Comparisons of clinicopathological correlations between immediate and slow graft function in renal transplant recipients

Abstract: The functional recovery state of renal transplants can be divided into three types: immediate graft function (IGF), slow graft function (SGF) and delayed graft function (DGF). In contrast to the well-known clinical outcomes for IGF and DGF, the pathological findings and clinical outcomes of SGF are undetermined. This study evaluated possible clinicopathological correlations in 237 patients with SGF compared with patients with IGF. IGF and SGF were defined by serum creatinine levels (IGF < 1.2 mg/day l; SGF: ≥1.2 mg/dL) at day 14 after renal transplantation. Graft biopsy was performed on this day, and pathological classification was performed using the Banff schema. The SGF group of patients ( n  = 121) showed higher rates of cadaver donors and male recipients than the IGF group ( n  = 116), but there were no significant differences in recipient or donor age, numbers of HLA mismatches, types of immunosuppressant or follow-up periods between two groups. The SGF group showed higher serum creatinine levels at discharge, and a higher incidence of acute rejection than the IGF group (24.8% vs. 8.6%, P  < 0.05) and lower graft survival rates (1 year, 93.3% vs. 100%; 5 years, 85.4% vs. 98.6%, respectively; P  < 0.05). The presence of acute rejection in the SGF patients indicated a significantly decreased 5-year survival rate compared with the IGF group. The SGF group of patients with borderline pathology had a higher incidence of acute rejection than the IGF group, and significant increases in the expression of mRNA for pro-apoptotic genes (Fas-ligand, granzyme B and perforin) compared with the IGF group. In conclusion, SGF represents the activated immune state and is associated with poor graft outcome. Anti-rejection treatment or modified immunosuppressive regimen may thus be indicated for patients with SGF.     

Pharmacological preconditioning with low-dose cyclosporine or FK506 reduces subsequent ischemia/reperfusion injury in rat kidney.

BACKGROUND: Ischemia/reperfusion (I/R) injury in the early posttransplant period is closely associated with delayed recovery of graft function, increased acute rejection, and late allograft dysfunction. Pharmacological preconditioning with low-dose cyclosporine (CsA) or FK506 was performed to induce ischemic tolerance in rat kidney with I/R injury. METHODS: Low-dose CsA (3 mg/kg, administered i.v.) or FK506 (0.3 mg/kg i.v.) were used to induce ischemic tolerance in Sprague-Dawley rats, and the induction of heat shock protein (hsp) 70 by CsA or FK506 was evaluated overtime. Rats were pretreated with CsA or FK506 6 hr before I/R injury when hsp70 was maximally expressed, and were killed 24 hr later. The effect of pharmacological preconditioning on subsequent I/R injury was evaluated in terms of renal function, histopathology score, assays for apoptosis (DNA fragmentation analysis, TUNEL staining, expressions of pro-apoptotic genes, and caspase activity), and the expression of inflammatory cytokine genes (interleukin-1 and tumor necrosis factor-alpha). RESULTS: Preconditioning with low-dose CsA or FK506 significantly improved renal function and renal histology, compared to rats with I/R injury. Apoptotic cell death (typical DNA laddering and increased TUNEL-positive cells) in rat kidneys with I/R injury, was decreased by pretreatment with low-dose CsA or FK506. Increased expression of pro-apoptotic genes (Fas, Fas-ligand, caspase 1 and 3) and activated caspases in ischemic rat kidneys were decreased after CsA or FK506 pretreatment. CONCLUSIONS: Pretreatment with low-dose CsA or FK506 prevents subsequent I/R injury, and this effect may be related to the induction of hsp70. Pretreatment of renal donors with low-dose CsA or FK506 may result in an improvement in immediate posttransplant function.     

Identification of (1-pentylindol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone and its 5-pentyl fluorinated analog in herbal incense seized for drug trafficking

Four herbal incense products were seized from suspected drug abusers in Korea. The major ingredients in the herbal incense samples were purified, and their structures were elucidated using gas chromatography–electron ionization–mass spectrometry (GC–EI–MS), liquid chromatography–time-of-flight–mass spectrometry (LC–TOF–MS), and 1D and 2D nuclear magnetic resonance (NMR) spectroscopy. As a result, ingredients in the herbal incense were identified as (1-pentylindol-3-yl)-(2,2,3,3-tetramethylcyclopropyl)methanone and its 5-pentyl fluorinated analog [1-(5-fluoropentyl)indol-3-yl]-(2,2,3,3-tetramethylcyclopropyl)methanone. The former is being sold via the Internet as a "research chemical" named UR-144, and the latter is sold as 5F-UR-144. UR-144 is a selective full agonist of CB₂ cannabinoid receptor, and was first developed by Abbott Laboratories as an analgesic. It exhibits analgesic activity against both neuropathic and inflammatory pain associated mainly with the CB₂ receptor, but shows less psychotropic effects associated with the CB₁ receptor. Fluorination of the N-pentyl side chain of cannabimimetic compounds increases their cannabinoid receptor affinity such as with AM-2201, which shows both increased analgesic and psychotropic effects simultaneously. UR-144 and 5F-UR-144 can be classified as research chemicals based on their analgesic effects, but in practice are abused as psychotropic agents and can cause unexpected toxic effects. Thus, the trade and diversion of these chemicals should be monitored carefully for possible abuse. To our knowledge, this is the first report disclosing cyclopropylcarbonylindoles in herbal products.     

The Prognostic Factors That Influence Long-Term Survival in Acute Large Cerebral Infarction

Objective

We retrospectively evaluated the prognostic factors that can influence long-term survival in patients who suffered acute large cerebral infarction.

Methods

Between June 2003 and October 2008, a total of 178 patients were diagnosed with a large cerebral infarction, and, among them, 122 patients were alive one month after the onset of stroke. We investigated the multiple factors that might have influenced the life expectancies of these 122 patients.

Results

The mean age of the patients was 70±13.4 years and the mean survival was 41.7±2.8 months. The mean survival of the poor functional outcome group (mRS≥4) was 33.9±3.3 months, whereas that of the good functional outcome group (mRS≤3) was 58.6±2.6 months (p value =0.000). The mean survival of the older patients (≥70 years) was 29.7±3.4 months, whereas that of the younger patients (<70 years) was much better as 58.9±3.2 months (p value=0.000). Involvement of ACA or PCA territory in MCA infarction is also a poor prognostic factor (p value=0.021). But, other factors that are also known as significant predictors of poor survival (male gender, hypertension, heart failure, atrial fibrillation, diabetes mellitus, a previous history of stroke, smoking, and dyslipidemia) did not significantly influence the mean survival time in the current study.

Conclusion

Age (older versus younger than 70 years old) and functional outcome at one month could be critical prognostic factors for survival after acute large cerebral infarction. Involvement of ACA or PCA territory is also an important poor prognostic factor in patients with MCA territorial infarction.     

DNA flow cytometry of reclassified subtypes of malignant salivary gland tumors

Malignant salivary gland tumors are rare, constitute a heterogeneous group and are often difficult to diagnose histologically. This is borne out by the fact that in the present study 43.2% of 118 salivary gland tumors originally diagnosed as mucoepidermoid, acinic cell and adenoid cystic carcinomas had their original diagnosis altered upon reclassification. Patients with confirmed adenoid cystic carcinomas had a much worse prognosis than those with mucoepidermoid and acinic cell carcinomas.
DNA flow cytometry showed that very few of the above mentioned three types of malignant neoplasms revealed aneuploid DNA stemlines, indicating that this is not a relevant prognostic tumor marker within the groups. However, several of the tumors that had their diagnosis changed, mostly to undifferentiated adenoor squamous cell carcinomas, showed aneuploid DNA stemlines. The survival time of patients with aneuploid tumors was considerably reduced compared to those with diploid tumors. Among confirmed acinic cell, mucoepidermoid and adenoid cystic carcinomas the S-phase fraction was a significant prognostic factor, as it was among all tumors examined. This indicates that DNA aneuploidy and S-phase fractions are potential prognostic factors for malignant salivary gland tumors, and that DNA flow cytometry may assist the characterization of such tumors.     

Studies on Malayan filariasis in Bengkulu (Sumatera), Indonesia with special reference to vector confirmation

In an endemic focus of Brugia malayi in Bengkulu, Indonesia the microfilariae rate was 25%. The microfilariae showed nocturnal periodicity. Domestic cats in the same area were found to harbour B. pahangi, with a microfilariae rate of 23%. In the study area, the most prevalent man-biting Mansonia mosquitoes were Mn.bonneae (41%), followed by Mn.annulata (27%), Mn.uniformis (25%) and Mn.dives (7%). More Mansonia mosquitoes were collected outdoors than indoors between 1800-2200 hours. Natural infections with infective larvae of Brugia spp. were found in Mn.bonneae, Mn.dives, Mn.uniformis, Mn.annulata, and An.nigerrimus. Experimental infection studies revealed that Mn.annulata, Mn.bonneae, Mn.uniformis, An.nigerrimus and An.peditaeniatus permit the development of infective larvae. Under experimental condition, the vectorial competence is high in Mn.bonneae, intermediate in Mn.uniformis and low in An.hyrcanus group. It is concluded that the principal vectors of periodic B.malayi in the study area in Bengkulu are four Mansonia species (Mn.annulata, Mn.bonneae, Mn.uniformis and Mn.dives), and that the potential vectors include two Anopheles species (An.nigerrimus and An.peditaeniatus). This is the first record of Mn.bonneae being a vector of periodic B.malayi in Indonesia.     

Localization of ODAM,PCNA, and CK14 in regenerating junctional epithelium during orthodontic tooth movement in rats

Objective:To identify the regenerating junctional epithelium (JE) during orthodontic tooth movement in rats.Materials and Methods:Closed-coil springs were used to create a 20 g mesial force to the maxillary first molars. On days 1, 3, 7, 10, and 14 after force application, histologic changes in JE were examined by immunohistochemistry using proliferating cell nuclear antigen (PCNA), odontogenic ameloblast-associated protein (ODAM), and cytokeratin 14 (CK14).Results:On day 1, JE was destroyed and lost attachment to the tooth surface. Cell division activity was rarely observed in JE, and ODAM localization was weakly detected in damaged JE. By day 3, regenerating JE had not fully recovered. High cell proliferation activity and CK14 expression started to appear in most basal cells of JE. ODAM expression was reduced and appeared in a small area. By day 7, JE had almost recovered. Cell proliferation activity was still observed in several basal cells of JE, and ODAM expression was detected among JE cells. CK14 was hardly observed in JE except in the basal cells. By days 10 and 14, regenerated JE appeared. ODAM, PCNA, and CK14 expression was similar to that of the control.Conclusions:Damaged JE might recover rapidly during orthodontic tooth movement because basal cells of the remaining JE, which show higher proliferation activity, are involved in JE regeneration. Reduced ODAM expression during proliferation of JE cells may increase again after JE regeneration is complete. Therefore, ODAM may be associated with the normal function of JE.     

Development and validation of a questionnaire for diagnosing atopic dermatitis.

In this paper we describe the development and validation of a questionnaire for atopic dermatitis used in population surveys in Denmark. The Danish questionnaire was developed from the UK Working Party's questionnaire for atopic dermatitis and includes a severity score. The study included 61 children aged 3 to 14 years recruited from our Department of Dermatology, two kindergartens and a primary school. A validator was appointed to evaluate whether each child had current or previous atopic dermatitis. Compared to the validator's diagnosis, the sensitivity of the UK Working Party criteria was 90% (95% CI; 74-98) and the specificity was 97% (95% CI; 82-99). The criteria for atopic dermatitis have a satisfactory sensitivity and specificity for diagnosing current atopic dermatitis, but the natural course of the disease complicates the validation of investigational instruments. We suggest that future epidemiological studies aimed at establishing new knowledge on atopic dermatitis should include history, current symptoms and findings and a severity score.     

Soft-Tissue Cryoablation in Diffuse Locations: Feasibility and Intermediate Term Outcomes

PurposeTo assess whether diverse tumor location(s) show differences in percutaneous cryoablation (PCA) outcomes of cancer control, morbidity, and ablation volume reduction for many soft-tissue tumor types.Materials and MethodsA total of 220 computed tomography (CT)– and/or ultrasonography-guided percutaneous cryotherapy procedures were performed for 251 oligometastatic tumors from multiple primary cancers in 126 patients. Tumor location was grouped according to regional sites: retroperitoneal, superficial, intraperitoneal, bone, and head and neck. PCA complications were graded according to Common Terminology Criteria for Adverse Events (version 4.0). Local tumor recurrence and involution were calculated from ablation zone measurements, grouped into 1-, 3-, 6-, 12-, 18-, and 24-month (or later) statistical bins.ResultsTumor and procedure numbers for each site were 75 and 69 retroperitoneal, 76 and 62 superficial, 39 and 32 intraperitoneal, 34 and 34 bone, and 27 and 26 head and neck. Average diameters of tumor and visible ice during ablation were 3.4 and 5.5 cm, respectively. Major complications (ie, grade >3) attributable to PCA occurred after five procedures (2.3%). At 11 months average follow-up (range, 0–82 mo), a 10% total recurrence rate (26 of 251) was noted; three occurred within the ablation zone, for a local progression rate of 1.2%. Average time to recurrence was 4.9 months, and, at 21 months, the initial ablation zone had reduced in volume by 93%.ConclusionsCT-guided PCA is a broadly safe, effective local cancer control option for oligometastatic disease with soft-tissue tumors in most anatomic sites. Other than bowel and nerve proximity, PCA also shows good healing if proper visualization and precautions are followed.     

Intravenous calcitriol regresses myocardial hypertrophy in hemodialysis patients with secondary hyperparathyroidism

To evaluate the response of circulating intact parathyroid hormone (iPTH) on myocardial hypertrophy in hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT), echocardiographic and neurohormonal assessments were performed over a 15-week period in 15 HD patients with SHPT before and after calcitriol treatment and 10 HD control patients with SHPT not receiving calcitriol therapy. We prospectively studied a group of 15 patients with significantly elevated iPTH levels (iPTH >450 pg/mL) receiving calcitriol (2 microg after dialysis twice weekly). Clinical assessment, medication status, and biochemical and hematological measurements were performed once a month. Throughout the study, calcium carbonate levels were modified to maintain serum phosphate levels at less than 6 mg/dL, but body weight, antihypertensive medication, and ultrafiltration dose remained constant. In patients treated with calcitriol, an adequate reduction of iPTH levels was found (1,112 +/- 694 v 741 +/- 644 pg/mL; P < 0.05) without changes in values of serum ionized calcium (iCa++), phosphate, or hematocrit. Blood pressure (BP), cardiac output (CO), and total peripheral resistance (TPR) did not significantly change. After 15 weeks of treatment with calcitriol, M-mode echocardiograms showed pronounced reductions in interventricular wall thickness (13.9 +/- 3.6 v 12.8 +/- 3.10 mm; P = 0.01), left ventricular posterior wall thickness (12.5 +/- 2.4 v 11.3 +/- 1.8 mm; P < 0.05), and left ventricle mass index (LVMi; 178 +/- 73 v 155 +/- 61 g/m2; P < 0.01). However, in control patients, these changes were not found after the treatment period. In addition, sequential measurements of neurohormonal mediator levels in patients receiving calcitriol showed that plasma renin (18.5 +/- 12.7 v 12.3 +/- 11.0 pg/mL; P = 0.007), angiotensin II (AT II; 79.7 +/- 48.6 v 47.2 +/- 45.7 pg/mL; P = 0.001), and atrial natriuretic peptide (ANP; 16.6 +/- 9.7 v 12.2 +/- 4.4 pg/mL; P = 0.03) levels significantly decreased, whereas antidiuretic hormone (ADH), epinephrine, and norepinephrine levels did not change significantly. The percent change in LVMi associated with calcitriol therapy had a strong correlation with the percent change in iPTH (r = 0.52; P < 0.05) and AT II (r = 0.47; P < 0.05) levels. We conclude that the partial correction of SHPT with intravenous calcitriol causes a regression in myocardial hypertrophy without biochemical or hemodynamic changes, such as heart rate, BP, and TPR. The changes in plasma levels of iPTH and, secondarily, plasma levels of neurohormones (especially AT II) after calcitriol therapy may have a key role in attenuating ventricular hypertrophy in SHPT.