Periventricular white matter hyperintensity burden and cognitive impairment in early Parkinson's disease.

BACKGROUND AND PURPOSE: This study quantified the total brain and periventricular white matter hyperintensity (WMH) burdens in patients with early Parkinson's disease (PD) and explored their associations with cardiovascular risk factors and cognitive performance. METHODS: A total of 175 non-demented patients with early PD who had undergone baseline brain magnetic resonance imaging were included. Comprehensive neurocognitive testing was conducted to identify PD with mild cognitive impairment (PD-MCI) and to evaluate performances in individual cognitive domains. Cardiovascular risk was expressed as a modified Framingham 10-year cardiovascular risk score (mFRS). RESULTS: A total of 53.7% of this early PD cohort fulfilled the diagnostic criteria for PD-MCI. An increase in mFRS was significantly associated with increases in the total brain WMH (P = 0.015) and periventricular WMH (P = 0.040) burden, independent of age and gender. The periventricular WMH burden was significantly associated with PD-MCI (P = 0.046) in early PD, independent of cardiovascular risk factors. Patients in the 5th quintile of periventricular WMH burden were 8.6 times more likely to have PD-MCI compared with patients in the 1st quintile of periventricular WMH burden (P = 0.004). However, total brain WMH burden was not associated with PD-MCI (P = 0.158). In individual cognitive domains, heavier periventricular WMH burden was associated with worse executive function and visuospatial function independent of cardiovascular risk factors. CONCLUSION: Periventricular WMHs are a useful imaging biomarker for cognitive impairment in early PD. Cardiovascular risk factors, although associated with periventricular WMHs, were unable to fully explain the association between periventricular WMHs and cognitive impairment in early PD.

Mood and neural correlates of excessive daytime sleepiness in Parkinson's disease.

For patients with Parkinson's disease (PD), excessive daytime sleepiness (PD-EDS) is a debilitating non-motor symptom and may be affected by mood symptoms, especially depression and anxiety. Few neuroimaging works have attempted to identify the neural features of PD-EDS, but various findings were reported. The purpose of this study was to systematically review the literature on mood and neuroimaging correlates of PD-EDS. A MEDLINE, PubMed, EMBASE, and PsycInfo search for peer-reviewed original research articles on depression, anxiety, and neuroimaging in PD-EDS identified 26 studies on depression, nine on anxiety, and eight on neuroimaging. Half of the studies reported greater depression in PD-EDS-positive patients compared with PD-EDS-negative patients. There was a significantly positive correlation between depression and PD-EDS. Limited studies on anxiety in PD-EDS suggested a weak correlation between anxiety and EDS. For depression and anxiety, the effect sizes were medium when EDS was subjectively measured, but became small when EDS was objective measured. Current neuroimaging studies generally suggested diminished neural structural and functional features (eg, brain volume, white matter integrity as indicated by fractional anisotropy, and cerebral metabolism) in patients with PD-EDS. Future studies should apply objective and subjective measures of mood symptoms and EDS and improve the neuroimaging methodology via using multimodal techniques and whole-brain analysis to provide new clues on the mood and neural correlates of PD-EDS.

Progression of subcortical atrophy in mild Parkinson's disease and its impact on cognition.

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) is associated with pronounced grey matter atrophy in various brain regions. However, the association between atrophy patterns and progression from no cognitive impairment (NCI) to Parkinson's disease (PD)-MCI is not clearly known. We investigated the pattern and progression of atrophy in subcortical structures and its impact on cognition in patients with mild PD. METHODS: Sixty-five patients with mild PD with baseline and longitudinal clinical and neuropsychological assessments, and structural magnetic resonance imaging scans were studied. Movement Disorder Society Task Force criteria were used to classify patients with PD into PD-NCI (n = 54) and PD-MCI (n = 11). Based on progression over time, those who remained without cognitive impairment were classified as PD-stable (n = 42) and those who converted to MCI over 18 months were classified as PD-converters (n = 12). FreeSurfer was used to measure cortical thickness and subcortical volumes at baseline and follow-up. RESULTS: Parkinson's disease-MCI showed baseline thalamus atrophy and progressive atrophy in the thalamus, caudate, presubiculum, cornu ammonis 1 and 2-3, and significant memory and executive dysfunction compared with PD-NCI. PD-converters had greater accumbens atrophy at baseline and progressive atrophy in the thalamus, caudate and accumbens with dysfunctions in memory and executive domains. CONCLUSIONS: Progression of cognitive impairment in non-demented PD is associated with a specific pattern of subcortical atrophy. Findings from this study will allow future studies to investigate in the role of subcortical structures as a biomarker for PD dementia.

Depression, anxiety, and apathy in Parkinson's disease: insights from neuroimaging studies.

Depression, anxiety and apathy are common mood disturbances in Parkinson's disease (PD) but their pathophysiology is unclear. Advanced neuroimaging has been increasingly used to unravel neural substrates linked to these disturbances. A systematic review is provided of neuroimaging findings in depression, anxiety and apathy in PD. A PubMed, MEDLINE and EMBASE search of peer-reviewed original research articles on these mood disturbances in PD identified 38 studies on depression, eight on anxiety and 14 on apathy in PD. Most of the imaging studies used either position emission tomography or single-photon emission computed tomography techniques. These studies generally suggest increased neural activity in the prefrontal regions and decreased functional connectivity between the prefrontal-limbic networks in depressed patients. Functional imaging studies revealed an inverse correlation between dopaminergic density in the caudate and putamen with the severity of anxiety in PD. There was no consistent correlation between dopaminergic density of thalamus and anxiety. Studies demonstrated both positive and inverse correlations between apathy and metabolism or activity in the striatum, amygdalar, prefrontal, temporal and parietal regions. The clinical variability of study subjects and differences in image pre-processing and analytical strategies may contribute to discrepant findings in these studies. Both nigrostriatal and extra-nigrostriatal pathways (in particular the frontal region and its connecting areas) are affected in mood disorders in PD. Identifying the relative contributions of these neural pathways in PD patients with overlapping motor and mood symptoms could provide new pathophysiological clues for the development of better therapeutic targets for affected patients.

Association between white matter hyperintensity and medial temporal atrophy at various stages of Alzheimer's disease.

BACKGROUND AND PURPOSE: Whilst there is evidence implicating small vessel cerebrovascular disease in the pathogenesis of Alzheimer's disease (AD), its specific contribution to the pathophysiology of AD remains unclear. The burden of small vessel cerebrovascular disease visualized as white matter hyperintensity (WMH) and its association with medial temporal atrophy (MTA) at different stages of AD was studied. METHODS: One hundred and sixty-five cognitively normal (CN) community controls, 103 mild cognitive impairment (MCI) patients, 141 mild AD patients and 68 moderate-severe AD patients were studied. Clinical, cognitive and risk factor data were collected, and WMH and MTA were quantified by trained raters. The Jonckheere-Terpstra test for ordered alternatives was used to study the association between WMH and MTA in different stages of AD. RESULTS: The burden of total WMH increased significantly with increasing severity of AD, even after correcting for confounders. The proportion of CN, MCI, mild AD and moderate-severe AD subjects with severe burden of WMH was 6.7%, 9.7%, 28.4%, and 39.7%, respectively. A strong positive association between WMH severity and MTA was evident amongst MCI (P = 0.011) and mild AD (P = 0.003) subjects, but not in CN (P = 0.953) and moderate-severe AD subjects (P = 0.301). CONCLUSIONS: The burden of WMH increased significantly from the stage of CN to MCI to AD. The association between WMH and MTA was greatest at the stage of MCI and mild AD. This has implications on the strategy to slow the progression of AD, where measures to reduce WMH, including control of vascular risk factors, need to be optimized at the stage of MCI and mild AD.

Serum adipokine levels in renal transplant recipients.

BACKGROUND: Metabolic syndrome (MS) is a common complication in renal transplant (RTx) recipients. This study aimed to explore the alterations and interrelationship of various adipokines in RTx recipients with and without MS. METHODS: RTx recipients followed at our hospital were randomly selected for the cross-sectional study of MS. The modified Adult Treatment Panel III criteria adopted for Asian populations were used to define MS. Overnight fasting blood samples were obtained for determination of adipokines, including adiponectin, leptin, resistin, and visfatin. Univariate and multivariate logistic regressions were performed to determine parameters that were associated with serum adipokine levels. Pearson correlation analysis was performed between adipokines. RESULTS: A total of 280 RTx recipients were enrolled for the study. Seventy-three cases (26.1%) fulfilled the criteria of MS. A significantly higher serum leptin level was found in MS patients (16.61 ± 13.90 vs 8.00 ± 7.42 µg/mL; P < .0001). There was no significant difference in serum levels of adiponectin, resistin, and visfatin between the 2 groups. Serum adiponectin level was positively correlated with serum resistin (r = 0.422; P < .0001) and visfatin levels (r = 0.224; P < .0001). Serum resistin level was positively correlated with serum visfatin level. All but serum visfatin level were negatively correlated with estimated glomerular filtration rate. Univariate logistic regression revealed the following variables to be associated with serum leptin level: metabolic syndrome, sex, body weight, waist circumference, body mass index (BMI), hypertension, serum creatinine, fasting blood sugar, HbA1c, serum triglyceride, and uric acid. Multivariate analysis revealed that sex, body weight, BMI, and serum creatinine were associated with serum leptin level. CONCLUSIONS: Compared with RTx recipients without MS, patients with MS were associated with significantly higher serum leptin levels and similar adiponectin, resistin, and visfatin levels. A close interrelationship was also found in the serum levels of these adipokines.

Changing pattern of mortality in renal transplant recipients: a single-center, 30-year experience.

INTRODUCTION: Patient survival among kidney transplant (KTx) recipients has improved remarkably in the past decades. The most common causes of death are cardiovascular disease in the West; in Taiwan, the answer remains uncertain. METHODS: From 1983 to 2012, KTx patients who underwent transplantation and were followed at our hospital were recruited for the study. For comparison, patients were stratified according to the transplant time as group 1, 1983-1989 (the initial era); group 2, 1990-1998 (the cyclosporine era); and group 3, 1999-2012 (the modern era, in which tacrolimus and mycophenolate mofetil were available). RESULTS: A total of 520 KTx patients (male:female ratio of 285:235) were performed in our hospital during the study period. A progressive improvement in patient survival rates (P < .0001) was noted among the 3 groups. At a mean follow-up duration of 9.55 ± 8.20 years, 83 recipients had died. Overall, the most common cause of death was infection (44.6%), followed by cardiovascular disease (21.7%), malignancy (12.0%), and hepatic failure (10.8%). Infection was the main cause of death in groups 1 and 2 (44.1% and 52.6%, respectively) but not in Group 3 (18.2%), although this trend did not reach statistical significance. Death owing to cardiovascular diseases became the most common cause of death (27.3%) in the modern era (group 3). CONCLUSION: The pattern of mortality among Taiwanese KTx patients has changed over the past 30 years. Infection is no longer the commonest cause of death.

Short-term prospective study of metabolic syndrome in renal transplant recipients.

BACKGROUND: Metabolic syndrome (MS) may affect patient and graft survival in renal transplant recipients. However, the evolution of MS during prospective follow-up remains uncertain. METHODS: Renal transplant patients were recruited for a study of MS in 2010 and then prospectively followed for 2 years. The modified Adult Treatment Panel III criteria adopted for Asian populations were used to define MS. RESULTS: A total of 302 cases (male:female = 154:148) with a mean duration of 10.5 ± 5.7 years after transplantation were enrolled. At initiation, 71 cases (23.5%) fulfilled the criteria of MS. At the end of follow-up, 11 cases had died and 21 had graft failure. Nine cases had insufficient data for reclassification. The remaining 261 cases completed a 2-year follow-up, and the prevalence of MS was 26.1% at the end of study. Of these, 7.79% (18 cases) of patients without MS had developed new-onset MS. Conversely, 16.9% (12 cases) with MS were free from MS at the end of study (P = .362). Patients with MS were associated with older age (57.1 ± 10.4 vs 52.6 ± 12.4 y; P = .006), more chronic allograft nephropathy (17.4% vs 7.1%; P = .01), proteinuria (22.5% vs 10.8%; P = .012), and use of more antihypertensive agents (1.49 ± 0.86 vs 0.80 ± 0.98; P < .0001). There was no significant change in serum creatinine in each subgroup. CONCLUSIONS: The status of MS in renal transplant patients is dynamic. MS patients were associated with more chronic allograft nephropathy and proteinuria.

Comparison of tuberculosis infection rates in a national database of renal transplant patients with data from a single center in Taiwan.

Successful renal transplantation (RT) improves quality of life and patient survival. Advances in immunosuppressants for RT have improved the prevention and treatment of acute rejection as well as reduced the risk of chronic graft damage, but immunodeficiency may render patients vulnerable to opportunistic infections. We conducted this study to compare the difference in tuberculosis (TB) infection rates between a single institution and a national database of RT recipients in Taiwan. There were 153 patients with TB (3.2%) among 4,835 RT recipients in the database during the period 2000-2009, with a higher prevalence of men (P = .018) and diabetes patients (P = .029). In our institution's registry, 33 patients (2.7%) developed 35 episodes of TB infection among 1,209 RT recipients, but there were no significant differences in general characteristics among different subgroups. Interestingly, the use of cyclosporine was significantly more frequent in RT recipients with TB than in those without in both the national database and in our institution. In contrast, TB infection was negatively correlated with the use of tacrolimus (TAC) and mycophenolate (MPA). RT recipients with TB infection had poor survival (P = .0013) and low graft survival (P = .0003). Taken together, analyses of the national database and the RT patients in our institution revealed that the use of long-term cyclosporine-based immunosuppressive agents was associated with a greater risk of developing post-transplantation TB compared with that of other immunosuppressive agents, but the chronicity and accumulation effect of TAC and MPA should be observed despite the negative correlation found herein. In conclusion, post-transplantation TB is a serious health threat and one of the major causes of death among RT recipients, and a high index of suspicion to ensure early diagnosis and prompt initiation of treatment for TB is crucial. The use of optimal immunosuppressive agents to minimize acute rejection, monitoring of high-risk recipients, prompt diagnosis, and appropriate treatment are required to manage TB infection in endemic areas such as Taiwan.

The potential role of Th17 cells and Th17-related cytokines in the pathogenesis of lupus nephritis.

T helper type 17 (Th17) cells, a novel distinct subset of Th cell, can secrete interleukin (IL)-17 in humans. Although recent data suggest that Th17 cells and IL-17 play an important role in the pathogenesis of lupus nephritis (LN), the expression of Th17-related cytokines in the kidneys of SLE patients has not been studied in detail. In the present study, we investigated circulating Th17-cell frequencies using flow cytometry and serum Th17-related cytokine levels by enzyme-linked immunosorbent assay (ELISA) in 24 LN patients (17 patients with class IV and seven patients with class V) and 12 healthy controls. We also investigated glomerular Th17-related cytokine expression in LN patients and minimal change nephropathy (MCN) patients using immunohistochemistry. Our results showed significantly higher median frequencies of circulating Th17 cells in LN patients (0.68%) than in healthy controls (0.12%, p < 0.001). Serum levels of IL-17, IL-6 and IL-23 were significantly higher in LN patients (median 7.26, 232.60 and 37.01 pg/ml, respectively) than in healthy controls (median 0.82, 34.60 and 7.42 pg/ml, respectively; all p < 0.001). Circulating Th17-cell frequencies were positively correlated with SLEDAI, renal SLEDAI and histological activity index, the degree of cellular crescent and endocapillary proliferation. Significantly higher levels of glomerular IL-17 and IL-23 expression were observed in renal biopsies from class IV LN patients as compared to those from MCN patients and normal controls. Glomerular IL-17 and IL-23 expression levels were positively correlated with renal SLEDAI and histological activity index for LN patients. Our results suggest the potential role of the IL-23/Th17 axis in the intra-renal inflammation of SLE.

Long-term outcomes of living kidney donors over the past 28 years in a single center in Taiwan.

BACKGROUND: The chronic shortage of kidneys for transplantation has increased the number of living donations, but demand remains high, which has created a long waiting list of end-stage kidney disease patients. Donors with decreased renal mass may suffer a higher risk of developing proteinuria, hypertension (HTN), and chronic renal disease (CKD) during long-term follow-up. METHODS: We retrospectively retrieved medical data of living kidney donors at our hospital over the past 28 years. RESULTS: There were 45 male and 60 female donors with a mean donation age of 46.34 ± 12.47 years (range = 20-70y). The mean follow-up duration was 4.67 ± 4.78 years. The serum creatinine (Cr) at donation was 0.93 ± 0.22 mg/dL, while the latest Cr was 1.26 ± 0.45 mg/dL (P < .001). The mean age at follow-up was 50.95 ± 14.57 years. At last follow-up, eight subjects (7.6%) displayed HTN requiring treatment, 10 (9.5%), proteinuria and 55.4%, an estimated glomerular filtration rate (eGFR) of less than 60 mL/min, including one with diabetic nephropathy at 10 years after donation who required long-term hemodialysis. Although gender did not correlate with occurrence of HTN, proteinuria, and CKD, the occurrence of CKD was associated with age at donation (P < .001, odds ratio [OR] = 1.076), and age at follow-up (P < .001, OR = 1.071). HTN donors were older (P = .036, OR = 1.057) with longer follow-up durations (P = .007, OR = 1.166) and had higher Cr values at donation (P = .044, OR = 94.4). Donors with proteinuria were not related to gender, follow-up duration, initial Cr, warm ischemic time, or duration of admission. eGFR was indeed worse after donation (P = .002). CONCLUSIONS: Our results indicated a significant proportion of living donors may develop CKD upon long-term follow-up. The factors affecting donor risk of CKD were baseline renal function, older age, and duration after kidney donation.

Follow-up and treatment of renal transplantation with nephropathic cystinosis in central Taiwan.

BACKGROUND: Cystinosis is a rare autosomal recessive disease caused by a defect in lysosomal cystine. The intracellular cystine accumulation causes damage in multiple organs and renal failure. We retrospectively evaluated the outcomes and complications of patients with nephropathic cystinosis after renal transplantation (RT) in Taiwan. METHODS: Only 2 nephropathic cystinosis patients (siblings) had RT out of the 1,196 RTs in our hospital over the past 30 years. The younger sister received a living-related RT from her mother. The elder sister received a second cadaveric RT owing to chronic allograft rejection one-half year before. RESULTS: They were diagnosed with cystinosis at ages 5 and 9 years, and received allografts at ages 13.4 (younger) and 19.8 and 26.4 (elder) years. They each experienced 1 episode of acute rejection at 6 months after the first RT. The elder sister suffered from obstructive nephropathy with progressive graft failure at age 26.4 years and was treated for vulvar condyloma and carcinoma in situ of cervix. The second graft kidney then maintained good kidney function. The younger sister delivered a girl without complication during gestation, and her renal function also remained good. At latest follow-up, they both had crystalline keratopathy and nephropathy, but no other system involvement. CONCLUSIONS: The extrarenal complications with nephropathic cystinosis are high. These 2 siblings had only have ocular involvement without further cysteamine therapy. However, long-term follow-up is required to monitor development of complications and determine their prognoses.

Antinucleosome antibodies as a potential biomarker for the evaluation of renal pathological activity in patients with proliferative lupus nephritis.

The objective of this study is to evaluate the correlation between antinucleosome antibodies and renal pathological activity in patients with proliferative lupus nephritis (LN). We evaluated 36 patients with proliferative LN, 14 non-renal lupus patients and 10 healthy volunteers. Lupus activity was assessed using the British Isles Lupus Assessment Group 2004 (BILAG 2004) index, serum anti-double stranded DNA (anti-dsDNA) levels, serum complement levels and daily urinary protein levels. All 36 lupus nephritis patients received renal biopsy. Antinucleosome antibodies were detected by enzyme-linked immunosorbent assay (ELISA). Our results showed that levels of serum antinucleosome antibodies were significantly higher in LN patients (median 90.35 units/ml, interquartile range [IQR] 37.38-135.23) than in non-renal SLE patients (median 5.45 units/ml, IQR 2.6-28.93, p <0.05) and in healthy volunteers (median 3.35 units/ml, IQR 2.95-5.23, p <0.001). Serum levels of antinucleosome antibodies were positively correlated with BILAG index (Spearman's r = 0.645, p <0.001) and serum anti-dsDNA antibody levels (r(s) = 0.644, p <0.01), while serum levels of antinucleosome antibodies were negatively correlated with serum levels of C3 (r(s) = -0.400, p <0.01) and C4 (r(s) = -0.300, p <0.05). Serum levels of antinucleosome antibodies were positively correlated with the histological activity index of LN (r(s) = 0.368, p <0.05). However, there was no significant correlation between serum levels of antinucleosome antibodies and the histological chronicity index. In conclusion, the serum level of antinucleosome antibodies is a potential biomarker for early recognition of renal involvement and evaluation of disease activity in SLE. Our preliminary results suggested that serum levels of antinucleosome antibodies might be a potential biomarker in evaluating pathological activity of LN.

Malignant lymphoma of the kidney mimicking rapid progressive glomerulonephritis.

Primary renal lymphoma (PRL) is rare and often presents as rapidly progressive renal failure. Most cases of PRL are large-cell lymphomas of B-cell lineage. Herein, we report a 75-year-old female patient with infiltrative CD20 (+) B-cell lymphoma who underwent 4 consecutive courses of chemotherapy with R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone) and after 12 sessions became free from hemodialysis in good general condition. Her serum creatinine level gradually decreased to 4.1 mg/dl with adequate urine output. Unfortunately, a relapse of CD20 (-) lymphoma developed rapidly involving other organs. She died with severe hospital-acquired pneumonia and febrile neutropenia after the last chemotherapy with R-MINE almost 1 year after onset of symptoms. We conclude that renal biopsy enables prompt diagnosis in rapidly progressive renal failure and immunophenotyping and also staging workup of the lymphoma in case of positive biopsy. Though rituximab improved response rate of PRL, it reduced expression of CD20. This may relate to frequent relapse/resistance after rituximab therapy and poor long-term patient survival.

High incidence of malignancy in polyomavirus-associated nephropathy in renal transplant recipients.

Human polyomaviruses (PV), including JC and BK virus, have been reported to cause polyomavirus-associated nephropathy (PVAN), in renal transplant patients. PV infection has been demonstrated to be associated with malignancies in animals; however, the association between malignancy and viral infections in humans is not clear. We retrospectively reviewed our 864 (M:F=502:362) kidney transplant patients over the past 25 years. We identified PVAN in 6 patients (0.69%), including BK nephropathy (n=5) and JC nephropathy (n=1). Three patients (50%) improved after reducing the immunosuppression, but 3 (50%) progressed to graft loss despite this reduction. Malignancy occurred in 5 out of the 6 patients (83%; P<.0001 compared with patients without PVAN), including transitional cell carcinoma (n=2), renal cell carcinoma (n=1), squamous cell carcinoma of skin (n=1) and Kaposi sarcoma (n=1). We concluded that kidney transplant patients with PVAN are at a significantly greater risk to develop malignancy. Whether this is due to a direct effect of PV infection or the result of overimmunosuppression remains to be determined in a future study.

Rapamycin attenuates unilateral ureteral obstruction-induced renal fibrosis.

Unilateral ureteral obstruction (UUO) is a well-characterized hydronephrosis model exhibiting interstitial inflammatory-cell infiltration and tubular dilatation followed by tubulointerstitial fibrosis of the obstructed kidney. Our recent report indicates that rapamycin is effective for 50% of transplant recipients with chronic allograft nephropathy. In this study, we investigate the effect of rapamycin on UUO-induced renal fibrosis. UUO or sham-operated rats were randomly assigned to rapamycin or vehicle and were killed on days 7 and 14 after UUO or sham operation. Rapamycin decreased cross-sectional and gross-morphology changes in the obstructed kidney significantly. Rapamycin markedly blunted the increase in weight of the obstructed kidney, obstructed kidney length, and the obstructed/non-obstructed kidney weight ratio (by 74.6, 42.8, and 61.6% on day 14, respectively, all P<0.01). The scores for tubular dilatation, interstitial volume, interstitial collagen deposition, and alpha-smooth muscle actin (alpha-SMA) after UUO were significantly reduced by rapamycin. Rapamycin also decreased the number of infiltrative anti-ED1-positive cells and the gene expression of transforming growth factor (TGF)-beta1 (84.8 and 80.2% on day 7) after UUO (both P<0.01). By double immunostaining and Western analysis, rapamycin blocked the TGF-beta1-induced loss of E-cadherin expression and de novo increase of the expression of alpha-SMA in a dose-dependent manner. In conclusion, rapamycin significantly attenuated tubulointerstitial damage in a UUO-induced rat model of renal fibrosis, suggesting that rapamycin may have the potential to delay the progression of tubulointerstitial renal fibrosis.

Acute pancreatitis following antilymphocyte globulin therapy in a renal transplant recipient.

Acute pancreatitis is a rare complication following OKT3 therapy, which to our knowledge has never been reported in patients treated with antilymphocyte globulin (ALG). We herein report a case of a kidney transplantation patient who developed acute pancreatitis 2 days after treatment with ALG for grade IIb acute rejection. The symptoms subsided after discontinuing this drug. Resumption of ALG therapy triggered another episode of acute pancreatitis. Therefore, the clinical course strongly suggests that ALG was the etiological factor of acute pancreatitis in this particular patient.

Differential expression of vascular endothelial growth factor, placenta growth factor and their receptors in placentae from pregnancies complicated by placenta accreta.

Placenta accreta is a pregnancy complication characterized by the presence of life-threatening uteroplacental neovascularization. The factors involving its development are unknown. Vascular endothelial growth factor (VEGF), placenta growth factor (PlGF) and their receptors (VEGFR) have important roles in vascular remodeling. We have investigated the differential expression of these proteins in placentae from placenta accreta (cases) and normal placentation (controls). Immunohistochemically, the expression of VEGFR-2 in the syncytiotrophoblast was significantly lower in cases than in controls during both the second and third trimesters (P = 0.005 and 0.002, respectively). However, VEGFR-2 expression in the cytotrophoblastic and extravillous trophoblastic cells and VEGFR-1, -3 and Ki-67 in the trophoblast populations were not significantly different between controls and cases (P > 0.05). Ki-67 immunostaining also showed that endothelial cells of the larger vessels were stained weaker in normal placenta than in placenta accreta. The majority of VEGFR-2 expression, as demonstrated by Western blot or reverse transcription polymerase chain reaction, was consistent with the immunohistochemical findings in the syncytiotrophoblast. Furthermore, enzyme-linked immunosorbent assay in the placental lysates showed that the women with placenta accreta demonstrated significantly higher VEGF (P = 0.001) and lower soluble VEGFR-2 (P = 0.015) concentrations than did women with normal pregnancy. PlGF and soluble VEGFR-1 levels did not show any significance in study groups (P > 0.05). These observations suggest that the participation of up-regulated VEGF and down-regulated VEGFR-2 (both membrane-bound and soluble forms) may be associated with the development of placenta accreta.

Sirolimus addition is beneficial for renal allograft dysfunction due to simultaneous acute rejection episode and calcineurin inhibitor nephrotoxicity.

We report a diabetic renal transplant recipient who experienced an episode of acute allograft rejection in the 6th month posttransplant when there was an attempt at steroid withdrawal. The acute rejection was steroid resistant. Furthermore calcineurin inhibitor nephrotoxicity was exacerbated by rescue therapy with tacrolimus conversion. The allograft dysfunction ultimately stabilized upon institution of sirolimus and minimization of tacrolimus.

Predominance of Th1 cytokine in peripheral blood and pathological tissues of patients with active untreated adult onset Still's disease.

OBJECTIVE: To determine the type 1 T helper (Th1)/type 2 T helper (Th2) balance in the peripheral blood (PB) and pathological tissues of patients with active untreated adult onset Still's disease (AOSD). METHODS: The percentages of interferon gamma (IFNgamma)- and interleukin (IL)4-producing Th cells in the PB of 20 patients with active untreated AOSD, 20 patients with active rheumatoid arthritis (RA), and 20 healthy controls were determined by intracellular staining and flow cytometry. Serum levels of IL18 and soluble IL2 receptor were measured by enzyme linked immunosorbent assay. Levels of IFNgamma and IL4 messenger (m) RNA expression were examined by real time quantitative polymerase chain reaction in biopsy specimens of evanescent rash and synovitis from 8 patients with AOSD. RESULTS: Significantly higher IFNgamma-producing Th cells and Th1/Th2 ratio in PB were found in patients with AOSD than in healthy controls. Percentages of IFNgamma-producing Th cells and Th1/Th2 ratio in PB correlated significantly with clinical activity score and serum IL18 levels in patients with AOSD. Increased ratio of Th1/Th2 cytokine transcripts was seen in the biopsy specimens of evanescent rash and synovitis from patients with AOSD compared with normal skin controls and patients with OA. Th cell cytokine pattern in PB and cytokine mRNA expression in synovium were similar for patients with AOSD and with RA. After 3 months' treatment, clinical remission was associated with a marked decrease in the percentages of cytokine-producing Th1 cells, but not of the Th2 cells. CONCLUSION: A predominance of Th1 cytokine may precipitate the pathogenesis of AOSD.