Cystatin C relates to metabolism in healthy, pubertal adolescents.

INTRODUCTION: The cystatin C (CysC) serum level is a marker of glomerular filtration rate and depends on age, gender, and pubertal stage. We hypothesize that CysC might overall reflect energy homeostasis and be regulated by components of the endocrine system and metabolites in pubertal adolescents. METHODS: Serum CysC levels and further possible effector parameters in 5355 fasting, morning venous blood samples from 2035 healthy participants of the LIFE Child cohort study (age 8 to 18 years) were analyzed. Recruitment started in 2011, with probands followed up once a year. Linear univariate and stepwise multivariate regression analyses were performed. RESULTS: Annual growth rate, serum levels of thyroid hormones, parathyroid hormone, insulin-like growth factor 1, hemoglobin A1c (HbA1c), uric acid, and alkaline phosphatase show relevant and significant associations with CysC serum concentrations (p <0.001). Furthermore, male probands' CysC correlated with the body mass index and testosterone among other sexual hormones. Multivariate analyses revealed that uric acid and HbA1c are associated variables of CysC independent from gender (p <0.001). In males, alkaline phosphatase (p <0.001) is additionally significantly associated with CysC. Thyroid hormones show significant correlations only in multivariate analyses in females (p <0.001). CONCLUSIONS: The described associations strongly suggest an impact of children's metabolism on CysC serum levels. These alterations need to be considered in kidney diagnostics using CysC in adolescents. Additionally, further studies are needed on CysC in children.

Cystic masses of the lateral neck - Proposition of an algorithm for increased treatment efficiency.

Preoperative discrimination of solitary cervical branchial cleft cysts from cystic lymph node metastasis often is challenging. Surgical excision of the cystic formation and consecutive histopathological examination of tissue specimens are the only means resulting in the correct diagnosis. However, in case of malignancies surgery on the lateral neck prior to the definitive treatment is considered to negatively influence the patients' outcome. The rate of cystic lymph node metastasis in patients presenting with a lateral branchial cleft cyst, localization of the primary tumour and oncological outcome were investigated. Retrospective chart review of 131 patients presenting clinically with solitary lateral cervical cysts between. A malignant tumour was detected in 12 patients (9.2%). Malignant tumours were significantly more frequent in patients older than 40 years of age (22.0%; p = 0.0001). In patients older than 40 years of age with solitary lateral cervical cysts a malignancy should be presumed.

Evaluation of early anatomical changes following canaloplasty with anterior segment spectral-domain optical coherence tomography and ultrasound biomicroscopy.

PURPOSE: To analyse structural changes in conjunctiva, sclera and Schlemm's canal (SC) following canaloplasty with optical coherence tomography (AS-OCT) and ultrasound biomicroscopy (UBM). METHODS: Fifteen patients undergoing canaloplasty were included in this prospective study. AS-OCT images were acquired pre- and 1, 7, 30 and 90 days postoperatively. UBM was performed 3 months postoperatively. The surgical site was evaluated for the presence of SC, transscleral filtration, a scleral lake and the visibility of intra-Schlemm-sutures. The height and width of SC were measured at the 3 and 9 o'clock limbus position. RESULTS: After canaloplasty, SC was detectable with AS-OCT in 93% of the patients on day 1. The increase in height was higher than that in width (height: +369%, p = 0.0004, width: +152%, p = 0.002). IOP was negatively correlated to SC's width 1 week postoperatively (r = -0.63, p = 0.04) and to SC's height until 3 months (r = -0.66, p = 0.02) postoperatively. Using UBM, a reflection of the traction sutures indicated SC's position in all patients. Transscleral filtration was found in all patients using AS-OCT, demonstrating a peak 1 week postoperatively. At 3 months, a scleral lake could be visualized in 50% and 83% of patients using AS-OCT and UBM, respectively. CONCLUSIONS: AS-OCT offers a high resolution for imaging superficial conjunctival areas and SC after canaloplasty, whereas UBM is capable of detecting deeper structures such as scleral lakes or intra-canal-sutures. The results imply a correlation of the dilation of SC with the IOP-lowering effect and an early pronounced transscleral filtration following canaloplasty.

Central corneal thickness determination in corneal edema using ultrasound pachymetry, a Scheimpflug camera, and anterior segment OCT.

PURPOSE: The purpose of this study is to determine the influence of post-surgical corneal edema on the reliability and reproducibility of central corneal thickness (CCT) measurements by a Scheimpflug camera (Pentacam), ultrasound pachymetry (USP), and anterior-segment spectral-domain optical coherence tomography (AS-OCT). METHODS: Thirty-two patients planned for cataract surgery (n = 16) or vitrectomy (n = 6) were included in a prospective study. The non-surgery eye was used as control. Two investigators acquired two measurements each, with the Pentacam (Oculus, Germany) and the AS-OCT (Heidelberg Engineering, Germany) in a randomized order, followed by USP (Tomey SP-100, Germany). CCT was evaluated using the apex value for Pentacam, the corneal apex cut in AS-OCT and averaging eight single measurements for USP. Coefficients of variation (COV) and intra-class correlation coefficients (ICC) were determined. RESULTS: Post-surgery corneas showed a thickness of (investigators 1 and 2): Pentacam (615.9 ± 58.02 µm and 615.1 ± 60.17 µm), USP (601.4 ± 63.77 µm and 614.5 ± 70.91 µm), AS-OCT (608.8 ± 65.67 µm and 606.9 ± 64.41 µm) ,with no significant difference (ANOVA p > 0.99). The COVs (investigators 1 and 2) for control eyes were: Pentacam (0.78 ± 0.52 and 0.70 ± 0.76), USP (0.66 ± 0.29 and 0.98 ± 0.44), AS-OCT (0.59 ± 0.61 and 0.59 ± 0.40). The COVs (investigators 1 and 2) for post-surgical eyes were: Pentacam (0.98 ± 1.25 and 0.97 ± 0.73), USP (0.73 ± 0.64 and 1.35 ± 0.85), AS-OCT (1.34 ± 1.57 and 1.19 ± 1.18).The ICC was determined in post-surgery corneas (ICC > 0.96) and control corneas (ICC > 0.95). CONCLUSION: USP measurements have the highest user dependence. Post-surgical corneal edema leads to higher intraobserver variability. All methods reached a high level of agreement in CCT determination in edematous as well as healthy corneas.

Long term effect of trabeculectomy on retrobulbar haemodynamics in glaucoma.

PURPOSE: Previous reports showed increased flow velocities in retrobulbar vessels after glaucoma surgery in the first weeks. Colour Doppler imaging was performed to investigate the long-term effects of trabeculectomy on retrobulbar haemodynamics in patients with primary open-angle glaucoma (POAG). METHODS: In a prospective study 30 patients (mean age 63.2 ± 15.4 years) with POAG were included. Colour Doppler imaging was performed before 1-2 weeks, after 2 months, after 4-6 months, and up to 3 years after trabeculectomy to determine the peak systolic and end-diastolic velocities in the ophthalmic artery, central retinal artery, and the short nasal and temporal posterior ciliary arteries. RESULTS: Mean follow-up was 416 ± 246 days. In the first postsurgical period mean intraocular pressure (IOP) decreased after trabeculectomy from 25 ± 6 mmHg to 9 ± 4 mm Hg (p < 0.0001) and then increased in the further follow-up to 13 ± 3 mmHg (p < 0.05) without any anti-glaucomatous medication. Colour Doppler imaging revealed a significant increase of the end-diastolic velocities of the central retinal artery at all postoperative visits compared to pre-surgery (p < 0.003) and of the end-diastolic velocities in the temporal posterior ciliary arteries (p < 0.003). The change of blood flow parameters that increased during follow-up was significantly correlated to the change in ocular perfusion pressure and IOP. CONCLUSIONS: End-diastolic velocities of the central retinal artery and of the temporal posterior ciliary arteries increased after successful trabeculectomy and remained stable in a longer period - even if IOP rose significantly in the follow-up.

Intrathecal morphine is superior to intravenous PCA in patients undergoing minimally invasive cardiac surgery.

Aim of our study was to evaluate the beneficial effect of low dose intrathecal morphine on postoperative analgesia, over the use of intravenous patient controlled anesthesia (PCA), in patients undergoing fast track anesthesia during minimally invasive cardiac surgical procedures. A randomized controlled trial was undertaken after approval from local ethical committee. Written informed consent was obtained from 61 patients receiving mitral or tricuspid or both surgical valve repair in minimal invasive technique. Patients were assigned randomly to 2 groups. Group 1 received general anesthesia and intravenous patient controlled analgesia (PCA) pump with Piritramide (GA group). Group 2 received a single shot of intrathecal morphine (1.5 µg/kg body weight) prior to the administration of general anesthesia (ITM group). Site of puncture was confined to lumbar (L1-2 or L2-3) intrathecal space. The amount of intravenous piritramide used in post anesthesia care unit (PACU) and the first postoperative day was defined as primary end point. Secondary end points included: time for tracheal extubation, pain and sedation scores in PACU upto third postoperative day. For statistical analysis Mann-Whitney-U Test and Fishers exact test (SPSS) were used. We found that the demand for intravenous opioids in PACU was significantly reduced in ITM group (P <0.001). Pain scores were significantly decreased in ITM group until second postoperative day (P <0.01). There was no time delay for tracheal extubation in ITM group, and sedation scores did not differ in either group. We conclude that low dose single shot intrathecal morphine provides adequate postoperative analgesia, reduces the intravenous opioid consumption during the early postoperative period and does not defer early extubation.

Activation of PI3K is associated with reduced survival in renal cell carcinoma.

OBJECTIVES: The epidermal growth factor receptor- (EGFR) activated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt) pathway is associated with tumorigenesis and progression. The aims of the present study were to determine the expression patterns of Akt pathway parameters PI3K, phosphatase and tensin homolog (PTEN), phosphor-Akt (p-Akt) and their combination, for their possible prognostic value in renal cell carcinoma (RCC). PTEN dephosphorylates the liquid product of PI3K. METHODS: Tumor samples from 176 RCC patients were investigated for PTEN, p-Akt and PI3K expression by immunohistochemistry. Expression levels were correlated to clinical variables and postoperative outcome by uni- and multivariate statistical analysis. RESULTS: The various expression levels within the tumor samples were independent of histological grade and tumor stage, due to different levels of activation of the PI3K/p-Akt pathway. The activation of PI3K protein was found to be significantly associated with reduced survival times (p = 0.0304, multivariate analysis). Analysis of combined biomarker expressions showed that decreased long-term survival was correlated with PTEN low/p-Akt high expression (p < 0.05). CONCLUSIONS: Activation of the PI3K pathway is significantly associated with adverse clinical outcome in RCC. Analysis of biomarker combinations might identify high-risk patients and a subsequent need to adapt treatment modalities. Molecular pathways regulating PI3K activation appear to be promising targets for drug development in the clinical management of RCC patients.

Membranous expression and prognostic implications of epidermal growth factor receptor protein in human renal cell cancer.

BACKGROUND: It has been indicated that altered expression of the epidermal growth factor receptor (EGFR) promotes the invasive and metastatic potential of a variety of human malignancies. Therefore, the aim of the present study was to determine EGFR expression in clear cell renal cell carcinomas (RCC) to evaluate its prognostic relevance for the clinical course of the disease. MATERIALS AND METHODS: EGFR protein expression, detected by immunohistochemistry and tissue microarray analysis (TMA), was investigated in a cohort of 149 randomly selected patients subjected to tumor nephrectomy for RCC. RESULTS: The tumor cells preferably exhibited a homogeneous membrane-bound reactivity for EGFR; EGFR overexpression was detected in 70 (47%) of the primary tumor specimens, but in only 12 (9%) of the benign tissue samples (p<0.0001; Fisher's t-test). Tumor-associated EGFR staining was stratified into three groups: I: low staining score (n=75, 50%); II: intense expression (n=56, 38%); and III: strong overexpression (n = 18, 12%). Strong reactivity for EGFR was identified as predicting the patients' survival both during uni- and multivariate analysis (p=0.03). Interestingly, the overall survival of the intense expression group surpassed even the low expression group (p=0.023). CONCLUSION: The observation that primary RCC specimens exhibit EGFR at higher levels when compared with benign renal parenchyma indicates its role in tumor development and progression. The availability of more refined prognostic factors would assist decision making in terms of the value of more aggressive treatment options for prognostically defined subgroups of patients. Additionally, if overexpression of EGFR identifies RCC with a more aggressive biological behavior, the latter receptor might serve as a novel target for a more effective therapeutical approach to RCC.

Cathepsin D expression in renal cell cancer-clinical implications.

BACKGROUND: Whereas the expression of Cathepsin D (Cath D) is suggested to enhance the biological aggressiveness of human malignancies, its role in renal cell carcinoma (RCC), however, has not been investigated. METHODS: By tissue microarray analysis, tumor and benign tissue samples from 176 RCC patients were investigated for Cath D expression by immunohistochemistry and Western blots. Expression levels were correlated to clinical variables and to the postoperative outcome. RESULTS: High Cath D expression levels were detected in 29%/9% of tumor and benign tissue samples, respectively (p < 0.0001). In case of a high vs. low Cath D expression level, development of distant metastases was observed in 12% vs. 88% of cases (p < 0.05). With a median follow-up of 50 (2-146) months, high level Cath D expression was correlated with an improved long-term survival when compared with patients presenting with decreased expression [median long-term survival: 82 vs. 53 months in case of a high vs. low expression level] (p < 0.05). CONCLUSIONS: The Cath D staining pattern predicted a reduced risk for metastatic spread and tumor dependent death, hereby indicating its role as a biological variable revealing additional prognostic information for renal cell cancer patients. Increased expression of Cath D in tumor vs. benign tissue samples might indicate a role for the development and progression of RCC.

Uridine abrogates mitochondrial toxicity related to nucleoside analogue reverse transcriptase inhibitors in HepG2 cells.

OBJECTIVE: To assess in vitro if uridine may be suitable to prevent or treat mitochondrial toxicity related to nucleoside analogue reverse transcriptase inhibitors (NRTIs). METHODS: Human HepG2-hepatocytes were exposed to NRTIs with or without uridine for 25 days. Cell growth, lactate production, intracellular lipids, mitochondrial DNA (mtDNA) and the ratio between the respiratory chain components COX II (mtDNA-encoded) and COX IV (nuclear-encoded) were measured. RESULTS: HepG2 cells exposed to zalcitabine (177 nM) without uridine developed a severe depletion of mtDNA (to 8% of wild-type mtDNA levels), resulting in a decline of cell proliferation and COX II levels, with increased lactate and lipid accumulation. Uridine fully abrogated the adverse effects of zalcitabine on hepatocyte proliferation and normalized lactate synthesis, intracellular lipids and COX II levels by adjusting mtDNA levels to about 65% of NRTI-unexposed control cells. This effect was dose-dependent, with a maximum at 200 microM of uridine. Uridine also rapidly and fully restored cell function when added to cells with established mitochondrial dysfunction (zalcitabine for 15 days) despite continued zalcitabine exposure. Uridine also normalized cell proliferation in HepG2 cells exposed to 36 microM of stavudine and protected HepG2-cells exposed to 7 microM of zidovudine + 8 microM of lamivudine (pyrimidine analogues), but failed to improve cell function or mtDNA in cells exposed to 11.8 or 118 microM of didanosine (a purine analogue). CONCLUSIONS: The pyrimidine precursor uridine may attenuate the mitochondrial toxicity of antiretroviral pyrimidine NRTIs in vitro, and its supplementation may represent a promising strategy in the prevention or treatment of mitochondrial toxicities in HIV-infected patients.