Heparin-binding EGF-like growth factor (HB-EGF) antisense oligonucleotide protected against hyperlipidemia-associated atherosclerosis.

BACKGROUND AND AIMS: Heparin-binding EGF-like growth factor (HB-EGF) is a representative EGF family member that interacts with EGFR under diverse stress environment. Previously, we reported that the HB-EGF-targeting using antisense oligonucleotide (ASO) effectively suppressed an aortic aneurysm in the vessel wall and circulatory lipid levels. In this study, we further examined the effects of the HB-EGF ASO administration on the development of hyperlipidemia-associated atherosclerosis using an atherogenic mouse model. METHODS AND RESULTS: The male and female LDLR deficient mice under Western diet containing 21% fat and 0.2% cholesterol content were cotreated with control and HB-EGF ASOs for 12 weeks. We observed that the HB-EGF ASO administration effectively downregulated circulatory VLDL- and LDL-associated lipid levels in circulation; concordantly, the HB-EGF targeting effectively suppressed the development of atherosclerosis in the aorta. An EGFR blocker BIBX1382 administration suppressed the hepatic TG secretion rate, suggesting a positive role of the HB-EGF signaling for the hepatic VLDL production. We newly observed that there was a significant improvement of the insulin sensitivity by the HB-EGF ASO administration in a mouse model under the Western diet as demonstrated by the improvement of the glucose and insulin tolerances. CONCLUSION: The HB-EGF ASO administration effectively downregulated circulatory lipid levels by suppressing hepatic VLDL production rate, which leads to effective protection against atherosclerosis in the vascular wall.

Targeted delivery of antisense oligonucleotides to pancreatic ß-cells.

Antisense oligonucleotide (ASO) silencing of the expression of disease-associated genes is an attractive novel therapeutic approach, but treatments are limited by the ability to deliver ASOs to cells and tissues. Following systemic administration, ASOs preferentially accumulate in liver and kidney. Among the cell types refractory to ASO uptake is the pancreatic insulin-secreting ß-cell. Here, we show that conjugation of ASOs to a ligand of the glucagon-like peptide-1 receptor (GLP1R) can productively deliver ASO cargo to pancreatic ß-cells both in vitro and in vivo. Ligand-conjugated ASOs silenced target genes in pancreatic islets at doses that did not affect target gene expression in liver or other tissues, indicating enhanced tissue and cell type specificity. This finding has potential to broaden the use of ASO technology, opening up novel therapeutic opportunities, and presents an innovative approach for targeted delivery of ASOs to additional cell types.

Protoporphyrin-induced cholestasis in the isolated in situ perfused rat liver.

The pathogenesis of liver disease in protoporphyria has been presumed to result from the hepatic deposition of protoporphyrin. To examine the effects of protoporphyrin on hepatic bile flow and histopathology, studies were performed employing an isolated, in situ, rat liver perfusion system. Rat livers in the control group were perfused with 0-80 mumol sodium taurocholate/h. Rat livers in the experimental group were perfused with sodium taurocholate and (a) sufficient quantities of protoporphyrin to produce maximal canalicular secretion and (b) perfusate protoporphyrin concentrations of 0.01, 0.1, and 1 muM. The administration of protoporphyrin sufficient to achieve maximal canalicular secretion was found to significantly reduce bile flow in rats infused with 0, 40, and 80 mumol sodium taurocholate/h. Linear regression analysis defined the relationship between bile flow and biliary bile acid secretion and showed that the bile acid-independent fraction of bile flow was reduced (P < 0.01). Bile acid-dependent flow was unaffected and there was no significant difference in biliary bile acid secretion rates between control and protoporphyrin-perfused livers. Perfusion of rat livers with varying concentrations of protoporphyrin demonstrated the reduction of bile flow was dose-related. Analysis of perfusate enzyme activity did not reveal abnormalities that could account for the cholestasis. Studies to evaluate the effect of protoporphyrin on regional hepatic hemodynamics were inconclusive. Histopathological studies of control and protoporphyrin-perfused rat livers did not show abnormalities on light microscopy. However, canalicular dilatation, distortion, and loss of microvilli were present in the protoporphyrin-perfused livers examined by transmission electron microscopy. Although ultraviolet microscopy showed diffuse fluorescence of the hepatocytes and canaliculi of protoporphyrin-perfused livers, the deposition of protoporphyrin in amorphous or crystalline forms was notably absent in studies with polarizing and transmission electron microscopy. These studies provide evidence that protoporphyrin has hepatotoxic properties that affect the canalicular secretory apparatus. The mechanism(s) responsible for the injury require further clarification.

ACAT1 and ACAT2 membrane topology segregates a serine residue essential for activity to opposite sides of the endoplasmic reticulum membrane.

A second form of the enzyme acyl-CoA:cholesterol acyltransferase, ACAT2, has been identified. To explore the hypothesis that the two ACAT enzymes have separate functions, the membrane topologies of ACAT1 and ACAT2 were examined. A glycosylation reporter and FLAG epitope tag sequence was appended to a series of ACAT cDNAs truncated after each predicted transmembrane domain. Fusion constructs were assembled into microsomal membranes, in vitro, and topologies were determined based on glycosylation site use and accessibility to exogenous protease. The accessibility of the C-terminal FLAG epitope in constructs was determined by immunofluorescence microscopy of permeabilized transfected cells. Both ACAT1 and ACAT2 span the membrane five times with their N termini in the cytosol and C termini in the ER lumen. The fourth transmembrane domain is located in a different region for each protein, placing the putative active site ACAT1 serine (Ser(269)) in the cytosol and the analogous residue in ACAT2 (Ser(249)) in the ER lumen. Mutation of these serines inactivated the ACAT enzymes. The outcome is consistent with the hypothesis that cholesterol ester formation by ACAT2 may be coupled to lipoprotein particle assembly and secretion, whereas ACAT1 may function primarily to maintain the balance of free and esterified cholesterol intracellularly.

Referrals for movement disorder surgery: under-representation of females and reasons for refusal.

OBJECTIVE: Referral of movement disorder patients for deep brain stimulation surgery was examined to determine whether referred patients were representative of gender proportions in our population, and reasons why patients do not proceed to surgery. METHODS: Demographic information on referrals to the surgical program was retrospectively reviewed from our database and from a detailed chart review. RESULTS: Although almost equal numbers of movement disorder patients are male and female, of the 91 patients referred for surgery, only 31% were female. Sixty-one percent of referred patients did not undergo surgery. Of these, the majority were denied for medical reasons, including cognitive decline (21%), psychiatric concerns (5%) and neurological reasons (42%). CONCLUSIONS: Almost one-third of patients referred for movement disorder surgery were denied for medical reasons. This underscores the importance of evaluation of all potential patients by a multidisiplinary team to fully assess suitablity for stereotactic surgery. Interestingly, women were under-represented in those referred. In order that all appropriate patients have the opportunity to consider surgery, education of both physicians and patients, and different strategies to approach females regarding surgery may allow more patients to benefit from this treatment.

Lack of elevation of platelet factor IV in plasma from patients with myocardial infarction.

Platelet factor IV and beta-thromboglobulin are protein constituents of platelet granules. Elevated levels of these proteins in plasma have been used as sensitive indicators of platelet degranulation. Clearance of platelet factor IV is much faster than that of beta-thromboglobulin after release of the proteins in vivo. Although increases of platelet factor IV have been observed in patients with infarction, the implication that they reflect pathogenetic phenomena such as coronary thrombosis has not been assessed explicitly. Accordingly, plasma samples obtained serially from 52 patients with acute myocardial infarction under rigorous conditions verified to minimize platelet degranulation in vitro were evaluated prospectively. Correlative studies were performed to detect left ventricular mural thrombus, and coronary thrombosis was assessed independently in selected patients with indium-111 platelet scintigraphy. Platelet factor IV was normal at the time of admission in patients with infarction, averaging 6.3 +/- 3.3 ng/ml, similar to values in 44 other patients with chest pain without subsequent infarction (5.7 +/- 2.7 ng/ml) and in 25 normal subjects (4.3 +/- 1.6 ng/ml). Platelet factor IV generally did not increase during hospitalization in patients with infarction despite recurrent chest pain, development of left ventricular thrombus or documented recurrent infarction. However, platelet factor IV increased consistently after invasive procedures, accounting for 104 of the total of 110 increases due to platelet activation in vivo as reflected by persistence of elevated levels of beta-thromboglobulin. Thus, platelet factor IV values generally remain normal despite acute myocardial infarction. Rare increases that occur reflect platelet degranulation in vitro due to sampling artifact or perturbations of platelets in vivo due to invasive procedures.(ABSTRACT TRUNCATED AT 250 WORDS)

Polychlorinated naphthalenes in air and snow in the Norwegian Arctic: a local source or an Eastern Arctic phenomenon?

PCNs were measured in air and snow during separate field campaigns at Ny-Alesund (April 2001) and Tromsø (February/March 2003) in the Norwegian Arctic. Air concentrations ranged from 27 to 48 and 9 to 47 pg sigmaPCN m(-3) for Ny-Alesund (n=6) and Tromsø (n=10), respectively. These concentrations (including the tri-chlorinated naphthalenes) greatly exceeded concentrations previously measured in the Canadian Arctic, but did fall within the upper range of concentrations observed over the eastern Arctic Ocean and regional seas. Local sources appear to be affecting concentrations observed at both sites, with the presence of several hexa-chlorinated naphthalenes at Tromsø probably attributed to local/regional sources. Use of air mass back trajectories at Tromsø revealed that background air concentrations in the Norwegian Arctic are likely to range between <9 and 20 pg sigmaPCN m(-3) and that contemporary concentrations derived close to potential sources (i.e. arctic towns) may equal or exceed those of PCBs. The mean concentration in surface snow was 350 and 240 pg sigmaPCN L(-1) (meltwater) (or 0.014 and 0.01 pg g(-1) (snow)) at Ny-Alesund and Tromsø, respectively. The wide variation in concentrations observed between fresh snowfalls could be explained by different snow densities (as a surrogate of snow surface area), rather than attributed to varying air concentrations. A statistically significant inverse relationship was found between snow density and concentrations of tri- to penta-chlorinated homologues and compliments similar findings for the polychlorinated biphenyls (PCBs). This suggests that the vapour-sorbed quantity changes rapidly with snow ageing/compaction; with implications for the fate of these chemicals in the Arctic.

Dorsal column stimulation. Its effect on the somatosensory evoked response.

Several authors have shown that dorsal column stimulation (DCS) modifies appreciation of pain. We studied the effects of DCS on the somatosensory evoked response (SER) in six subjects. Somatosensory evoked responses to stimulation of the tibial nerve and effects of varying frequencies and intensities of DCS on SER components were recorded. During DCS there was attenuation of late SER components with little effect on early components. Stimulus intensities greater than necessary to relieve pain suppressed all SER components. Our findings suggest that the minimal effective DCS variables to relieve pain are those that produce selective suppression of late SER components.

Cerebral perfusion imaging with iodine 123-labeled amines.

Two amines, N-isopropyl p-iodoamphetamine and N,N,N'-trimethyl-N'-[2-hydroxyl-3-methyl-5-iodobenzyl]-1,3-prop anediamine, have been labeled with iodine 123. The brain uptake of these radioactive tracers is proportional to cerebral blood flow. These tracers are retained in the brain for a sufficiently long time so that imaging can be performed with standard, readily available instrumentation. Transaxial tomography with amines is useful in acute cerebral infarction, in which the x-ray computed tomographic scan may be normal for several days after onset of symptoms while the uptake of radioisotope-labeled amines will be altered immediately after the onset of the stroke. It is also useful in examining patients with cerebral vascular disease and in the preoperative examination of patients with partial epilepsy.

Parkinson's disease: a test of the multifactorial etiologic hypothesis.

We studied the relative etiologic importance upon the development of Parkinson's disease (PD) of occupational exposure to herbicides and other compounds, ionizing radiation exposure, family history of PD and essential tremor, smoking, and history of various viral and other medical conditions. We identified patients (n = 130) with neurologist-confirmed idiopathic PD through contacts with Calgary general hospitals, long-term care facilities, neurologists, the Movement Disorder Clinic, and the Parkinson's Society of Southern Alberta, and selected two matched (by sex and age +/- 2.5 years) community controls for each case by random digit dialing. We obtained lifetime work, chemical, radiation, medical, and smoking exposure histories and family histories of PD and essential tremor by personal interviews, and analyzed the data using conditional logistic regression for matched sets. After controlling for potential confounding and interaction between the exposure variables, using multivariate statistical methods, having a family history of PD was the strongest predictor of PD risk, followed by head trauma and then occupational herbicide use. Cases and controls did not differ in their previous exposures to smoking or ionizing radiation; family history of essential tremor; work-related contact with aluminum, carbon monoxide, cyanide, manganese, mercury, or mineral oils; or history of arteriosclerosis, chicken pox, encephalitis, hypertension, hypotension, measles, mumps, rubella, or Spanish flu. These results support the hypothesis of a multifactorial etiology for PD, probably involving genetic, environmental, trauma, and possibly other factors.

Parkinson's disease and exposure to agricultural work and pesticide chemicals.

This population-based case-control study of 130 Calgary residents with neurologist-confirmed idiopathic Parkinson's disease (PD) and 260 randomly selected age- and sex-matched community controls attempted to determine whether agricultural work or the occupational use of pesticide chemicals is associated with an increased risk for PD. We obtained by personal interviews lifetime occupational histories, including chemical exposure data, and analyzed the data using conditional logistic regression for matched sets. In the univariate analysis, a history of field crop farming, grain farming, herbicide use, or insecticide use resulted in a significantly increased crude estimate of the PD risk, and the data suggested a dose-response relation between the PD risk and the cumulative lifetime exposure to field crop farming and to grain farming. However, in the multivariate analysis, which controlled for potential confounding or interaction between the exposure variables, previous occupational herbicide use was consistently the only significant predictor of PD risk. These results support the hypothesis that the occupational use of herbicides is associated with an increased risk for PD.

The colitis of Behçet's syndrome.

A 29-year-old woman with Behçet's syndrome developed a severe colitis that ultimately required colectomy. The colectomy specimen showed extensive mucosal ulceration with varying longitudinal, fissuring, and aphthoid configurations, usually occurring within a background of normal or focally inflamed mucosa, and associated with a lymphocytic vasculitis involving submucosal veins. A review of the literature reveals 29 additional cases of colitis complicating Behçet's syndrome. The colitis is characterized by multiple ulcers of diverse size, appearance, and depth of penetration involving any portion of the large bowel, occasionally with coexistent ileal or anal disease. Vasculitis may be the underlying process. Although it resembles other types of colitis, particularly Crohn's colitis, differences in clinical and pathologic features suggest that the colitis of Behçet's syndrome represents a distinct condition.

Dysplasia in Barrett's esophagus. A clinicopathologic study of six patients.

To evaluate the consequences of dysplasia in Barrett's esophagus, six patients with esophageal mucosal biopsies showing dysplastic Barrett's mucosa in the absence of clinically evident esophageal carcinoma were identified and their clinicopathologic features reviewed. The patients, four men and two women, averaged 60 years and had long histories of gastroesophageal reflux. Four patients had high-grade dysplasia; two had low-grade. Dysplastic Barrett's mucosa appeared to arise most commonly from specialized-type Barrett's mucosa. After a mean follow-up of 29 months, four patients, all with high-grade dysplasia, had esophageal resections. Three of the four were found to have invasive adenocarcinoma, which extended through the esophageal wall in two patients. The fourth patient had a noninvasive adenomatous polyp ("Barrett's adenoma"), an infrequently described form of dysplasia in Barrett's esophagus. The two patients with low-grade dysplasia had developed no clinical indications of carcinoma. The results confirm that dysplastic Barrett's mucosa, particularly the high grade, is a morphologic marker for adenocarcinoma. Biopsy surveillance of patients with Barrett's esophagus is histologically feasible, but prospective studies are required to prove its effectiveness.

Marked eosinophilia in esophageal mucosal biopsies.

The significance of marked eosinophilic infiltration in esophageal mucosal biopsy specimens was evaluated in 11 patients. The patients were generally young, with an average age of 14.6 years; all had diffuse intraepithelial eosinophilia in several biopsies. Ten patients (91%) had evidence for reflux esophagitis, which was associated with esophageal stricture in three of the six patients older than 1 year. Marked esophageal eosinophilia might therefore indicate prolonged or severe gastroesophageal reflux. One patient with peripheral eosinophilia, a history of asthma, and concurrent idiopathic eosinophilic gastroenteritis lacked evidence of reflux and represents a case of idiopathic esophagitis. Critical review of the literature establishes three additional cases. Idiopathic eosinophilic esophagitis is an unusual variant of idiopathic, but presumably allergic, eosinophilic infiltration of the gastrointestinal tract.

Hepatic epithelioid hemangioendothelioma: biological questions based on pattern of recurrence in an allograft and tumor immunophenotype.

Epithelioid hemangioendothelioma (EHE) is best considered a vascular neoplasm of intermediate malignancy. Although usually progressive, the clinical course is highly unpredictable. The present communication describes a case of extensive recurrent hepatic EHE, limited to the liver allograft and initially manifest as an insidious seeding of individual tumor cells in areas of perivenular inflammation associated with rejection. A detailed immunophenotypic characterization of this and a small series of EHE was carried out in an effort to highlight subtle disease recurrence and to gain possible insights into tumor biology associated with this intriguing disease. In a series of five cases of hepatic EHE, CD34 (QB-END/10) was found to be more sensitive than Factor VIII (F-VIII) for recognition of the disease, similar to previous reports. The former diffusely and distinctly stained both epithelioid and dendritic tumor cells, whereas staining for the latter was focal, indistinct, and showed a high background. Although the tumor cells were negative for some markers of dendritic or macrophage maturation, such as CD1a, S100 protein, Mac 387, CD68, and LN3, there was marked infiltration of hepatic EHE by factor XIIIa + (F-XIIIa), Mac 387+, CD68+, and LN3+ macrophages and dendrocytes, most of which were interpreted as reactive. The "reactive" macrophage and dendrocyte populations were present throughout the fibrotic stroma and intermingled with the epithelioid clusters of EHE. Interestingly, a small subset of tumor cells coexpressed CD34 or F-VIII and F-XIIIa, the last of which is normally restricted to cells of the monocyte/macrophage lineage and cytokine activated microvascular endothelium in vitro. The known association of F-XIIIa+ dendrocytes with granulation tissue, repair and fibrogenesis, and the modulation of F-XIIIa and F-VIII expression by inflammatory cytokines led us to speculate that EHE lesions may derive from primitive "reticuloenothelial" cells that can differentiate along endothelial and dendritic pathways. The EHE lesions may represent a neoplastic analogue of wound healing. Thus, the variability in F-VIII staining, the strong expression of CD34, the infiltration of EHE lesions with F-XIIIa+ dendrocytes, and the coexpression of CD34 and F-XIIIa on a subset of tumor cells may have an important biological basis.

Chronic liver allograft rejection: a National Institute of Diabetes and Digestive and Kidney Diseases interinstitutional study analyzing the reliability of current criteria and proposal of an expanded definition. National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database.

A study was conducted to assess the inter and intrarater agreement for the histopathologic features and diagnosis of chronic rejection (CR) and several other important causes of late liver allograft dysfunction. On two occasions, five pathologists, experienced with liver transplantation, reviewed a set of 49 slides representing a range of diagnoses, without knowledge of the clinical history or liver injury test results. The readings were correlated with the original histopathologic diagnosis, liver injury tests, and clinicopathologic follow-up. Assessment of biopsy adequacy (kappa = 0.69) and portal tract counts (kappa = 0.79) showed good to excellent intrarater agreement, whereas interrater agreement for these variables was moderate to good, respectively (kappa = 0.44 and 0.65). Likewise, the intrarater agreement for the diagnosis of CR (kappa = 0.68), hepatitis (kappa = 0.77), and obstructive cholangiopathy (kappa = 0.55) showed good to excellent agreement, whereas the interrater agreement for these same diagnoses ranged from fair to good (kappa = 0.58, 0.46, and 0.25, respectively). In 18 specimens, there was a near unanimous diagnosis of CR across both readings. These biopsies were obtained at a median of 7.1 months (range, 42 days to 4.9 years) after transplantation, and the average number of portal tracts was 8.4 (range, 4-15). Interestingly, only 13 of these 18 specimens showed bile duct loss in >50% of the portal triads; the remaining cases showed atrophy/pyknosis of the biliary epithelium in a majority of small bile ducts. Clinicopathologic correlation showed that these 18 biopsies were obtained from 16 grafts from 15 patients, 14 of whom ultimately required retransplantation or died of or with CR, whereas two of the grafts/patients recovered. A high rate of sensitivity (92%) and a somewhat lower, but acceptable, rate of specificity (71% to 80%) was found for the diagnosis of CR. Chronic rejection and other causes of late liver allograft dysfunction can be diagnosed reliably by a group of pathologists experienced with liver transplantation, and the diagnosis of CR correlates with clinical course and liver function abnormalities. Expanded criteria for the diagnosis of CR are presented, and potential problem areas for practicing pathologists are discussed.

Liver preservation for transplant. Evaluation of hepatic energy metabolism by 31P NMR.

31P NMR spectroscopy proved to be an excellent, dynamic, nondestructive method for assessing the liver during cold flush and pulsatile perfusion experiments. 31P NMR spectroscopy was used to measure ATP decay, inorganic phosphate appearance, and phosphate chemical shift in the excised mouse livers subjected to cold and warm ischemia. Cold flush followed by cold preservation in saline, Krebs-Henseleit buffer, or Collins' solution showed that Collins' solution resulted in the slowest ATP decay. In temperature-controlled experiments (5 degrees -37 degrees C), ATP decay was much slower with lower temperature. In separate pulsatile perfusion experiments with oxygenated Krebs-Henseleit buffer, hepatic ATP was unchanged for at least 6 hr at 20 degrees C. At 37 degrees C, the NMR spectrum showed changes in the diphosphoesters region, but the ATP remained stable during the 6-hr perfusion. These studies suggest that for long periods of liver preservation, an adequate perfusion method should be developed.

Mucosal perfusion and reactivity of the rat small intestinal allograft.

During acute rejection (AR), the endothelial targeting seen in the mucosal vessels of the intestinal allograft (IA) could impair the blood supply and response to luminal stimuli. To study the effect of AR in the perfusion and reactivity of the IA mucosa, we measured the mucosal blood flow in the ileum (IL) of 2 groups of control rats (Lewis and ACI) and in the native and grafted IL of syngeneic (ACI to ACI) and allogeneic (donor ACI to recipient Lewis) rats. Using reflectance spectrophotometry and laser-Doppler flowmetry, parameters of mucosal oxygen saturation (ISO2), hemoglobin content (IHB), and blood flow (FLOW) were obtained at baseline and after saline and 50% dextrose (D50) stimulation. When compared to controls, the isograft IL had similar perfusion (ISO2, IHB, and FLOW). The allograft IL showed ischemia (similar ISO2, and lower ISO2 and FLOW). In the allografts, the ISO2 and FLOW were lower than in the isografts. In response to D50, the native IL of all groups showed an increased IHB and FLOW (hyperemia); the isografts showed an increase only in IHB (partial response); the allografts did not show any response at all. In summary, the mucosal perfusion in the rejecting allografts, but not in the isografts, showed ischemia. The response to D50 seen in the native ilea was only partial in the isografts and absent in the allografts. Because these changes occurred before the onset of mucosal ulcerations, we postulate that they could be used as early indicators of AR.

Adenovirus hepatitis in the adult allograft liver.

BACKGROUND: Adenovirus hepatitis in the allograft liver is an uncommon condition hitherto recognized only in pediatric patients. We describe two adult cases. METHODS: Clinical information was obtained by reviewing the medical records. The diagnosis of adenoviral infection was made by immunohistochemistry or culture. RESULTS: Both patients had received recent antirejection treatment and presented with fever, hepatic dysfunction, and progressive leukopenia. One patient had some viral inclusions resembling those described in herpes simplex infections. Adenovirus was cultured from the liver in both cases and from the lung in one case. Both patients were treated by decreasing the immunosuppression and intravenous acyclovir, but died. CONCLUSIONS: Adenovirus infection should be considered when evaluating adult liver transplant patients with necrotizing lesions or microabscess formation at allograft biopsy. A review of the literature shows that most previously reported infections have led to graft loss or death, but occasional remissions of disease are also on record.

Central venulitis in the allograft liver: a clinicopathologic study.

BACKGROUND: Central venulitis denotes a histologic lesion of the allograft liver characterized by perivenular and subendothelial mononuclear inflammation of the terminal hepatic venules associated with varying degrees of perivenular hepatocyte dropout. Although this lesion has generally been considered a manifestation of acute rejection, some have suggested that it instead represents tacrolimus hepatotoxicity. METHODS: We therefore compared the clinicopathologic features of 30 episodes of isolated central venulitis with 22 episodes of combined central venulitis and typical portal acute rejection occurring in 27 patients. Nineteen of the patients received tacrolimus and eight received cyclosporine as primary immunosuppression. RESULTS: No significant differences were found between the two groups, except that isolated central venulitis more often displayed a mild inflammatory component (P=0.007) with small lymphocytes as the predominant cell type (P=0.002). None of the patients had tacrolimus or cyclosporine levels that exceeded the therapeutic range, and none had other clinical evidence of drug toxicity. Usual antirejection therapy was instituted in all but two episodes; response was evident in 93% (28 of 30) of the isolated central venulitis and 86% (19 of 22) of the central venulitis-portal acute rejection group, with histologic regression documented in all follow-up specimens (four and five, respectively). Due to persistent central venulitis, two cyclosporine patients were switched to tacrolimus, with prompt resolution. CONCLUSIONS: These findings are inconsistent with the concept that central venulitis represents drug toxicity and indicate instead that it is a form of acute allograft rejection.