2011 Vol. 25, No. 6
Visceral leishmaniasis or kala-azar is a potent parasitic infection causing death of thousands of people each year. Medicinal compounds currently available for the treatment of kala-azar have serious side effects and de-creased efficacy owing to the emergence of resistant strains. The type of immune reaction is also to be considered in patients infected with Leishmania donovani (L. donovani). For complete eradication of this disease, a high level modern research is currently being applied both at the molecular level as well as at the field level. The computa-tional approaches like remote sensing, geographic information system (GIS) and bioinformatics are the key re-sources for the detection and distribution of vectors, patterns, ecological and environmental factors and genomic and proteomic analysis. Novel approaches like GIS and bioinformatics have been more appropriately utilized in determining the cause of visearal leishmaniasis and in designing strategies for preventing the disease from spread-ing from one region to another.
Tacrolimus ointment and pimecrolimus cream have proved to be suitable for the treatment of atopic dermati-tis. We conducted a meta-analysis of the efficacy, adverse events/withdrawal of tacrolimus versus pimecrolimus in the treatment of atopic dermatitis. According to our meta-analysis, 0.1% tacrolimus was more effective than 1% pimecrolimus in the treatment of adult patients and moderate to very severe pediatric patients, and more 0.1% mild pediatric patients treatal with pimecrolimus withdrew from the trials because of a lack of efficacy or the oc-currence of adverse events, compared with mild pediatric patients treated with 0.03% tacrolimus. The combined analyses of tacrolimus with pimecrolimus showed that tacrolimus was more effective than pimecrolimus (week 3: RR=0.67, 95%CI=0.56-0.80; week 6/end of study: RR=0.65, 95%CI=0.57-0.75), and fewer tacrolimus-treated patients withdrew because of a lack of efficacy (RR=0.32, 95CI%=0.19-0.53) or the occurrence of adverse events (RR=0.43, 95%CI=0.24-0.75), compared with pimecrolimus-treated patients. In conclusion, tacrolimus has higher efficacy and better tolerance than pimecrolimus in the treatment of atopic dermatitis.
Iptakalim is a new ATP-sensitive potassium (KATP) channel opener, and it inhibits the proliferation of pulmo-nary arterial smooth muscle cells (PASMCs) and pulmonary vascular remodeling. However, the underlying mech-anism remains unclear. In the present study, we found that iptakalim significantly decreased pulmonary artery pressure, inhibited pulmonary ariery remodeling and PKC-α overexpression in chronic hypoxia in a rat pulmonary hypertension model. Iptakalim reduced hypoxia-induced expression of PKC-α, and abolished the effect of hypoxia on PASMC proliferation significantly in a dose-dependent manner in vitro. Moreover, these effects were abol-ished by glibenclamide, a selective KATP channel antagonist. These results indicate that iptakalim inhibits PASMC proliferation and pulmonary vascular remodeling induced by hypoxia through downregulating the expression of PKC-α. Iptakalim can serve as a novel promising treatment for hypoxic pulmonary hypertension.
The proliferation of glomerular mesangial cells (GMC) and secretion of the extracellular matrix (ECM) in rat with Thy-1 nephritis (Thy-1N) resembling human mesangioproliferative glomerulonephritis have been explored for many years; however, the molecular mechanisms of GMC proliferation and ECM production remain unclear. Our previous studies have demonstrated that the thrombospondin-1 (TSP-1) gene was involved in mediating rat GMC proliferation and ECM synthesis induced by sublytic C5b-9 in vitro. In the present study, the roles of the TSP-1 gene in GMC proliferation, ECM production, and urinary protein secretion in Thy-1N rats were determined by using TSP-1 small hairpin RNA, and the results revealed that silencing of the TSP-1 gene in rat renal tissues could diminish GMC proliferation (P < 0.01) and ECM secretion (P < 0.01) as well as urinary protein secretion (P < 0.05) in Thy-1N rats. Together, the current findings suggested that TSP-1 gene expression was required for GMC proliferation and ECM production in Thy-1N rats.
Diabetic nephropathy is a major cause of end-stage renal disease (ESRD) in the general population. It is es-timated that diabetic nephropathy will eventually develop in about 40% of all patients with diabetes; therefore, prevention is critical for delaying the development and progression of diabetic kidney disease. Despite extensive efforts, medical advances are still not successful enough to prevent the progression of the disease. In the present study, we focused on the comparison of combination therapies and whether they offered additional renopro-tection. Type 2 diabetes mellitus was induced by intraperitoneally administering streptozotocin (90 mg/kg) in neonatal rats and then these rats were treated with rosiglitazone (1.0 mg/kg) in combination with glimepiride (0.5 mg/kg) or with pioglitazone (2.5 mg/kg) in combination with glimepiride (0.5 mg/kg). Diabetic nephropathy markers were evaluated by biochemical and ELISA kits and renal structural changes were examined by light mi-croscopy and transmission electron microscopy. Results show that the combination of pioglitazone with glimepir-ide is more effective in amelioration of diabetic nephropathy than rosiglitazone with glimepiride drug therapy due to glycemic control, suppressing albumin excretion rate, total protein excretion rate and augmented TNF-a signal-ing during the development of streptozotocin induced type 2 diabetic nephropathy.
We studied the fracture resistance of maxillary premolars restored with recent restorative materials. Fifty max-illary premolars were divided into five groups: Group 1 were unprepared teeth; Group 2 were teeth prepared with-out restoration; Group 3 were teeth restored with tetric ceram HB; Group 4 were teeth restored with InTen S; and Group 5 were teeth restored with Admira. The samples were tested using a universal testing machine. Peak loads at fracture were recorded. The teeth restored with Admira had the highest fracture resistance followed by those re-stored with InTen-S and tetric ceram HB. Prepared, unrestored teeth were the weakest group. There was a signifi-cant difference between the fracture resistance of intact teeth and the prepared, unrestored teeth. There was also a significant difference among the tested restorative materials. Teeth restored with Admira showed no significant difference when compared with the unprepared teeth. It was concluded that the teeth restored with Admira exhib-ited the highest fracture resistance.
The aim of this study was to examine how somatic mutations of the GATA4 gene contributed to the genesis of ventricular septal defect (VSD). The coding and intron-exon boundary regions of GATA4 were sequenced of DNA samples from peripheral blood cells and cardiac tissues of twenty surgically treated probands with VSD. Seven novel heterozygous variants were detected in cardiac tissues from VSD patients, but they were not detected in the peripheral blood cells of VSD patients or in 500 healthy control samples. We replicated 14 single nucleotide polymorphisms (SNPs) reported in NCBI. Bioinformatics analysis was performed to analyze the possible mecha-nism by which mutations were linked to VSD. Among those variants, c. 1004C>A (p.S335X) occurred in the highly conserved domain of GATA4 and generated a termination codon, which led to the production of truncated GATA4. The seven novel heterozygous GATA4 mutations were only identified in cardiac tissues with VSD, sug-gesting that they are of somatic origin. A higher mutation rate in cardiac tissues than in peripheral blood cells im-plies that the genetic contribution to VSD may have been underestimated.
In the present study, we evaluated computed tomography pulmonary angiography (CTPA) in guiding therapeu-tic decisions and monitoring patients undergoing percutaneous catheter fragmentation in acute massive pulmonary embolism. From Jan 2003 to Dec 2009, 35 patients were diagnosed with acute massive pulmonary embolism by CTPA (T0) and treated with percutaneous catheter fragmentation. The severity was assessed by CT obstruction index (Qanadli index) and compared with Miller index. CTPA, oxygen saturation (SaO2) and pulmonary artery pressure were performed as follow-up index. The mean percentage of Qanadli index was (55±13)% (range, 40%-75%), and Miller index was (62±15)% (range, 45%–85%). Correlations between them were statistically signifi-cant (r = 0.867, P < 0.0001). The Qanadli index showed significant reduction [T0: (55±13)%; T1: (12±10)%; P < 0.001] in 33 patients. Significant correlation was observed between the Qanadli index, SaO2 (r = 0.934), and pulmonary artery pressure (r = 0.813). The Qanadli index provides an accurate method for distinguishing massive pulmonary embolism from sub-massive pulmonary embolism. It can be used to determine therapeutic options and monitor clinical outcomes.
2011, 25(6): 438-443. doi: 10.1016/S1674-8301(11)60058-4
Phosphatase of regenerating liver-3 (PRL-3) is a member of the protein tyrosine phosphatase (PTP) superfamily and is highly expressed in cancer metastases. For better understanding of the role of PRL-3 in tumor metastasis, we applied a rapid and efficient method for generating PRL-3 floxed mice and investigated its phenotypes. A BAC retrieval strategy was applied to construct the PRL-3 conditional gene-targeting vector. Exon 4 was selected for deletion to generate a nonfunctional prematurely terminated short peptide as it will cause a frame-shift mutation. Conditional knockout PRL-3 mice were generated by using the Cre-loxP system and were validated by Southern blot and RT-PCR analysis. Further analysis revealed the phenotype characteristics of PRL-3 knockout mice and wildtype mice. In this study, we successfully constructed the PRL-3 conditional knockout mice, which will be helpful to clarify the roles of PRL-3 and the mechanisms in tumor metastasis.
Active Motif Finder (AMF) is a novel algorithmic tool, designed based on mutations in DNA sequences. Tools available at present for finding motifs are based on matching a given motif in the query sequence. AMF describes a new algorithm that identifies the occurrences of patterns which possess all kinds of mutations like insertion, de-letion and mismatch. The algorithm is mainly based on the Alignment Score Matrix (ASM) computation by com-paring input motif with full length sequence. Much of the effort in bioinformatics is directed to identify these mo-tifs in the sequences of newly discovered genes. The proposed bio-tool serves as an open resource for analysis and useful for studying polymorphisms in DNA sequences. AMF can be searched via a user-friendly interface. This tool is intended to serve the scientific community working in the areas of chemical and structural biology, and is freely available to all users, at http://www.sastra.edu/scbt/amf/.