cluster of differentiation 80), CD86 (cluster of differentiation 86), and MHCII (major histocompatibility complex class II molecules) of dendritic cells and suppressed secretion of inflammatory cytokines and chemokine receptor type 7. Co-culture with tubular epithelial cells or hypoxia-pretreated tubular epithelial cell-derived conditional medium promoted bone marrow-derived dendritic cell maturation. Exosomes purified from the supernatant of cultured marrow-derived dendritic cells showed upregulated microRNA 21 under hypoxia, whereas anti-microRNA 21 treated tubular epithelial cells promoted co-cultured marrow-derived dendritic cell maturation. CONCLUSIONS: Both oxygen concentration and tubular epithelial cells participate in regulating dendritic cell maturation, directly or indirectly through the microRNA 21 signal pathway.

[The roles of holothurian glycosaminoglycan combined with cisplatin on proliferation and chemotherapeutic response in A549 human lung adenocarcinoma cell].

Objective: To investigate the effects and mechanism of Holothurian Glycosaminoglycan (hGAG) alone in combination with cisplatin (DDP) on apoptosis of pulmonary adenocarcinoma cell A549. Methods: A549 cells were separately treated with blank, hGAG, DDP and hGAG combined with DDP (hGAG + DDP). The cell morphology in 4 groups was observed using light microscope. CCK8 assay was used to determine the cell viability. Flow cytometry by Hoechst 33258 and AnnexinV-FITC/PI staining was applied to detect cell apoptosis. Western blot was then used to detect the protein expression of Bax, Bcl-2, survivin and caspase-3. Results: After treatment for 24 h, the inhibitory rates of A549 cells in control, hGAG, DDP and hGAG + DDP groups were 0, (19.74±5.39)%, (42.01±2.57)% and (53.89±4.58)%, respectively. Moreover, after treatment for 48 h and 72 h, the inhibitory rates in each group were 0, (23.17±4.78)% and (29.17±4.21 )%, (54.00±7.64)% and (59.35±7.31)%, as well as (77.58±4.26)% and (79.94±4.58)%, respectively. The cell viability was significantly lower in drug treatment groups compared with those in control group at the same time point (P<0.05). Hochest 33258 staining showed that no obvious apoptotic cells were detected in the control group, while apoptotic cells were visible in hGAG, cisplatin and combination groups. Flow cytometry showed that cell apoptotic rates were (2.38±0.59)%, (12.59±4.22)%, (16.36±3.63)% and (44.60±5.45)% in the control, hGAG, DDP and hGAG + DDP groups, respectively. The cell apoptosis was significantly lower in drug treatment groups compared with those in control group at the same time point (P<0.05). Furthermore, western blot results showed that the expression of Bax and caspase-3 protein was increased (P<0.05), whereas Bcl-2 and survivin was decreased (P<0.05) in the hGAG+ DDP group compared with cisplatin alone (P<0.05). Conclusions: HGAG can inhibit the proliferation and promote the apoptosis of human lung adenocarcinoma A549 cells. Meanwhile, it can strengthen the chemosensitivity of A549 cells to DDP via up-regulation of Bax, caspase-3 and down-regulation of Bcl-2 and survivin.

Antitumor effect of miR-27b-3p on lung cancer cells via targeting Fzd7.

OBJECTIVE:   Lung cancer is the most common malignancy with the highest mortality rate among cancers. microRNAs (miRNAs) have been confirmed to be closely related to the physiological disorder, especially the tumor process. This study aimed to investigate the effect of miR-27b-3p on lung tumor cells. MATERIALS AND METHODS: The expressions of miR-27b-3p in lung tumors and adjacent non-tumors lung tissues were compared. We test the bonding effect of miR-27b-3p on the Fzd7 promoter, and miR-27b-3p effects on the Fzd7 expression in both NCI-H446 and A549 cells. Then, effects of miR-27b-3p and Fzd7 on these cells viability, survival and apoptosis were detected, respectively. In addition, the possible mechanism of miR-27b-3p affected these cells apoptosis was explored by analyzing the expression of apoptosis-related factors. RESULTS: We found that miR-27b-3p was low expressed in lung tumors compared to adjacent non-tumorous lung tissues. miR-27b-3p directly targeted Fzd7 promoter and negatively regulated Fzd7 expression. Fzd7 promoted NCI-H446 and A549 cells viability and survival, inhibited cells apoptosis. However, miR-27b-3p effects on these cells were quite the opposite to Fzd7. The expressions of apoptosis-related factors were associated positively with miR-27b-3p and showed a negative correlation with Fzd7 expression. CONCLUSIONS: The miR-27b-3p was lowly expressed in lung cancer tissues, and played the role of a tumor suppressor. It could promote cell apoptosis and suppress cancer cells viability and survival via down-regulating Fzd7. It suggested that miR-27b-3p might be a potential target for the prophylaxis and treatment of lung cancer.

Serum hepcidin in haemodialysis patients: associations with iron status and microinflammation.

Hepcidin plays a key role in iron homeostasis. This cross-sectional study measured the serum hepcidin levels of 48 maintenance haemodialysis patients and 20 age-matched healthy control subjects using a competitive enzyme-linked immunosorbent assay (C-ELISA). Serum hepcidin, interleukin (IL)-6 and high-sensitivity C-reactive protein levels were significantly higher in maintenance haemodialysis patients compared with control subjects. In all patients, there was a positive correlation between serum hepcidin levels and ferritin, transferrin saturation and IL-6, and an inverse correlation between serum hepcidin and unsaturated iron-binding capacity, total iron-binding capacity (TIBC) and transferrin. Linear regression analyses showed that ferritin and TIBC were independently associated with serum hepcidin levels. In conclusion, serum hepcidin levels are associated with iron status and microinflammation (defined as hsCRP < 15 mg/l, without clinical manifestation of inflammation) in maintenance haemodialysis patients. The C-ELISA method for measuring serum hepcidin should facilitate the routine measurement of hepcidin in clinical practice.

Assessment of urinary N-acetyl-ß-glucosaminidase as an early marker of contrast-induced nephropathy.

Early detection and timely intervention are important for improving contrast-induced nephropathy (CIN) prognosis. Whether urinary N-acetyl-ß-glucosaminidase (NAG) is a useful marker for early detection of CIN was investigated in 590 patients undergoing diagnostic coronary angiography (CA) and/or therapeutic percutaneous coronary intervention (PCI) for acute coronary syndromes or stable angina, and who received low-osmolality nonionic contrast agent. Urinary NAG, osmolality and serum creatinine were measured before and 1, 2 and 6 days after contrast agent exposure. CIN occurred in 33 patients; its incidence in high-risk patients (pre-existing renal dysfunction with/without diabetes mellitus) was significantly higher than in others. In patients with CIN, urinary NAG and serum creatinine levels on days 1 and 2 were significantly higher than at baseline and compared with patients without CIN; mean levels were gradually returning to baseline by day 6. Compared with serum creatinine, urinary NAG levels peaked earlier in CIN patients and increased much more. The results suggest that, following CA and/or PCI, CIN occurs to a certain degree and that NAG may be a useful early CIN marker as it is noninvasive, simple, inexpensive and sensitive.

First-principles investigation on electronics characteristics of benzene derivatives with different side groups.

The electronics properties for benzene derivatives with different side groups connected to two gold electrodes with symmetric contacts are investigated by using first-principles methods based on the density functional theory. We have found that a bias can induce a transition from the electron-withdrawing behaviors to the electron-denoting behaviors for the OH side group in a phenoldithiol molecule. The degree of asymmetry of the I-V characteristics and the magnitudes in current depend remarkably on the type and number of attached side groups. The detailed analysis illustrates that the "doping" effect of the side groups and the asymmetry of potential profile in devices under different bias polarities are intrinsic origins leading to such observed phenomena. The results show that it is feasible to import some particular characteristics to a benzene-dithiol molecular device through an attachment of different side groups.

Rapidly progressive vanishing white matter disease in a child with previously inconspicuous brain MRI.

In this pediatric case of vanishing white matter disease with early onset, rapidly progressive course, and fatal outcome, the white matter vanishing process in patient was for the first time documented morphologically in detail: An initial magnetic resonance imaging documented a normal appearing brain maturation. Rapid progressive brain lesions initiated morphologically DE NOVO in the former well myelinated deep white matter were observed six months later after disease onset, including concentric ongoing signs of restricted proton diffusion cytotoxic edema on diffusion weighted imaging. Cyst-like defects at the lesion center of the deep white matter were detected more clearly on MRI ten months later. A pathomechanism like tumor necrosis factor induced oligodendrocyte apoptosis and primary demyelination was postulated. The case demonstrates that in the presence of clinically progressive symptoms, the development of VWM is possible even if first MRI findings are negative.

Disarrangement of fiber tracts and decline of neuronal density correlate in glioma patients--a combined diffusion tensor imaging and 1H-MR spectroscopy study.

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) and MR spectroscopy are noninvasive, quantitative tools for the preoperative assessment of gliomas with which the quantitative parameter fractional anisotropy (FA) and the concentration of neurometabolites N-acetylaspartate (NAA), choline (Cho), creatine (Cr) of the brain can be determined. Measurements of FA and NAA reflect the integrity of fiber tracts and the presence of neurons, respectively. This investigation examines changes of FA and NAA and compares these different aspects in architecture of gliomas after spatial coregistration. METHODS: DTI and chemical shift (1)H-MR spectroscopy was performed in 34 healthy volunteers and 69 patients with histologically confirmed (n = 48) or morphologically suspected (n = 21) non-necrotic brain glioma. Volumes of interest (VOIs) were placed in the tumor center (TC), the tumor border (TB), the normal-appearing white matter adjacent to the tumors (TNWM), and in the white matter of the contralateral hemisphere (NWMC). Median FA values and NAA/Cr and NAA/Cho ratios were calculated in the patients' VOIs and the gray and white matter of the volunteers. Correlations of FA values and NAA ratios were calculated. RESULTS: Continuous changes of FA and NAA from the tumor center to the periphery (the adjacent white matter and the contra-lateral hemisphere, respectively) were observed, where median values were: TC: 0.73 +/- 0.45, 0.47 +/- 0.58, 0.17 +/- 0.15 (NAA/Cr, NAA/Cho, FA); TB: 1.06 +/- 0.53, 1.00 +/- 0.15, 0.23 +/- 0.08; TNWM: 1.42 +/- 2.48, 1.21 +/- 0.95, 0.34 +/- 0.09; and NWMC: 1.63 +/- 0.72, 1.56 +/- 1.34, 0.38 +/- 0.08. Correlation of median FA values and NAA ratios in the cumulative group of patients was high (r = 0.99 [NAA/Cr], 0.95 [NAA/ Cho] at P < .01). Correlation between the individual NAA ratios and the FA values was moderate (r = 0.53 [NAA/Cr], 0.51 [NAA/Cho] at P < .01). CONCLUSION: In gliomas, the degree of tissue organization decreases continuously from the surrounding tissue toward the center of the tumor accompanied by a concordant decrease of NAA. This uniform behavior of FA and NAA reflects a decreasing integrity of both neuronal structures and fibers.

Characterization of the type A cholecystokinin receptor hormone-binding domain: use of contrasting and complementary methodologies.

Insights into the molecular basis of binding of the peptide hormone, cholecystokinin, to its G protein-coupled receptor is of substantial interest and may contribute to the successful production and refinement of receptor-active drugs. A number of methodological approaches provide complementary data to contribute to these insights. These include receptor mutagenesis, ligand structure-activity data, conformational analysis of ligand and receptor fragments, and photoaffinity labeling. In this work, we compare and contrast each of these methods and provide our current view of the cumulative impact of the current data on molecular conformational models of the agonist-occupied type A cholecystokinin receptor. These support the key roles played by extracellular loop and tail regions of this receptor for binding its natural peptide ligand.

Receptor biology and signal transduction.

This year has witnessed substantial advances in receptor biology and signal transduction that are relevant to the function and regulation of the healthy pancreas and to the pathogenesis and potential therapy of pancreatitis and pancreatic carcinoma. There has been an expansion in the cast of pancreatic regulatory molecules, now including protease-activated receptors, chemokines, and chemokine receptors. There have been new insights into the cellular distribution and signaling initiated at the classic pancreatic receptors. There have also been dramatic advances in insights into the structure of G protein-coupled receptors, with the first solution of a crystal structure of a member of this superfamily, and into the molecular basis of ligand binding and activation of these important molecules. This will clearly improve the opportunities for the rational design and refinement of receptor-active drugs. In addition to these fundamental advances, there has been renewed attention to the expression, function, and regulation of receptors and signaling pathways in pancreatic cells present in the setting of pancreatitis and pancreatic carcinoma. It is hoped that this will contribute toward earlier diagnosis, more successful therapy, and new chemopreventive strategies for these illnesses.

Clinicopathological evaluation in non-episode biopsies of renal transplant allograft.

Histopathological findings in renal allograft with stable function remain unclear. We therefore performed non-episode biopsy in the long-surviving renal allograft to investigate the histopathological changes. Our data show that, although arteriolopathy is characteristic of drug-induced nephropathy, it is unrelated to dosage and concentration of cyclosporine or tacrolimus in non-episode biopsy. We evaluated therefore the clinicopathological findings of arteriolopathy in this study. Non-episode biopsy was defined as follows: as serum creatinine level lower than, 2.0 mg/dl and a urinary protein level lower than 500 mg/day. A total of 65 biopsy specimens were enrolled in this study as non-episode biopsy. Twenty-nine specimens revealed arteriolopathy. There were no statistically significant differences between arteriolopathy and dosage or concentration of cyclosporine or tacrolimus. Arteriolopathy in non-episode biopsy was related to time of biopsy, kidney age, hypertension, and hyperlipidemia, suggesting that it is important for graft survival to strictly control blood pressure and blood lipid level.

Structurally related peptide agonist, partial agonist, and antagonist occupy a similar binding pocket within the cholecystokinin receptor. Rapid analysis using fluorescent photoaffinity labeling probes and capillary electrophoresis.

The molecular basis of ligand binding to receptors provides important insights for drug development. Here, we explore domains of the cholecystokinin (CCK) receptor that are critical for ligand binding, using a novel series of fluorescent photolabile probes, receptor proteolysis, and rapid high resolution separation of peptide fragments by capillary electrophoresis. Each probe incorporated the same fluorophore and a photolabile p-benzoylphenylalanine at the amino terminus of the pharmacophoric domain (residue 24 of CCK-33) of CCK analogues representing full agonist, partial agonist, and antagonist of this receptor. Each was used to label the CCK receptor expressed on Chinese hamster ovary-CCKR cells, with the labeled domain then released by cyanogen bromide cleavage. Capillary electrophoresis with laser-induced fluorescence detection achieved an on-capillary mass sensitivity of 1.6 attomoles (10(-18) mol), with an excellent signal-to-noise ratio. Each of the biologically divergent, but structurally similar probes saturably and specifically labeled the same receptor domain, consistent with conservation of "docking" determinants. This had an apparent mass of 2.9 kDa, most consistent with the first extracellular loop domain. An additional probe having its site of covalent attachment in a different region of the probe (residue 29 of CCK-33) labeled a distinct receptor fragment with differential migration on capillary electrophoresis (third extracellular loop). Identification of the specific receptor residue(s) covalently linked to the amino-terminal probes must await further fragmentation and sequence analysis.

Morphological findings in non-episode biopsies of kidney transplant allografts treated with FK506 or cyclosporine.

We conducted an analysis of biopsy specimens of non-episode renal allografts from patients treated with tacrolimus (FK506) or cyclosporine (CsA) to evaluate chronic drug-induced nephropathy in stable allografts. A total of 38 biopsy specimens from stable functioning renal allografts were examined. The patients had been treated with FK506 (n = 16) or CsA (n = 18) as main immunosuppressant for 0.3 to 7.4 years. Of the 38 biopsy specimens, 15 showed mild drug-induced arteriolopathy (hyalinosis or insudative change of arterioles and small arteries) with striped-form interstitial fibrosis, 10 showed minimum interstitial cellular infiltration (borderline rejection), 2 showed IgA nephropathy, 4 showed evidence of chronic rejection (transplant nephropathy) and 12 showed no abnormal findings. Of 34 renal allograft biopsy specimens with stable function, 22 (65%) showed pathological evidence of drug-induced nephropathy. There were no significant qualitative or quantitative differences between FK506- and CsA-associated nephropathy.