Inhibitors of tumor progression loci-2 (Tpl2) kinase and tumor necrosis factor alpha (TNF-alpha) production: selectivity and in vivo antiinflammatory activity of novel 8-substituted-4-anilino-6-aminoquinoline-3-carbonitriles

Tumor progression loci-2 (Tpl2) (Cot/MAP3K8) is a serine/threonine kinase in the MAP3K family directly upstream of MEK. Recent studies using Tpl2 knockout mice have indicated an important role for Tpl2 in the lipopolysaccharide (LPS) induced production of tumor necrosis factor alpha (TNF-alpha) and other proinflammatory cytokines involved in diseases such as rheumatoid arthritis. Initial 4-anilino-6-aminoquinoline-3-carbonitrile leads showed poor selectivity for Tpl2 over epidermal growth factor receptor (EGFR) kinase. Using molecular modeling and crystallographic data of the EGFR kinase domain with and without an EGFR kinase-specific 4-anilinoquinazoline inhibitor (erlotinib, Tarceva), we hypothesized that we could diminish the inhibition of EGFR kinase by substitution at the C-8 position of our 4-anilino-6-aminoquinoline-3-carbonitrile leads. The 8-substituted-4-anilino-6-aminoquinoline-3-carbonitriles were prepared from the appropriate 2-substituted 4-nitroanilines. Modifications to the C-6 and C-8 positions led to the identification of compounds with increased inhibition of TNF-alpha release from LPS-stimulated rat and human blood, and these analogues were also highly selective for Tpl2 kinase over EGFR kinase. Further structure-activity based modifications led to the identification of 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-[(1-methyl-1H-imidazol-4-yl)methylamino]quinoline-3-carbonitrile, which demonstrated in vitro as well as in vivo efficacy in inhibition of LPS-induced TNF-alpha production.     

Effects of zoledronate versus placebo on spine bone mineral density and microarchitecture assessed by the trabecular bone score in postmenopausal women with osteoporosis: A three‐year study

The trabecular bone score (TBS) is an index of bone microarchitectural texture calculated from anteroposterior dual‐energy X‐ray absorptiometry (DXA) scans of the lumbar spine (LS) that predicts fracture risk, independent of bone mineral density (BMD). The aim of this study was to compare the effects of yearly intravenous zoledronate (ZOL) versus placebo (PLB) on LS BMD and TBS in postmenopausal women with osteoporosis. Changes in TBS were assessed in the subset of 107 patients recruited at the Department of Osteoporosis of the University Hospital of Berne, Switzerland, who were included in the HORIZON trial. All subjects received adequate calcium and vitamin D3. In these patients randomly assigned to either ZOL (n = 54) or PLB (n = 53) for 3 years, BMD was measured by DXA and TBS assessed by TBS iNsight (v1.9) at baseline and 6, 12, 24, and 36 months after treatment initiation. Baseline characteristics (mean ± SD) were similar between groups in terms of age, 76.8 ± 5.0 years; body mass index (BMI), 24.5 ± 3.6 kg/m²; TBS, 1.178 ± 0.1 but for LS T‐score (ZOL–2.9 ± 1.5 versus PLB–2.1 ± 1.5). Changes in LS BMD were significantly greater with ZOL than with PLB at all time points (p < 0.0001 for all), reaching +9.58% versus +1.38% at month 36. Change in TBS was significantly greater with ZOL than with PLB as of month 24, reaching +1.41 versus–0.49% at month 36; p = 0.031, respectively. LS BMD and TBS were weakly correlated (r = 0.20) and there were no correlations between changes in BMD and TBS from baseline at any visit. In postmenopausal women with osteoporosis, once‐yearly intravenous ZOL therapy significantly increased LS BMD relative to PLB over 3 years and TBS as of 2 years. © 2013 American Society for Bone and Mineral Research.     

Efficacy and safety of the TAIS coronary stent implantation: nine month multicenter study

AIM: Assessment of clinical and angiographic results of a balloon-expandable steel matrix stent TAIS in patients with atherosclerosis of the coronary arteries with no history of previous interventions in the course of an open non-randomized multicenter trial. MATERIAL AND METHODS: The TAIS stent was implanted in 187 patients into 199 stenoses. 47% patients had clinical manifestations of unstable angina pectoris. 29% cases were complicated. The length of the stenoses reached 11.3 +/- 5.4 mm, 22% stenoses were prolonged. RESULTS: This coronary stenting was effective in 100% cases, neither acute nor subacute thromboses were seen. Myocardial infarction without occlusion of the stent developed in 3 patients. The incidence of cardial complications (death, angina, restenosis, repeated revascularization) in 6 month follow-up was 11.8%. An angiographic control in 6 months was made in 184 patients (194 stenoses). The vascular diameter loss index was 0.40 +/- 0.21, a restenosis level--10.7%. A logistic regression analysis has revealed significant correlations between the length of the stent and a target vascular diameter with subsequent restenosis. Repeated revascularization was performed in all the patients with stent restenosis. After control angiography cardiac complications developed in 13.9% patients. Nine month follow-up registered cardiac complications in 17.6% cases. CONCLUSION: The TAIS stent was found effective in prevention of thrombosis and restenosis in patients with a relatively high risk of intervention.     

Does off‐pump coronary artery bypass surgery reduce secretion of plasminogen activator inhibitor‐1?

Prior studies showed that postoperative increase in plasminogen activator inhibitor-1 (PAI-1) levels is associated with an increased risk of graft occlusion after coronary artery bypass surgery (CABG). This prospective study aimed to compare the changes of PAI-1 antigen levels after off-pump and on-pump CABG. Forty-four patients admitted for elective CABG were randomised to on-pump (n=22) or off-pump (n=22) surgery. Serum samples were collected for estimation of PAI-1 and tissue plasminogen activator (t-PA) antigen levels preoperatively and 2 h after the operation. The groups were similar in terms of age, weight, gender ratio and extent of coronary disease, left ventricular function and number of grafts per patient. Fibrinogen and t-PA levels increased postoperatively in both the groups when compared with baseline values. After operation, statistical analysis revealed that increase of PAI-1 values was higher in off-pump group (44.1+/-9.1 vs. 25.3+/-6.9) than on-pump group (37.2+/-5.5 vs. 27.3+/-7.8, p=0.002). This study shows that increase in PAI-1 antigen values in patients who undergo off-pump (beating heart) CABG is significantly higher than in those who undergo conventional CABG with cardiopulmonary bypass.     

Evaluation of Pulmonary and Extrapulmonary Tuberculosis in Immunocompetent Adults: A Retrospective Case Series Analysis

Objective

It was the aim of this study to evaluate the demographic factors and clinical features of extrapulmonary tuberculosis (EPTB) compared to those of pulmonary tuberculosis (PTB) among adult immunocompetent patients.

Subjects and Methods

A total of 427 patients with clinically, radiologically and histopathologically confirmed TB were enrolled in the study, in our clinic at a tertiary care hospital in Turkey, during a 5-year period (2007-2012). Patient data were obtained retrospectively. Among the 427 patients, 55 patients with both PTB and EPTB and who were using steroids or had taken immunosuppressive drugs were excluded from the study.

Results

Of the 372 patients, 227 (61%) were males and 168 (45.2%) had EPTB; 204 (54.8%) patients had PTB. The most frequent sites of EPTB were the lymph nodes (n = 45, 12.1%), pleura (n = 40, 10.7%) and brain (n = 7, 1.8%). The most common symptoms were cough (n = 174, 46.7%), night sweats (n = 127, 34.1%) and fever (n = 123, 33%). Compared to EPTB patients, PTB patients were less likely to have received Bacillus Calmette-Guérin vaccination (odds ratio 0.41, 95% confidence interval 0.2-0.63; p < 0.001). Eighty-one (48.2%) of the EPTB and 146 (71.6%) of the PTB patients were males. Pulmonary involvement was more common among men (n = 146, 71.6%) than among women (n = 58, 28.2%; p = 0.000).

Conclusion

There was a high incidence of EPTB in our study. Early diagnosis of EPTB is crucial for treatment, and atypical presentations of TB should be kept in mind for immunocompetent patients living in endemic areas. Females especially should be investigated for EPTB.Key Words: Tuberculosis, Extrapulmonary tuberculosis, Clinical features     

Inter- and intraobserver reliability of the Crowe and Hartofilakidis classifications in the assessment of developmental dysplasia of the hip in adult patients

Background

The purpose of this study is to investigate the inter- and intraobserver reliability of Crowe and Hartofilakidis classifications in the assessment of developmental dysplasia of the hip in adult patients.

Materials and methods

Two consultant orthopedic surgeons classified 141 dysplastic hips on 103 standard anterior–posterior pelvis radiographs according to the Crowe and Hartofilakidis classifications. Assessments were performed in random order by each observer on two separate occasions, at least 4?weeks apart. Kappa statistics were used to establish a relative level of agreement between observers for the two readings and between separate readings by the same observer.

Results

At the first readings, interobserver reliability analysis revealed kappa coefficient of 0.71 for the Crowe classification and 0.54 for the Hartofilakidis classification. At the second reading, the kappa coefficient was 0.72 for the Crowe classification and 0.75 for the Hartofilakidis classification. Intraobserver reliability analysis revealed kappa coefficients of 0.71 for the Crowe and 0.80 for the Hartofilakidis classification for observer A, and 0.76 and 0.70 for observer B.

Conclusions

In conclusion, we have found substantial inter- and intraobserver agreement for Crowe classification and substantial to moderate agreement for Hartofilakidis classification in this study. Both classification systems assess the different aspects of developmental dysplasia of hip in adults. Each system has advantages and disadvantages. We suggest using both of these classifications together to increase the accuracy.     

The dangerous fifth chamber: congenital left atrial appendage aneurysm

Aneurysms of the left atrial appendage are extremely rare. Enlargement of the left atrial appendage can be congenital or acquired. Dysplasia of the left atrial muscles leads to congenital left atrial appendage aneurysm and usually presents as atrial tachyarrhythmia or embolic events in the second or third decade of life. We report a case of an asymptomatic 12-year-old child with a congenital left atrial appendage aneurysm. Transthoracic and transoesophageal echocardiography demonstrated a large left atrial appendage aneurysm without thrombus or spontaneous echo-contrast. The patient was successfully treated with surgical resection of the aneurysm.     

Vaccination of bovines against Echinococcus granulosus (cystic echinococcosis)

Hydatid disease is an important human zoonosis. Humans become infected from carnivores that are infected with the Echinococcus granulosus tapeworm. Carnivores become infected after consuming hydatid cysts from grazing animals, which are generally sheep, goats and cattle. A vaccine, known as EG95, can protect sheep and goats against cystic echinococcosis. This paper describes the adaptation of the EG95 vaccine for use in cattle. The monitoring of results used serology and also infection with E. granulosus eggs, followed by necropsy. Immunisation with living E. granulosus oncospheres showed that cattle could be immunised against E. granulosus. Immunisation of cattle with EG95 plus QuilA was also successful. A dose-response and adjuvant trial showed best results were achieved with 250 μg of antigen and 5mg of the adjuvant QuilA, which was 5 times the recommended sheep dose. After two vaccinations given one month apart, 90% protection was maintained for 12 months. At 12 months a third vaccination boosted protection to 99% which was maintained for a further 11 months.