Elevated serum PAR-1 levels as an emerging biomarker of inflammation to predict the dengue infection severity

The present study was designed to check the serum levels of protease-activated receptor (PAR-1) in patients during different phases of dengue severity. Moreover, a correlation between serum PAR-1 levels and hematological parameters, inflammatory cytokine levels, and liver functional changes was also determined. Based on the World Health Organization criteria, the study population was divided into: nonsevere dengue fever (DF; n = 30), severe dengue hemorrhagic fever (DHF; n = 19), and severe dengue shock syndrome (DSS; n = 11). The platelet count (PLT) and hematocrit (HCT) were analyzed using an automated hematology analyzer and liver function enzymes aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphate (ALP), bilirubin were checked by auto-analyzer using diagnostic kits. Moreover, the levels of inflammatory mediators C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-17 (IL-17), and PAR-1 were determined using respective ELISA kits. The HCT levels were elevated and platelet count decreased significantly during dengue complications (DHF and DSS) compared to the DF patients, while the levels of liver functional biomarkers AST, ALT, ALP, and bilirubin remained elevated in DHF and DSS groups than in the corresponding DF group. Similarly, the inflammatory cytokine levels of CRP, TNF-α, IL-6, and IL-17 in DHF and DSS subjects were markedly increased when observed against DF subjects. Notably, the PAR-1 levels were significantly elevated in DHF and DSS groups than in the DF group and positively correlated with changes in HCT levels, inflammatory biomarkers, and liver enzymes. Our findings conclude that PAR-1 levels persistently increased with the severity of the dengue infection and are strongly associated with various clinical manifestations. Thus, PAR-1 levels can be used as a diagnostic marker for assessing dengue severity.     

Limb salvage surgery in bone tumour with modular endoprosthesis

 Thirty-three patients with bone tumours were treated by resection of the growth and reconstruction with a Kotz modular endoprosthesis. The average follow-up was for 50 months, ranging from 14 to 79 months. At the last review, 12 patients (36%) had died due to the tumour and 9 others (27%) had metastases. All 4 patients with proximal tibial reconstruction had poor functional results, due to an extension lag or to knee stiffness. Four of the six tumours of the proximal femur were complicated by local recurrence or dislocation of the hip, and had poor or fair functional results. Of the patients with distal femoral reconstruction, 17 out of 22 had excellent or good functional results. Reconstruction with a modular prosthesis after resection of a tumour gives excellent or good functional results in more than three-fourths of the cases of distal femur reconstruction, but it should be used with caution in the proximal tibia and proximal femur.

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Resumé  33 patients avec une tumeur(s) osseuse(s) ont ete traites par résection chirurgicale suivie d’une reconstruction avec endoprothese modulaire de Kotz. Les patients étaient suivis pour une periode allant de 14 a 79 mois (50 mois). Au dernier bilan 12 malades (36%) avaient une mort liee a la-tumeur. Le resultat fonctionnel a ete insatisfaisant chez tous les patients ayant subi une reconstruction tibiale proximale: soit un deficit de l’extension due genou ou la raideur. Dans les deux-tiers des cas (4 sur 6) avec reconstruction femorale proximale, des complications ont été observees: recidive locale, luxation de la tete femorale et mauvais voir mediocre resultat fonctionnel. Plus des trois quarts des patients avec reconstruction femorale distale (17/22) ont eu un bon voir excellent resultat fonctionnel. Le type de reconstruction avec prothèse modulaire apres résection tumorale parait bien indiquée chez des patients avec grosse tumeur osseuse et souhaitant preserver une mobilité adequate. Cette chirurgie peut donner un bon ou excellent resultat fonctionnel dans plus de 3/4 des cas de reconstruction distale du femur, mais elle doit être utilisée avec précaution dans la reconstruction tibiale et femorale proximales vu le risque de complications a type de luxation de la tête femorale et de déficit de l’extension.

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Accepted: 8 July 1998     

Factors affecting mechanism and kinetics of drug release from matrix-based oral controlled drug delivery systems

Matrix technologies have often proven popular among the oral controlled drug delivery technologies because of their simplicity, ease in manufacturing, high level of reproducibility, stability of the raw materials and dosage form, and ease of scale-up and process validation. Technological advancements in the area of matrix formulation have made controlled-release product development much easier than before, and improved upon the feasibility of delivering a wide variety of drugs with different physicochemical and biopharmaceutical properties. This is reflected by the large number of patents filed each year and by the commercial success of a number of novel drug delivery systems based on matrix technologies. Matrix-based delivery technologies have steadily matured from delivering drugs by first-order or square-root-of-time release kinetics to much more complex and customized release patterns. In order to achieve linear or zero-order release, various strategies that seek to manipulate tablet geometry, polymer variables, and formulation aspects have been applied. Various drug, polymer, and formulation-related factors, which influence the in situ formation of a polymeric gel layer/drug depletion zone and its characteristics as a function of time, determine the drug release from matrix systems. Various mathematical models, ranging from simple empirical or semi-empirical (Higuchi equation, Power law) to more complex mechanistic theories that consider diffusion, swelling, and dissolution processes simultaneously, have been developed to describe the mass transport processes involved in matrix-based drug release. Careful selection of an appropriate model for drug release provides insight to the underlying mass transport mechanisms and helps in predicting the effect of the device design parameters on the resulting drug-release rate. Thus, a basic understanding of release kinetics and appropriate mechanisms of drug release from matrix system and their inter-relationships may minimize the number of trials in final optimization, thereby improving formulation development processes.     

Prognostic significance of metastasis-associated protein S100A4 (Mts1) in prostate cancer progression and chemoprevention regimens in an autochthonous mouse model.

PURPOSE: We recently showed that metastasis-promoting Mts1 gene (S100A4) and protein is overexpressed during progression of prostate cancer in humans. The purpose of this study was to assess the expression of S100A4 during autochthonous prostate cancer progression in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Because oral consumption of green tea polyphenols (GTP) has been shown to inhibit metastasis and prostate cancer in TRAMP, we further assessed the significance of S100A4 during chemoprevention regimen. EXPERIMENTAL DESIGN: Male TRAMP mice 8 weeks of age were equally divided into two groups. A freshly prepared 0.1% GTP solution in tap water was supplied thrice a week to experimental animals as the sole source of drinking fluid for 24 weeks, whereas the control group of animals received the same tap water throughout the experiment. The animals were sacrificed at 0, 8, 16, and 24 weeks of GTP feeding and were analyzed for S100A4 and E-cadherin. Additional untreated and treated nontransgenic controls were also included in the study. RESULTS: With the progression of age and prostate cancer growth in TRAMP mice, an increase in the expression of S100A4 at mRNA and protein level in dorsolateral prostate, but not in nontransgenic mice, occurred. GTP feeding to TRAMP mice resulted in marked inhibition of prostate cancer progression, which was associated with reduction of S100A4 and restoration of E-cadherin. CONCLUSIONS: S100A4 represents a promising marker for prostate cancer progression and could be employed as a biomarker in chemoprevention regimens.