Decreased Activity and Genetic Polymorphisms of CYP2C19 in Behçet's Disease

Behçet's disease (BD) is a systemic autoimmune disorder. Cytochrome P450 enzymes (CYPs) are responsible for various drug metabolism reactions as well as those of endogenous substances which may be associated with autoimmune disease susceptibility. Recently, we reported that in patients with BD, CYP2C9 seems to be down‐regulated due to inflammation. In the same Turkish patients with BD, we investigated whether also CYP2C19 activity is decreased. Lansoprazole (30 mg) was given as a probe drug to evaluate CYP2C19 activity in 59 patients with BD and 27 healthy control volunteers. An HPLC method was used to determine plasma lansoprazole and its metabolite, 5‐hydroxy lansoprazole, concentrations. The genotyping for CYP2C19 *2, *3 and *17 polymorphisms was made using PCR‐RFLP. The median lansoprazole/5‐hydroxy lansoprazole metabolic ratio (MR) in patients with BD was 2.6‐fold higher as compared to the healthy control group (p = 0.001, 22.6 (1.3–26) and 8.8 (0.5–140) as median and range, respectively). The CYP2C19*17*17 genotype frequency was found to be significantly less in the BD group as compared to the healthy controls (1.7% versus 14.8% in controls, p = 0.01). Additionally, colchicine treatment did not affect the CYP2C19 enzyme activity in six patients (p = 0.43). In conclusion, the patients with BD had lower CYP2C19 enzyme activity and lower frequency of the CYP2C19*17 allele as compared to those of the healthy controls. Further studies are warranted on the mechanisms underlying this relation. This study should also be applied to other autoimmune diseases similarly characterized by local or systemic inflammation.     

Protective effect of astaxanthin against cisplatin-induced gastrointestinal toxicity in rats

European Surgery - The aim of the present study was to demonstrate astaxanthin’s attenuating effects against cisplatin (CIS)-induced gastrointestinal toxicity in a rat model....     

The possible role of interleukin-33 as a new player in the pathogenesis of contrast-induced nephropathy in diabetic rats

Introduction: Patients with diabetic kidney disease (DKD) are more prone to contrast-induced nephropathy (CN). Apoptosis and autophagy were found to be essential in the pathogenesis of DKD. Interleukin-33 (IL-33) is a cytokine, but its role in DKD and CN is unknown. As IL-33 is modulated by apoptosis, we aimed to determine the relationship between IL-33 apoptosis and autophagy in DKD with CN. Materials and methods: Thirty male Sprague–Dawley rats were enrolled and randomly allocated into three groups. The first group was comprised of healthy rats (HRs), whereas the other two groups were made up of diabetic rats (DRs) and diabetic rats with CN (DRs?+?CN). All groups except the HRs received 50?mg/kg/day of streptozotocin (STZ). The DRs?+?CN group was induced by administering 1.5?mg/kg of intravenous radiocontrast dye on the 35th day. Results: We observed increased IL-33 in the kidney tissue following induction of CN in the DRs. The DRs showed moderate immunopositivity, and the DRs?+?CN showed severe immunopositivity for caspase-3, cleaved caspase-3, caspase-8, caspase-9, LC3B, and Beclin-1 in tubular cells and glomeruli. The DRs also showed moderate immunopositivity in tubular cells, and the DRs?+?CN group showed severe immunopositivity for IL-33 in tubular cells. Increased caspase-3 was found in both glomeruli and tubuli; however, we could not demonstrate IL-33 in glomeruli. This could be secondary to inactivation of IL-33 via increased caspase-3 activity. Conclusion: The release of IL-33 from necrotic cells might induce autophagy, which can further balance the effects of increased apoptosis secondary to CN in DKD.     

Does pedicle screw fixation under age 5 cause spinal canal narrowing? A CT study with minimum 5 years follow-up

Purpose

The aim of this retrospective study was to evaluate the changes in the vertebral body and spinal canal area in a group of patients who had pedicle screw fixation under age 5 for the treatment of congenital spinal deformity at least 5 year follow-up.

Methods

11 patients who had been operated due to spinal deformity under age 5 with who had a CT examination at least 5 years after the initial operation were included in the study. All patients underwent hemivertebrectomy and transpedicular fixation procedures at an average age of 3.18 years (range 2–5 years). All had preoperative CT to evaluate the congenital deformities. Measurements were done at the instrumented vertebrae as well as the un-instrumented ones above and below them to evaluate; vertebral body parameters, pedicle parameters and spinal canal area of upper instrumented vertebra (UIV), lower instrumented vertebra (LIV), upper adjacent un-instrumented vertebra and lower adjacent un-instrumented vertebra.

Results

The average follow-up was 7.2 (range 5–12) years. Six of the patients were over age 10 during the final CT examination while 5 were at age 7. Female-to male ratio was 8–3. Measurement of all the parameters in 22 instrumented and 22 non-instrumented segments showed a proportional increase rather than a decrease at each segment. The percentage of canal area growth at UIV and LIV was 21 and 17.5 %, respectively.

Conclusion

Pedicle screw instrumentation has no adverse effect on further spinal body, pedicle and canal growth and does not result in iatrogenic spinal canal stenosis.

     

Solitary bone metastasis in the tibia as a presenting sign of endometrial adenocarcinoma: a case report and the review of the literature

Background Metastasis to bone from endometrial adenocarcinoma is rare, when metastasises it usually locates in axial skeleton. Metastasis to extremities is extremely rare. Additionally the detection of the bone metastasis as a presenting feature is uncommon. In the present study we report the 10th cases of bone metastasis in the literature which located at tibial diaphysis and originated from endometrial adenocarcinoma as a presenting feature of the primary disease. Case Single tibial lesion was observed in a 70 years old woman. Biopsy confirmed metastatic adenocarcinoma of the unknown origin. We couldn’t find the primary origin with aggressive work-up. Tibial lesion regressed with radiotherapy. Endometrial adenocarcinoma is detected after the end of disease-free one year with the symptom of vaginal bleeding. After 47 months from initial tibial lesion and 35 months from gynaecologic operation, patient is still alive and disease free. Discussion Patients with endometrial adenocarcinoma presenting an isolated skeletal metastasis may exhibit an unusual group with a better prognosis. This study was presented as a poster exhibition at the 5th Meeting of Asia-Pasific Musculo Skeletal Tumour Society held between 23 and 25, April 2004, Izmir, Turkey.     

Development of Orally Applicable,Combinatorial Drug–Loaded Nanoparticles for the Treatment of Fibrosarcoma

Nanoparticulate systems have been receiving a significant attention especially for the treatment of cancer but one of the main hurdles is to produce these developed and high-tech nanosystems in large quantities. Anticancer drug formulations are generally designed for parenteral administrations but oral administration is still the most convenient route. In this study, orally applicable nano-sized chitosan nanoparticles (NPs) were successfully prepared using Nano Spray Dryer. It is possible to produce these NPs in large quantities by simply increasing the processing time using the machine without changing any parameter. A chemotherapeutic agent (imatinib mesylate; IMA) and nonsteroidal anti-inflammatory drug (dexketoprofen trometamol) were loaded together in these NPs. NPs were also functionalized with polyethylene glycol and folic acid to obtain long circulating NPs and tumor targeting. The antitumoral activities of formulations showed that these developed NPs can enhance the effectiveness. Animal experiments were performed on fibrosarcoma-bearing mice model, and the treatment with 0.8 mg/μL/kg IMA-loaded chitosan NPs was found to be successful to slow down the growth of tumors. The tumor tissues were removed from the animals and enzymatic activities were evaluated. The inhibitory effect of tyrosine kinase was found to be enhanced from 36.4% to 68.4% when IMA was used in combination with dexketoprofen trometamol. Furthermore, all dried NPs were found to be stable for more than a year at 25°C. Presented results show that these developed combinatorial drug–loaded NPs can be used for the treatment of fibrosarcoma, and these data can provide an insight, new strategies for productions or alternatives in cancer treatment.     

Expression profile of Toll-like receptor 4 in rat testis and epididymis throughout postnatal development

Toll-like receptors (TLRs) belonging to pattern recognition receptors are involved in maintaining testicular and epididymal immune homeostasis. The purpose of the current study was to investigate TLR4 expression in rat testis and epididymis throughout postnatal development. Weak staining was detected in peritubular myoid cells and immature Sertoli cells while no staining was observed in gonocytes during prepubertal period. However, TLR4 expression began to appear in spermatocytes in pubertal period and gradually increased in spermatids. An intense staining was observed in steps 5–19 spermatids in post pubertal and mature periods. Similarly, TLR4 expression in the testes steadily increased from pubertal period to mature period. Puberty also caused a significant increase in TLR4 expression in epididymis. TLR4 expression in cauda epididymis was lower as compared to those of other epididymal segments. The majority of epididymal epithelial cells exhibited apical TLR4 expression, whereas basal cells showed intense intracytoplasmic immunoreaction. We detected an intense staining in epididymal smooth muscle cells. The expression levels of TLR4 showed dynamic changes in both spermatogenic cells, and entire testicular and epididymal tissues during postnatal development. These results suggest that TLR4 expression contributes not only to inflammation but also to the development of spermatogenic cells.