Synthesis and Pharmacological Activity of N-[β-(<Emphasis Type="Italic">para</Emphasis>-substituted benzoyl)ethyl]isoleucine and -Methionine

A series of N-[β-(p-substituted benzoyl)ethyl]-isoleucine and -methionine derivatives have been synthesized via the alkylation of amino acids with p-substituted β-diethylaminopropiophenone hydrochlorides. Some of the synthesized compounds possess significant antiinflammatory activity. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 7, pp. 26 – 27, July, 2005.     

Disease-Specific Quality-of-Life Questionnaires in Rhinitis and Rhinosinusitis: Review and Evaluation

Quality of life (QoL) measurements are the best approximation of the burden of disease for the patient. Patient-reported outcome measurements (PROMs) estimate health-related quality of life (HRQoL). PROMs can be generic or disease-specific. Generic PROMs allow comparisons between different diseases but can be relatively insensitive for measuring changes within a disease. Recommended QoL questionnaires in allergic rhinitis and rhinoconjunctivitis are the RQLQ (or adapted versions), in chronic rhinosinusitis, the SNOT-22 or RSOM-31, and in acute rhinosinusitis, the modified SNOT-16. PROMs can be used both for daily clinical work and for research. In daily practice, a quick evaluation of the questionnaire directly indicates how the patient is doing. It makes sure that symptoms important for the patient are not overlooked and, during the consultation, the physician can elaborate on specific aspects of the symptomatology. It is important, especially in research, to realize that disease-specific questionnaires are only validated for specific diseases and are not automatically valid for other diseases.     

Cystatin C and Cystatin SN As Possible Soluble Tumor Markers in Malignant Uveal Melanoma

BackgroundThe aim of the study was to determine the concentration of endogenous cystatin C and cystatin SN, as potential tumor biomarkers, in the serum and biological fluids of the eye in both healthy controls and patients with uveal melanoma.Patients and methodsThe concentration of both cystatins was determined in the intraocular fluid (IOF), tear fluid, and serum of patients with uveal melanoma and compared to baseline measurements in IOF, tears, serum, cerebral spinal fluid, saliva and urine of healthy controls.ResultsThe concentration of cystatin C in all the biological matrices obtained from healthy controls significantly exceeded the concentration of cystatin SN and was independent of gender. Cystatin C concentrations in the tear fluid of patients with uveal melanoma (both the eye with the malignancy, as well as the contralateral, non-affected eye), were significantly greater than cystatin C concentrations in the tear fluid of healthy controls and was independent of tumor size. The concentration of cystatin SN in IOF of patients with uveal melanoma was significantly less than the corresponding concentration of cystatin SN in healthy controls.ConclusionsThe ratio of cystatins (CysC:CysSN) in both the serum and tear fluid, as well as the concentration of cystatin SN in IOF, would appear to strongly suggest the presence of uveal melanoma. It is further suggested that multiple diagnostic criteria be utilized if a patient is suspected of having uveal melanoma, such as determination of the cystatin C and cystatin SN concentrations in serum, tears, and IOF, ocular fundus and ultrasound imaging, and biopsy with histopathological evaluation.Key words: uveal melanoma, cystatins, biomarkers, diagnosis     

National integration of European standards.

Over the last 20 years, increasing life expectancy has becomea major determinant of increasing cancer incidence, and theWorld Health Organization has estimated that with this ageingof populations there could, by 2020, be 16 million new casesper year and 10 million deaths. In Europe, where primary prevention,screening and application of modern cancer therapies have ledin recent years to generally decreasing trends in age-standardizedmortality rates, it has nevertheless been estimated that therewill be 1.25 million cancer deaths     

Multiphoton Imaging of the Glomerular Permeability of Angiotensinogen

Patients and animals with renal injury exhibit increased urinary excretion of angiotensinogen. Although increased tubular synthesis of angiotensinogen contributes to the increased excretion, we do not know to what degree glomerular filtration of systemic angiotensinogen, especially through an abnormal glomerular filtration barrier, contributes to the increase in urinary levels. Here, we used multiphoton microscopy to visualize and quantify the glomerular permeability of angiotensinogen in the intact mouse and rat kidney. In healthy mice and Munich-Wistar-Frömter rats at the early stage of glomerulosclerosis, the glomerular sieving coefficient of systemically infused Atto565-labeled human angiotensinogen (Atto565-hAGT), which rodent renin cannot cleave, was only 25% of the glomerular sieving coefficient of albumin, and its urinary excretion was undetectable. In a more advanced phase of kidney disease, the glomerular permeability of Atto565-hAGT was slightly higher but still very low. Furthermore, unlike urinary albumin, the significantly higher urinary excretion of endogenous rat angiotensinogen did not correlate with either the Atto565-hAGT or Atto565-albumin glomerular sieving coefficients. These results strongly suggest that the vast majority of urinary angiotensinogen originates from the tubules rather than glomerular filtration.The renin–angiotensin system (RAS) is one of the most important regulatory mechanisms of body fluid, electrolyte homeostasis, and BP.^1–4 RAS in the kidney is independently regulated from RAS in the systemic circulation, and it has been implicated in the development of hypertension and kidney diseases. For example, renal epithelial cell-specific overexpression of human angiotensinogen (AGT) in human renin transgenic mice resulted in increased renal angiotensin II, hypertension, and renal fibrosis without any changes in circulating angiotensin II.⁵ Also, Dahl salt-sensitive rats, which show low plasma renin activity under high salt feeding, had higher renal angiotensin II content in the kidney compared with normal salt-fed control animals.⁶ Although all components that are necessary for angiotensin II production are expressed in the kidney,³ AGT is, currently, the only component that is noninvasively measurable in the urine of patients. The level of urinary AGT reflects the activity of the intrarenal RAS, and it is associated with pathologic states in several experimental^7,8 and clinical studies.^9,10 Although the major source of the circulating AGT is the liver, we and others have previously shown that AGT is produced in the proximal tubules through a de novo pathway.^3,11 Intravenously injected human recombinant AGT (hAGT), which has little affinity for enzymatic cleavage by rodent renin because of high species specificity,^12,13 was undetectable in the urine of angiotensin II-induced hypertensive rats,⁸ suggesting that the increase in urinary AGT is likely of tubular rather than glomerular (plasma) origin. However, the plasma level of AGT is much greater than the plasma level of urinary AGT, and therefore, the increase in urinary AGT in a kidney injury model could result from the damage of the glomerular filtration barrier (GFB) and AGT leakage into the urine.Therefore, the present study was conducted to measure exactly how much AGT is filtered through the GFB and ultimately, excreted through the urine in normal circumstances and the glomerulosclerosis model of Munich-Wistar-Frömter (MWF) rats that shows significant GFB damage. We compared the glomerular permeability of AGT with the glomerular permeability of albumin, because albumin (66 kD) has a molecular mass similar to AGT (∼60 kD); also, the increase in its urinary excretion closely reflects the decline of renal function. Indirectly, these studies also addressed the currently highly debated issue of the glomerular filtration of albumin.^14–19 To compare the glomerular processing of these two proteins, we employed intravital multiphoton fluorescence microscopy, which has been used by our laboratory^15,20,21 and the laboratories of others,^16–19 to directly and quantitatively visualize the glomerular permeability of macromolecules.