Synthesis of some pyrazolines and pyrimidines derived from polymethoxy chalcones as anticancer and antimicrobial agents

The synthesis of a series of certain polymethoxy chalcones and some derived pyrazole, pyrimidine, and thiazolopyrimidine ring structures is reported. Eleven compounds 4 , 6 , 9 , 11 , 14–17 , 22 , 24 , and 25 were selected by the National Cancer Institute (NCI) to be screened for their in‐vitro anticancer activity, whereas all the synthesized compounds were evaluated for their in‐vitro antimicrobial activity. Compounds 4 , 6 , and 11 were found to possess a significant broad spectrum antitumor potential against most of the tested subpanel tumor cell lines. The pyrazolines 4 and 6 displayed remarkable growth inhibitory activities (GI₅₀ MG‐MID values of 2.10 and 1.38 µM, respectively), together with moderate cytostatic effects (TGI MG‐MID values of 47.9 and 42.7 µM, respectively). Meanwhile, the pyrimidin‐2‐one 11 showed a noticeable overall tumor growth inhibitory activity, together with high cytostatic and cytotoxic efficacies (GI₅₀, TGI and LC₅₀ MG‐MID values of 3.39, 17.4, and 61.7 µM, respectively). On the other hand, compounds 3 , 4 , 13 , 15 , 19 , 20 , and 23 were found to be the most active antimicrobial members in this investigation with a broad spectrum of activity. Compound 23 was four times superior to ampicillin against Pseudomonas aeruginosa. The best antifungal activity was demonstrated by compounds 4 , 5 , and 11 which possessed almost half the activity of clotrimazole against Candida albicans. Collectively, the obtained biological results suggest that compound 4 could be considered as a possible dual antimicrobial‐anticancer agent.     

The novel histone deacetylase inhibitor,AR‐42, inhibits gp130/Stat3 pathway and induces apoptosis and cell cycle arrest in multiple myeloma cells

Multiple myeloma (MM) remains incurable with current therapy, indicating the need for continued development of novel therapeutic agents. We evaluated the activity of a novel phenylbutyrate‐derived histone deacetylase inhibitor, AR‐42, in primary human myeloma cells and cell lines. AR‐42 was cytotoxic to MM cells at a mean LC₅₀ of 0.18 ± 0.06 μmol/l at 48 hr and induced apoptosis with cleavage of caspases 8, 9 and 3, with cell death largely prevented by caspase inhibition. AR‐42 downregulated the expression of gp130 and inhibited activation of STAT3, with minimal effects on the PI3K/Akt and MAPK pathways, indicating a predominant effect on the gp130/STAT‐3 pathway. AR‐42 also inhibited interleukin (IL)‐6‐induced STAT3 activation, which could not be overcome by exogenous IL‐6. AR‐42 also downregulated the expression of STAT3‐regulated targets, including Bcl‐xL and cyclin D1. Overexpression of Bcl‐xL by a lentivirus construct partly protected against cell death induced by AR‐42. The cyclin dependent kinase inhibitors, p16 and p21, were also significantly induced by AR‐42, which together with a decrease in cyclin D1, resulted in G₁ and G₂ cell cycle arrest. In conclusion, AR‐42 has potent cytotoxicity against MM cells mainly through gp130/STAT‐3 pathway. The results provide rationale for clinical investigation of AR‐42 in MM.     

Accuracy of routine magnetic resonance imaging in meniscal and ligamentous injuries of the knee: comparison with arthroscopy

The aim of this study was to detect the accuracy of routine magnetic resonance imaging (MRI) done in different centres and its agreement with arthroscopy in meniscal and ligamentous injuries of the knee. We prospectively examined 70 patients ranging in age between 22 and 59 years. History taking, plain X-ray, clinical examination, routine MRI and arthroscopy were done for all patients. Sensitivity, specificity, accuracy, positive and negative predictive values, P value and kappa agreement measures were calculated. We found a sensitivity of 47 and 100%, specificity of 95 and 75% and accuracy of 73 and 78.5%, respectively, for the medial and lateral meniscus. A sensitivity of 77.8%, specificity of 100% and accuracy of 94% was noted for the anterior cruciate ligament (ACL). We found good kappa agreements (0.43 and 0.45) for both menisci and excellent agreement (0.84) for the ACL. MRI shows high accuracy and should be used as the primary diagnostic tool for selection of candidates for arthroscopy. Level of evidence: 4.     

A prospective clinical, economic, and quality-of-life analysis comparing endovascular aneurysm repair (EVAR), open repair, and best medical treatment in high-risk patients with abdominal aortic aneurysms suitable for EVAR: the Irish patient trial.

PURPOSE: To report the results of a trial comparing endovascular aneurysm repair (EVAR) to open repair (OR) and best medical therapy (BMT) involving high-risk patients with abdominal aortic aneurysms (AAA) suitable for EVAR. METHODS: From 2002 to 2007, 1083 patients with aortic aneurysm disease were referred to a tertiary care university hospital. Of these, 162 (119 men; mean age 76 years) were high-risk patients with AAAs anatomically suitable for EVAR. Following comprehensive consultation with the patient, the family, and the primary physician, elective treatment was selected: OR (n=52), EVAR (n=66), or BMT (n=44). Outcomes were compared using Kaplan-Meier survival analyses and a parameter that measured the quality time spent without symptoms of disease or toxicity of treatment (Q-TWIST). RESULTS: Four-year freedom from aneurysm-related death following EVAR (96.7%) was markedly better compared to BMT (66.8%; p=0.002) and was similar to OR (93.9%, p=0.483). Four-year freedom from major adverse clinical events was significantly better with EVAR (78%) compared with BMT (28%; p=0.001) and was equivalent to OR (75%; p=0.519). The 4-year intervention-free survival rate for EVAR (95%) almost matched OR (98%; p=0.410). At 4 years, Q-TWIST was 3.64 years for EVAR patients, 3.60 years for OR, and 2.22 years for BMT. Q-TWIST significantly improved with EVAR compared to OR (p<0.003). In the cost analysis, 52 high-risk patients were treated with OR over the 5-year period (2002-2007) at a total inpatient cost of 1,257,457 euro. The 66 patients treated with EVAR (14 patients more than OR) incurred a lower cost of 1,129,138 euro. Including the cost of follow-up over 4 years, the mean cost per patient was 18,476 euro for EVAR and 24,252 euro for OR, a savings of 5,776 euro per patient treated with EVAR. CONCLUSION: In high-risk patients, EVAR reduces aneurysm-related death compared to BMT. Equated to the gold standard of open repair, EVAR, as a "one-time procedure," substantially reduces operative morbidity, hospital stay, costs, and utilization of intensive care facilities if performed in a high-volume center.     

Endoscopic antireflux repairs

The high prevalence of gastroesophageal reflux disease (GERD) in the Western societies has accelerated the need for new modalities of treatment. Currently, medical and surgical therapies are widely accepted among patients and physicians. New potent antisecretory drugs and the development of minimally invasive surgery for the management of reflux are at present the pivotal and largely accepted approaches to treatment. The minimally invasive treatment revolution, however, has stimulated several new endoscopic techniques. At present, the data is limited and further studies are necessary to compare the advantages and disadvantages of the various endoscopic techniques to medical and laparoscopic management of GERD. Further trials and device refinements will assist clinicians. In this article, we present an overview of the various techniques that are currently in practice and under study. We report the efficiency and durability of various endoscopic therapies for GERD. The potential for widespread use of these techniques will also be discussed. Articles and abstracts published in English on this topic were retrieved from Pubmed. Due to limited number of studies and various trials, strict criteria were not used for the pooled data presented, however, an effort was made to avoid bias by including only studies that used off-PPI scoring as baseline and intent to treat.     

A novel approach to the intraoperative assessment of the uncinate margin of the pancreaticoduodenectomy specimen

Background. Currently, there is no consensus regarding the pancreaticoduodenectomy (PD) margins examined intraoperatively or the technical protocol for frozen section examination. The aim of this work was to summarize our experience regarding the intraoperative examination of the uncinate margin and to compare it with the published literature. Materials and methods. Our local protocol for the intraoperative assessment of the uncinate margin of the PD specimen is described in this article. A PubMed® search limited to English language publications using terms along the theme of pancreaticoduodenectomy and margin was performed. Retrieved articles were categorized according to whether they discussed frozen section margin examination. Results. Ten articles published between 1981 and 2005 were retrieved which discussed the intraoperative examination of PD specimens. Of the 10 articles, 5 discussed the intraoperative consultation for diagnostic purposes only, 2 discussed the consultation for both diagnostic purposes and assessment of margins, and 3 discussed intraoperative assessment of margins only. Of the total of five articles that discussed the intraoperative assessment of margins, none detailed the technical protocol for examining the uncinate margin. Discussion. Our proposed protocol for the intraoperative assessment of the uncinate margin of PD specimens allows for its accurate evaluation and has not been described previously in the English literature.     

Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline from the American College of Physicians

RECOMMENDATION 1: In patients with respiratory symptoms, particularly dyspnea, spirometry should be performed to diagnose airflow obstruction. Spirometry should not be used to screen for airflow obstruction in asymptomatic individuals. (Grade: strong recommendation, moderate-quality evidence.) RECOMMENDATION 2: Treatment for stable chronic obstructive pulmonary disease (COPD) should be reserved for patients who have respiratory symptoms and FEV1 less than 60% predicted, as documented by spirometry. (Grade: strong recommendation, moderate-quality evidence.) RECOMMENDATION 3: Clinicians should prescribe 1 of the following maintenance monotherapies for symptomatic patients with COPD and FEV1 less than 60% predicted: long-acting inhaled beta-agonists, long-acting inhaled anticholinergics, or inhaled corticosteroids. (Grade: strong recommendation, high-quality evidence.) RECOMMENDATION 4: Clinicians may consider combination inhaled therapies for symptomatic patients with COPD and FEV1 less than 60% predicted. (Grade: weak recommendation, moderate-quality evidence.) RECOMMENDATION 5: Clinicians should prescribe oxygen therapy in patients with COPD and resting hypoxemia (Pao2 < or =55 mm Hg). (Grade: strong recommendation, moderate-quality evidence.) RECOMMENDATION 6: Clinicians should consider prescribing pulmonary rehabilitation in symptomatic individuals with COPD who have an FEV1 less than 50% predicted. (Grade: weak recommendation, moderate-quality evidence.).