Caveolae are bottleshape-like invaginations of the plasma membrane. After internalization they are involved in endocytosis, transcytosis, potocytosis, and pinocytosis. Our recently expanded knowledge has made clear that various molecules and macromolecular complexes enter the cells after docking on caveolar receptors, before subsequent internalization of the caveolae. The internalization is initiated by the ligand receptor interaction. Folate, cholesterol, serum lipoproteins, and liposomes are among the most common examples. It is important to point out that, in contrast to the classic clathrin-dependent endocytosis, the caveolar internalization pathway seems to avoid the lysosomes. Internalized caveolae fuse with caveosomes, and the caveosomes deliver their contents into other subcellular (non-lysosomal) compartments. The bypass of the acidic and harmful milieu might be a major advantage for drug delivery via the caveolar pathway. Not all cell types have caveolae. Cells, where the Caveolin I protein is not expressed, do not develop caveolar invaginations. However, these cells have caveolar-equivalent plasma membrane domains, so-called "lipid rafts." Lipid rafts are assembled from the same lipid constituents and proteins as caveolae, but they are flat. Specific ligands may also dock on appropriate receptors of the raft domain. As a complication, certain types of ligand-covered raft receptors can migrate to clathrin-coated pits and get internalized via clathrin-coated vesicles. Nevertheless, suitable ligands or antibodies developed against proteins of the caveolar/raft domains may selectively direct the attached drug carrier to the less harmful caveolar/raft pathway. Thus, understanding of caveolar transport may help in the rational design of more effective drug carriers.

Transitory ascites demonstrated by abdominal US is a clue to the diagnosis of an acute abdominal attack of HAE. The possibility of HAE should always be considered whenever unexplained abdominal pain recurs with or without ascites.

Cancer hypoxia correlates with therapeutic resistance and metastasis, suggesting that hypoxic adaptation is a critical survival advantage for cancer stem cells (CSCs). Hypoxic metabolism, however, may be a disadvantage in aerobic circulation as the extremely low incidence of metastasis-compared to the high circulating tumor-cell numbers (CTCs)-appears to suggest. As rare metastatic CSCs still survive, we searched for a mechanism that protects them from oxygen in circulation. CSCs form multicellular spheroids in vitro from virtually all cancers tested. We asked, therefore, whether cancers also form spheroids in vivo and whether circulating spheroids play a role in metastasis. We used metabolic, apoptotic and hypoxia assays, we measured aerobic barriers and calculated hypoxia vs. spheroid-size correlations. We detected metabolic/oxidative stress in spheroids, we found correlation between stem cell presence and hypoxia and we showed that the size of hypoxic spheroids is compatible with circulation. To detect spheroids in patients, we worked out a new light-scatter flow cytometry blood test and assayed 67 metastatic and control cases. We found in vivo spheroids with positive stem cell markers in cancer blood and they showed exclusive correlation with metastasis. In conclusion, our data suggest that metastatic success depends on CSC-association with in vivo spheroids. We propose that the mechanism involves a portable "micro-niche" in spheroids that may support CSC-survival/adaptation in circulation. The new assay may establish a potential early marker of metastatic progression.Malignant cells can enter circulation very early from most cancers (circulating tumor cells, CTCs), 1 yet metastases do not occur until much later (e.g., in pancreatic cancer).2 Enumeration of circulating cancer cells is part of the diagnostic arsenal, but not considered a direct marker of metastasis. Part of the reason is that the majority of cells in most cancers are not capable of seeding metastatic growth.3 Metastatic dissemination is the function of cancer stem cells (CSC), but the overwhelming majority of CTCs do not show stem cell features. 4 An assay to detect circulating CSCs, therefore, could serve as a marker for metastatic predisposition, 5 but it is not available in the oncology practice today.To develop such an assay we took advantage of a unique feature of CSCs, spheroid formation. Spheroids are small multicellular organoids formed in vitro by cells from most cancers. Spheroids are stabilized by cellular contacts that may also play a role in differentiation (e.g., the P19 model).6 With most cancers only a subset of cells can form spheroids and these cells share features with CSCs. 7,8 The same has been demonstrated with cell lines from a variety of tissues. 9 The almost universal potential for spheroids suggests that it may be a basic feature of CSCs akin to clonogenicity or growth in soft agar.We reasoned that if in vitro spheroid formation reflects an important biological function, it may also occur in vivo. To investigate thi...

We measured serum cholesterol, triglyceride, and lipoprotein Lp(a) concentrations in serum of 37 patients with massive proteinuria of different origin, comparing values with those for age- and sex-matched controls and finding significantly increased Lp(a) concentration in the total group of patients compared with controls. Lp(a) concentration was not correlated with serum cholesterol, triglyceride, serum creatinine, daily urinary protein loss, or selectivity index. Selecting the patients according to their histological diagnosis obtained by renal needle biopsy, we found divergent results in seven patients with minimal change disease (MCD) compared with 11 patients with membranoproliferative glomerulonephritis. Lp(a) in MCD patients did not differ from that controls (101 +/- 102 and 90 +/- 115 mg/L) and correlated positively with total daily urinary protein loss (r = 0.7962, P less than 0.05). In contrast, the patients with membranoproliferative glomerulonephritis had significantly higher Lp(a) values than the controls (219 +/- 222 mg/L), and Lp(a) concentrations correlated negatively with the daily protein loss in urine (r = -0.6545, P less than 0.05). The most surprising results were the marked Lp(a) concentrations in serum of three patients with primary amyloidosis and nephrosis syndrome. Our results indicate a regulatory role of the kidney in the metabolism of Lp(a) and different effects on the serum Lp(a) concentration, depending on the type of damage to renal tissue.

IntroductionLipid-lowering therapy should achieve target levels. We assessed the change of the achievement of targets and the mean low-density lipoprotein cholesterol (LDL-C) levels in high-risk Hungarian patients.Material and methodsSix studies performed with patients of general practitioners (GPs) and specialists between 2004 and 2008 were evaluated: 9,508 patients from GPs and 2809 from specialist practices (total 12,317).ResultsDuring this 4-year period the LDL-C level decreased by 0.73 mmol/l and the LDL-C goal achievement rate increased from 14 to 32% in patients treated by GPs. LDL-C showed a decrease of 0.48 mmol/l and the goal achievement rate changed from 20 to 43% in patients treated by specialists. In the majority of the patients not achieving the LDL-C goal (57% for specialists and 89% for GPs) there was no modification in the current therapy. In addition to emphasizing the priority of LDL-C lowering, we should also strive for residual risk reduction, which means raising high-density lipoprotein cholesterol (HDL-C) and lowering triglyceride levels. There was no significant improvement in HDL-C or triglyceride levels during the examined period.ConclusionMore attention needs to be paid to changing treatment of patients to achieve target levels.