Study of apoptosis-related interactions in colorectal cancer.

Abnormalities in apoptotic functions contribute to the pathogenesis of colorectal cancer. In this study, molecular interactions behind the apoptotic regulation have been explored. For this purpose, enrichment analysis was performed considering microRNAs (miRNAs) that putatively target TP53 and altered during colon cancer. This revealed gene associated with both TP53 and miRNAs. Further analysis showed that a significant molecular interaction between the shortlisted candidates (TP53, miR-143, KRAS, BCL2, and PLK1) exists. Mutation study was conducted to confirm the clinical relevance of candidates. It showed that the mutation extent does not significantly alter survival in patients thus making these candidates suitable as drug targets. Overall, we showed the importance of interactions between TP53, miR-143, KRAS, BCL2, and PLK1 with respect to colorectal cancer using bioinformatics approach.

Allelic polymorphism in the Plasmodium vivax dihydrofolate reductase gene among Indian field isolates.

In total, 129 Plasmodium vivax isolates from different geographical areas in India were analysed for point mutations in the P. vivax dihydrofolate reductase gene that were associated with pyrimethamine resistance. A gradual increase in the frequency of mutant genotypes was observed from north to south (p <0.0001). In the northern region (Delhi, Panna and Nadiad), the wild-type genotype was most prevalent, while the mutant genotype predominated in the coastal regions of southern India (Navi Mumbai, Goa and Chennai). Isolates from the Car-Nicobar islands showed only mutant genotypes. The differential geographical pattern of mutations may be associated with the transmission pattern.

Therapeutic evolution of benzimidazole derivatives in the last quinquennial period.

Benzimidazole, a fused heterocycle bearing benzene and imidazole has gained considerable attention in the field of contemporary medicinal chemistry. The moiety is of substantial importance because of its wide array of pharmacological activities. This nitrogen containing heterocycle is a part of a number of therapeutically used agents. Moreover, a number of patents concerning this moiety in the last few years further highlight its worth. The present review covers the recent work published by scientists across the globe during last five years.

Changes in bacterial profile during amebiasis: demonstration of anaerobic bacteria in ALA pus samples.

Little is known about the changes in gut resident flora during amebic colitis and amebic liver abscess (ALA) caused by Entamoeba histolytica infection. Fecal samples from ALA patients, from healthy E. histolytica negative and positive (asymptomatic) individuals, and from pre- and post-metronidazole-treated healthy volunteers and pus samples from ALA patients were tested for the presence of various bacterial genera using 16S rRNA-based primers. Statistically significant reduction in Lactobacillus due to E. histolytica infection was observed in asymptomatic individuals and ALA patients. On the other hand, reduction in Bacteroides, Bifidobacterium, and Clostridium in the same samples was due to metronidazole treatment. Two anaerobic genera, viz. Bacteroides and Peptostreptococcus, were detected in ALA pus samples, and this observation is unprecedented. In addition, PCR revealed metronidazole resistance genes in fecal and pus samples of metronidazole-treated individuals. Re-examination of the ameba-bacterium relationship in amebiasis is suggested.

EMT in cervical cancer: its role in tumour progression and response to therapy.

The prognosis of cervical patients significantly decreases as the cancer metastasizes to other parts of the body. The epithelial to mesenchymal transition (EMT) plays an important role in cervical cancer progression and metastasis. Recurrence is the primary cause of the increased number of deaths due to cervical cancer. Oncogenes, such as AEG1, Sam-68, FTS and miR-361-5p, induce EMT in cervical cancer. Tumour suppressors, such as LMX-1, SFRP1, klotho, and miR-155, suppress EMT in cervical cancer. Factors such as hypoxia, the radiation dose, cytokines, proteins, transcription factors, and signalling pathways also play an important role in the induction, progression and maintenance of EMT in cervical cancer. Overall, this review describes a wide range of factors with potential roles in EMT that have been identified to date, and this information could be important for the development of new and more effective therapeutics that ameliorate the negative impact of cervical pathogenesis via EMT.

Protective effect of sesamol against 6°Co γ-ray-induced hematopoietic and gastrointestinal injury in C57BL/6 male mice.

Protection of γ-ray-induced injury in hematopoietic and gastrointestinal (GI) systems is the rationale behind developing radioprotectors. The objective of this study, therefore, was to investigate the radioprotective efficacy and mechanisms underlying sesamol in amelioration of γ-ray-induced hematopoietic and GI injury in mice. C57BL/6 male mice were pre-treated with a single dose (100 or 50 mg/kg, 30 min prior) of sesamol through the intraperitoneal route and exposed to LD50/30 (7.5 Gy) and sublethal (5 Gy) dose of γ-radiation. Thirty-day survival against 7.5 Gy was monitored. Sesamol (100 mg/kg) pre-treatment reduced radiation-induced mortality and resulted survival of about 100% against 7.5 Gy of γ-irradiation. Whole-body irradiation drastically depleted hematopoietic progenitor stem cells in bone marrow, B cells, T cell subpopulations, and splenocyte proliferation in the spleen on day 4, which were significantly protected in sesamol pre-treated mice. This was associated with a decrease of radiation-induced micronuclei (MN) and apoptosis in bone marrow and spleen, respectively. Sesamol pre-treatment inhibited lipid peroxidation, translocation of gut bacteria to spleen, liver, and kidney, and enhanced regeneration of crypt cells in the GI system. In addition, sesamol pre-treatment reduced the radiation-induced pattern of expression of p53 and Bax apoptotic proteins in the bone marrow, spleen, and GI. This reduction in apoptotic proteins was associated with the increased anti-apoptotic-Bcl-x and PCNA proteins. Further, assessment of antioxidant capacity using ABTS and DPPH assays revealed that sesamol treatment alleviated total antioxidant capacity in spleen and GI tissue. In conclusion, the results of the present study suggested that sesamol as a single prophylactic dose protects hematopoietic and GI systems against γ-radiation-induced injury in mice.

Thrombotic thrombocytopenic purpura-like syndromes following bone marrow transplantation: an analysis of associated conditions and clinical outcomes.

The diagnosis and treatment of thrombotic thrombocytopenic purpura (TTP) in patients following BMT are often uncertain and unsuccessful. To better understand the evaluation and management of these patients, we describe 17 patients treated with plasma exchange for a presumptive diagnosis of TTP following BMT during a 10 year period, 1989-1998. Because of the uncertainty of the diagnosis, these patients are described as having a 'TTP-like syndrome'. All 17 patients had received an allogeneic BMT. Comparison with the other 245 patients who had an allogeneic BMT during the same period demonstrated that patients with a TTP-like syndrome more frequently had unrelated and/or HLA-mismatched donors, and had also experienced more serious complications: grade III-IV acute GVHD and systemic bacterial, fungal, and viral infections. Three months after the diagnosis of the TTP-like syndrome, only four of 17 patients (24%) were alive; currently only one patient survives. These data emphasize: (1) the diagnosis of TTP following BMT is uncertain because of the presence of multiple BMT-associated complications. (2) The outcome of patients with TTP-like syndromes following BMT is poor. (3) Urgent intervention with plasma exchange when TTP is suspected following BMT may not always be appropriate. Alternative explanations for the signs and symptoms should be considered and treated aggressively.

Association between complementary feeding practice and mothers education status in Islamabad.

OBJECTIVES: To examine the association between mother's education, complementary feeding practices and malnutrition amongst mothers attending outpatient clinics in Islamabad. METHODS: Mothers of 500 Pakistani infants attending the Paediatric Outpatient department at the Federal Government Services Hospital, Islamabad completed pretested questionnaires on mother's educational status and complementary feeding practices. RESULTS: A positive relationship was found between the nutritional status of infants and educational status of mothers (P < 0.001). The study revealed that the majority of infants with evidence of malnutrition belonged to the mothers with virtually no school education. A similar relationship was observed between the educational status of respondents and the introduction of complementary foods at an appropriate age (6 months) of infants (P < 0.001). CONCLUSION: Mother's education plays a vital role in increased receptivity to knowledge and awareness related to nutritional requirements of their infants.

Nitric oxide modulates basal and endothelin-induced coronary artery vascular smooth muscle cell proliferation and collagen levels.

The mechanisms governing the pathological accumulation of collagen in the extracellular matrix following angioplasty are complex, but may involve interactions between endothelium-derived paracrine agents and vascular cellular components. We tested the hypothesis that nitric oxide (NO) directly decreases collagen levels and decreases endothelin (ET-1)-stimulated increases in levels of specific collagen subtypes in coronary vascular smooth muscle cells (VSMC). Cultured VSMC were incubated for 48 h with the NO donor CAS 754 (10(-4) M), ET-1 (10(-8) M), or ET-1 plus CAS 754. In some experiments, angiotensin II (Ang II; 10(-8) M) was utilized in place of ET-1. Soluble collagen types I and III were quantitated with an ELISA method, and cell counts were performed. CAS 754 significantly inhibited cell proliferation (-17+/-2% v control), basal total protein synthesis (-65+/-7% v control), and basal collagen type I levels (-39+/-6% v control), but not collagen type III levels. ET-1 and Ang II both significantly stimulated cell proliferation (26+/-5% v control), total protein synthesis (169+/-6% v control), and collagen type I levels (200+/-11% v control). Ang II, but not ET-1, significantly increased collagen type III levels. Co-incubations of ET-1 and CAS 754 resulted in a significant decrease in cell proliferation, protein synthesis, and collagen levels (-23+/-2% v control, 90+/-5% v control, and 63+/-3% v control, respectively) compared to ET-1 alone. In contrast, co-incubation of Ang II and CAS 754 had no significant effect on cell proliferation, protein synthesis, and collagen levels seen with Ang II alone. These results demonstrate that NO inhibits basal collagen levels and cell division. Additionally, NO alters ET-1 stimulation of VSMC proliferation, protein synthesis, and production of extracellular matrix components. Thus, an imbalance in key endothelium-derived compounds could significantly impact upon extracellular matrix deposition following mechanical revascularization.

The effects of endothelin-1 on collagen type I and type III synthesis in cultured porcine coronary artery vascular smooth muscle cells.

Restenosis is the single most important factor limiting a favorable long-term outcome following mechanical revascularization. The vascular endothelium, through the release of key regulatory compounds, may regulate vascular structure by exerting fundamental control over collagen synthesis following injury to the vessel wall. We tested the hypothesis that endothelin (ET-1), an endothelium-derived peptide previously shown to be increased in pathological states, differentially stimulates porcine coronary vascular smooth muscle cell collagen types I and III synthesis. Monocultures of porcine coronary vascular smooth muscle were exposed to varying concentrations of endothelin over a 24-96-h time period. The medium was assayed for soluble collagen types I and III using a sensitive and specific ELISA method. Experiments were also done with the ET-1 antagonists PD 145065 and BQ123. Cell counts and viability were serially monitored. Experiments were also conducted with angiotensin II (A-II). A-II and ET-1 stimulated cell proliferation. ET-1 maximally stimulated collagen type I synthesis at 48 h at an optimal concentration of 10(-8) M, with no significant stimulation of collagen type III synthesis. The ETA specific antagonist BQ123 significantly inhibited the stimulatory effects of ET-1. A-II also stimulated collagen type I synthesis above basal levels, but was less efficacious than endothelin (95 +/- 5%, A-II, v 189 +/- 14% ET-1). In contrast to ET-1, A-II stimulated collagen type III synthesis (31 +/- 6% above basal, compared to -4 +/- 5% for ET-1). Results are also reported using smooth muscle cells from porcine aorta. The data demonstrate that ET-1 and A-II stimulate collagen synthesis by coronary artery vascular smooth muscle, and that they exert a differential effect over the two types of collagen that are present in the intima following balloon injury. Thus, the over expression of key regulatory compounds by endothelium following balloon injury could enhance collagen deposition and, consequently, play an integral role in intimal hyperplasia and restenosis.

Drug-induced thrombocytopenia.

Many drugs can induce thrombocytopenia mediated by drug-dependent antiplatelet antibodies. Recent studies have documented specific epitopes for drug-dependent antibody binding on glycoprotein Ib-IX, glycoprotein IIb-IIIa, and platelet-endothelial cell adhesion molecule-1. Molecular identification of antibody binding sites may help to identify susceptible individuals. Management of patients with unexpected thrombocytopenia who are taking multiple drugs remains a difficult clinical problem. A recent systematic review of all published case reports of drug-induced thrombocytopenia ranks drugs according to the strength of clinical evidence for a causal relation to thrombocytopenia. This database is available online at http://moon.ouhsc.edu/jgeorge.

Effects of thermal exposure on binding of heparin in vitro to the arterial wall and to clot and on the chronic angiographic luminal response to local application of a heparin film during angioplasty in an in vivo rabbit model.

Experimentally, heparin inhibits mechanisms that promote fibrosis, neointimal cellular proliferation, and thrombin bound to fibrin at the surface of intraluminal thrombus, but only in relatively high concentrations. A preliminary hypothesis was tested and confirmed in vitro that initial binding of 3H-heparin to mechanically injured porcine aorta is concentration-dependent over a 1,000-50,000 units/ml range (r = 0.9). The hypothesis was then tested in vitro that thermal exposure during contact of heparin to arterial tissue and to clot would enhance binding of the drug. 3H-heparin binding to clot, whole blood particulates, and washed erythrocytes was markedly enhanced by exposure to temperatures > 70 degrees C. Thermal exposure (80 degrees C x 40 s) also enhanced tissue persistence of the drug within porcine aorta subjected to a shear rate of 1,100(-1) in an annular Baumgartner chamber perfused with normal saline at 37 degrees C for 48 h. Heparin in vitro anticoagulant activity persisted after thermal exposure and binding to tissues. A new method was developed for local application of a heparin film that provides a maximum concentration with a tolerable systemic dose during an angioplasty procedure. In an in vivo rabbit model of mural fibrosis after iliac artery angioplasty, the 1-month mean angiographic luminal diameter loss (23% compared to the acute postangioplasty result by computer image analysis) in response to conventional balloon angioplasty (BA) and laser balloon angioplasty (LBA) was the same (P > 0.05). Local application of a heparin film (3,000 units at a concentration > 100,000 units/g), however, reduced the mean % loss in diameter 1 month after LBA (12%), but not after BA (29%), compared to arteries subjected to angioplasty without local heparin (P < .05). The results are consistent with the hypothesis that thermal energy enhances heparin binding to tissues and that local application of a heparin film favorably modulates arterial luminal responses to LBA, but not to BA, in this animal model.

Complications of plasma exchange in 71 consecutive patients treated for clinically suspected thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome.

BACKGROUND: With the increased frequency of diagnosis and improved survival of thrombotic thrombocytopenic purpura-hemolytic-uremic syndrome (TTP-HUS), the morbidity of plasma exchange (PE) treatment has become more important. STUDY DESIGN AND METHODS: Data were prospectively collected on 71 consecutive patients referred to the Oklahoma Blood Institute (OBI) for PE treatment for clinically suspected TTP-HUS from mid-1996 to mid-1999. Complications were defined as major or minor, and distinguished between those related to central venous catheter access or to the plasma. RESULTS: Twenty-one patients (30%) had 27 major complications, which caused two deaths. The major complications included 2 episodes of hemorrhage after subclavian line insertion (1 death), 1 pneumothorax requiring a chest tube, 12 systemic infections (1 death), 7 episodes of catheter thrombosis requiring removal of the central venous catheter, 2 episodes of venous thrombosis requiring anticoagulant treatment, 2 episodes of hypoxemia and hypotension, and 1 episode of serum sickness. Minor complications occurred in 22 additional patients (31%). Twenty-eight patients (39%) had no complications. CONCLUSIONS: The morbidity and mortality of catheter placement and PE are important considerations when PE treatment for clinically suspected TTP-HUS is anticipated.

Drug-induced thrombocytopenia: a systematic review of published case reports.

PURPOSE: To determine the strength of clinical evidence for individual drugs as a cause of thrombocytopenia. DATA SOURCES: All English-language reports on drug-induced thrombocytopenia. STUDY SELECTION: Articles describing thrombocytopenia caused by heparin were excluded from review. Of the 581 articles reviewed, 20 were excluded because they contained no patient case reports. The remaining 561 articles reported on 774 patients. DATA EXTRACTION: Two of the authors used a priori criteria to independently review each patient case report. Two hundred fifty-nine patient case reports were excluded from further review because of lack of evaluable data, platelet count of 100000 cells/microL or more, use of cytotoxic or nontherapeutic agents, occurrence of drug-induced systemic disease, or occurrence of disease in children. For the remaining 515 patient case reports, a level of evidence for the drug as the cause of thrombocytopenia was assigned. Data on bleeding complications and clinical course were recorded. DATA SYNTHESIS: The evidence supported a definite or probable causal role for the drug in 247 patient case reports (48%). Among the 98 drugs described in these reports, quinidine was mentioned in 38 case reports, gold in 11, and trimethoprim-sulfamethoxazole in 10. Of the 247 patients described in the case reports, 23 (9%) had major bleeding and 2 (0.8%) died of bleeding. CONCLUSIONS: Many reports of drug-induced thrombocytopenia do not provide evidence supporting a definite or probable causal relation between the disease and the drug. Future patient case reports should incorporate standard criteria to clearly establish the etiologic role of the drug.