Effects of atorvastatin on blood-brain barrier permeability during L-NAME hypertension followed by angiotensin-II in rats

Recent studies suggest that 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, can have direct effects on blood vessels beyond their cholesterol-lowering effects. We investigated the effects of atorvastatin on the functional and structural properties of blood-brain barrier (BBB) and the activity of astrocytes during the N(omega)-nitro-L-arginine methyl ester (L-NAME) hypertension followed by angiotensin (ANG) II. We found that decreases in concentration of serum catalase and plasma nitric oxide (NO) induced by L-NAME were significantly ameliorated by atorvastatin, whereas L-NAME-induced serum malondialdehyde and cholesterol concentration increases were significantly reduced by atorvastatin. The content of Evans blue (EB) dye significantly increased in cerebellum, left cerebral cortex and diencephalon regions but atorvastatin markedly reduced the increased BBB permeability to EB in the brain regions of animals treated with L-NAME and L-NAME plus ANG II. Brain vessels of L-NAME-treated animals showed a considerable loss of immunoreactivity of tight junction proteins, zonula occludens (ZO)-1 and occludin. Immunoreactivity for ZO-1 and occludin increased in animals treated with atorvastatin and L-NAME plus atorvastatin. Glial fibrillary acidic protein (GFAP) immunoreactivity was seen in few astrocytes in the brain sections of L-NAME, but immunoreactivity for GFAP increased in L-NAME plus atorvastatin-treated animals. We suggest that long-term L-NAME treatment may affect BBB permeability through disruption of tight junction proteins, at least partly, via decreased NO concentration and increased oxidant capacity; the improvement of BBB integrity and astrocytic activity would be more closely associated with the action of atorvastatin favoring the increase in anti-oxidant capacity and expression of tight junction proteins and GFAP.     

Detectability of liver metastases in malignant melanoma: prospective comparison of magnetic resonance imaging and positron emission tomography

PURPOSE: We evaluated the diagnostic accuracy of magnetic resonance imaging (MRI) and positron emission tomography (PET) for detection of liver metastases in malignant melanoma. MATERIAL AND METHODS: Thirty-five patients with 39 combined unenhanced MRI and fluorine-18 deoxyglucose (F-18 FDG) PET scans were prospectively studied. In discordant imaging findings final diagnosis was proven by clinical follow-up >6 months and demonstration of progressive liver metastases by at least one imaging method. Sensitivities and specificities were compared and the influence of lesion size and melanin content on diagnostic accuracy was determined. RESULTS: MRI and PET were concordantly negative for presence and number of liver metastases in 28 patients and positive in four patients. PET and MRI were false positive in one patient each. In one patient MRI showed a single metastases not seen by PET and in one patient MRI demonstrated more metastases at the first examination. In follow-up investigations MRI revealed more metastases than PET in both patients. The sensitivities for lesion detection were 47% (16/34) for PET and 100% for MRI. Lesion detectability by PET was related to lesion size (P < 0.0001) but not to melanin content. CONCLUSION: MRI is more sensitive in the detection of liver metastases in patients with malignant melanoma. Small lesions are easily missed by PET, while melanin content does not influence detectability by PET.     

Thyroglobulin increment after thyroid hormone withdrawal is a reliable indicator for the detection of significant remnants or metastases in patients with differentiated thyroid carcinoma

Serum thyroglobulin (Tg) measurement has a pivotal role in the management of differentiated thyroid carcinoma (DTC). Serum Tg increment after thyroid hormone discontinuation seems to be a better predictor of tumor recurrence, however, minimal Tg increment may not be a specific marker. This study tries to evaluate the importance of different levels of Tg increment after thyroid hormone discontinuation. Fifty-five patients (46 females and 9 males with mean age of 41.40 yrs) with DTC, treated with total or subtotal thyroidectomy and radioiodine-131 ((131)I) were studied. Ninety-one per cent of the patients had papillary carcinoma. Serum Tg and thyroid stimulating hormone (TSH) were measured using high sensitive IRMA assays during thyroxine (T4) suppression and after discontinuation of T4 treatment. The mean time interval between Tg on T4 and off T4 was 110.29+/-53.43 days and less than 180 days in all patients. Serum Tg level was increased >or= 1 ng/ml in 25 patients after discontinuation of T4. Of these patients, 17 had metastatic disease or a detectable thyroid remnant. Of 16 patients with unchanged Tg (-1or= 7 ng/ml had residual disease or metastases. If DeltaTg was unchanged or decreased, the negative predictive value was 83.3%. The sensitivity of WB(131)IS was 63.6% for the detection of thyroid remnant or metastases. Our study indicates that DeltaTg is a more reliable indicator of remnant disease than on T4-Tg or off T4-Tg levels.     

High-resolution CT imaging of the lung for patients with primary Sjogren's syndrome

PURPOSE: To assess pulmonary abnormalities in patients with primary Sjogren's syndrome (PSS) using high-resolution computed tomography (HRCT). MATERIAL AND METHODS: The HRCT scans of 24 patients with the diagnosis PSS were retrospectively reviewed regarding the presence, extension and distribution of 16 pathological findings. RESULTS: Nineteen patients (79.2%) showed pathological findings and in five patients (21.8%) the HRCT scan was judged to be normal. A predominance of abnormalities in the lower lobes and subpleural areas was detected. The following pathologies were found: bronchiectasis, thin-walled cysts and small pulmonary nodules (46.2%), ground-glass attenuation and emphysema (37.8%), interlobular-septal thickening (29.4%), honeycombing (25.2%), bronchial wall thickening, tree-in-bud pattern (21.0%), mosaic perfusion (16.8%), architectural distortion (12.6%). Airspace consolidation, air trapping, large nodules (10-30mm) and masses (>30mm), mediastinal lymph node enlargement (>15mm) and free pleural fluid were seen each in 4.2%. In 7 of the 11 patients with thin-walled cysts areas of ground-glass attenuation were detected. CONCLUSION: HRCT seems is contributive to the characterization of the wide variety of lung abnormalities in PSS. Airway disease alone or in association with the presence of varying degrees of interstitial disease represents the main findings in accordance with earlier reports. Unexpectedly, almost half of the patients had thin-walled cysts on the HRCT scans, which etiology is unclear but could be associated with areas of ground-glass attenuation indicating LIP.     

European School of Oncology Advanced Course on Cancer in the Elderly Liverpool, 29-30 April 2004

The ESO Advanced Course on Cancer in the Elderly took place in Liverpool-UK, 29-30 April 2004 under the chair of Riccardo A. Audisio and Matti A. Aapro. This successful event gathered 82 participants from 17 countries; posters were displayed presenting original research data, and 19 lecturers updated the audience on the latest findings regarding basic science, prevention, early detection, diagnosis, treatment options, as well as the social impact of this frequent malignancy. This Meeting Highlights collects the panelists views; it is intended to update on the cutting edge of the present knowledge, in order to improve our understanding of malignant disease affecting senior patients, and eventually to optimise their management.     

Sensitization of multidrug resistant human ostesarcoma cells to Apo2 Ligand/TRAIL-induced apoptosis by inhibition of the Akt/PKB kinase

Chemotherapeutic agents have been used for the treatment of patients with osteosarcoma (OS). However, inherent or acquired resistance to these agents is a serious problem in the management of OS patients. The emergence of the multidrug resistance (MDR) phenotype in cancer cells is often associated with the overexpression of P-glycoprotein, encoded by the multidrug resistance gene MDR-1. The administration of some of the most common chemotherapeutic agents to these cells becomes ineffective because of their P-gp-driven efflux from the cell. Apo2L/TRAIL is a member of the tumor necrosis factor (TNF) family of cytokines that is considered to induce death of cancer cells but not normal cells. Its powerful apoptotic activity is mediated through its cell surface death domain-containing receptors, TRAIL-R1/DR4 and TRAIL-R2/DR5, which in turn spread the signal in the cytosol through the activation of the caspase cascade. The Akt/PKB kinase is an important cell survival protein which is regulated by D3-phosphoinositides. High Akt expression and activity levels are well documented in many types of tumors, which very often show an altered PI3-K/Akt/PTEN pathway. In this study the U2OS human osteosarcoma cell line and its multidrug resistant (MDR) subline that overexpresses MDR-1 gene, MDR-U2OS, have been analyzed for their responsiveness to TRAIL. In conflict with the presence of active DR4 and DR5 receptors in both clones, U2OS cells exhibited only a low responsiveness to TRAIL, while the MDR-U2OS subline did exhibit a marked TRAIL sensitivity. An analysis of the post-receptor events showed that TRAIL responsiveness correlates with a reduced expression of endogenous Akt. In fact, expression in MDR-U2OS cells of a constitutively active Akt strongly decreased their sensitivity to TRAIL. The identification of Akt as a key modulator of TRAIL responsiveness could help to design TRAIL-based combinations for treatment of osteosarcoma. Moreover, the discovery that multidrug resistant osteosarcomas are highly sensitive to TRAIL-induced apoptosis indicates TRAIL as a new candidate for the treatment of multidrug resistant bone malignancies.     

Cell membrane modification for rapid display of proteins as a novel means of immunomodulation: FasL-decorated cells prevent islet graft rejection

Long-term display of exogenous proteins on the cell surface may have important research and therapeutic implications. We report a novel method for the cell-surface display of proteins that involves generation of a chimeric protein with core streptavidin, biotinylation of cells, and "decoration" with the protein. A chimeric protein with the extracellular portions of FasL (SA-FasL) was efficiently displayed on the cell surface within 2 hr without detectable cellular toxicity. Biotin and SA-FasL persisted on the cell surface for weeks in vitro and in vivo. Immunomodulation with SA-FasL-decorated splenocytes effectively blocked alloreactive responses in naive and presensitized rodents and prevented the rejection of allogeneic pancreatic islets. This approach may serve as an alternative to gene transfer-based expression with broad research and therapeutic applications.     

Molecular mechanisms of age-related hearing loss

Age-related hearing loss, known as presbyacusis, is characterized by the progressive deterioration of auditory sensitivity associated with aging and is the most common cause of adult auditory deficiency in the United States. Presbyacusis is defined as a progressive, bilateral, high-frequency hearing loss that is manifested on audiometric assessment by a moderately sloping pure tone audiogram. This condition affects approximately 23% of the population between 65 and 75 years of age and 40% of the population older than 75 years of age. In 1980, it was estimated that 11% of the population was 76 years or older and this number is expected to nearly double by the year 2030 [, Otolaryngol. Head Neck Surg. 100, 262]. When coupled with the fact that the population over 65 years of age is experiencing the most rapid progression of hearing loss, the potential socioeconomic ramifications are staggering. Interestingly, presbyacusis varies in its frequency across differing societies. This discrepancy has been attributed to many factors such as genetics, diet, socioeconomic factors, and environmental variables [, Otolaryngol. Head Neck Surg. 100, 266;. Scand. Audiol. 26 (1997) 133]. The purpose of this discussion is to illuminate the various molecular mechanisms underlying this age-related hearing loss and to offer insights into potential ways to mitigate the effects of aging on hearing impairment.     

Kotz and Ganz osteotomies in the treatment of adult acetabular dysplasia

In hips with acetabular dysplasia, we performed Kotz osteotomy (group 1) in 22 hips (20 patients; mean age 24.3 years) and Ganz osteotomy (group 2) in 23 hips (22 patients; mean age 23.1 years). Group 1 was followed 83.3 (56-112) months and group 2 40.9 (24-66) months. In group 1, Harris hip score improved from average 74.9 to 86.9, mean center edge (CE) angle from -4.5 degrees to 30.3 degrees, and mean vertical center edge (VCE) angle from 5.3 degrees to 36.2 degrees. In group 2, Harris hip score improved from average 76.6 to 91.1, mean CE angle from -5.9 degrees to 32.0 degrees, and mean VCE angle from 5.0 degrees to 41.3 degrees. Using Pauwels criteria, regression was observed in 12 hips in group 1 and one progressed. In group 2, 15 hips showed regression and three progressed. In patients treated with Ganz osteotomy, the complication rate was higher and the complications more serious than in patients treated with Kotz osteotomy. Most complications were, however, seen among the first ten patients treated with Ganz osteotomy. Although we detected no significant difference between the two groups in terms of clinical and radiological findings, we believe the outcome to be slightly better after a properly performed Ganz osteotomy.