NF-kappaB-independent down-regulation of XIAP by bortezomib sensitizes HL B cells against cytotoxic drugs

The proteasome inhibitor bortezomib has been shown to possess promising antitumor activity and significant efficacy against a variety of malignancies. Different studies demonstrated that bortezomib breaks the chemoresistance in different tumor cells basically by altering nuclear factor-kappaB (NF-kappaB) activity. NF-kappaB has been shown to be constitutively active in most primary Hodgkin-Reed-Sternberg (H-RS) cells in lymph node sections and in Hodgkin lymphoma (HL) cell lines and was suggested to be a central molecular switch in apoptosis resistance in HL. Here we report a bimodal effect of bortezomib in HL cells. Whereas high-dose bortezomib induced direct cytotoxicity that correlated with decreased NF-kappaB activity, low-dose bortezomib sensitized HL cells against a variety of cytotoxic drugs without altering NF-kappaB action. Strikingly, bortezomib induced marked XIAP down-regulation at the posttranslational level that was independent of the NF-kappaB status. Similarly, RNA interference (RNAi)-mediated XIAP down-regulation generated susceptibility to cytostatic agents. The results identify XIAP as an NF-kappaB-independent target of bortezomib action that controls the chemoresistant phenotype of HL cells.     

A case of granulomatous mastitis with erythema nodosum and arthritis

Idiopathic granulomatous mastitis is an inflammatory mass in the breast. Patients typically present with a firm breast mass, often associated with inflammation of the overlying skin. Nipple retraction, peau d’orange-like changes, and axillary adenopathy may be present. We describe a 23-year-old pregnant woman with arthritis, erythema nodosum, and mastitis.     

Opportunistic infections in patients with inflammatory bowel disease: prevention and diagnosis

Because of the increasing use of immunosuppressive and biological drugs, the occurrence of opportunistic infections has become a key safety issue for patients with inflammatory bowel disease (IBD). Consequently, improvement of healthcare workers' knowledge of this domain is urgent. In this review, the preventive measures that would help to reduce the rate of opportunistic infections in patients with IBD are listed, and the management of situations frequently confronting doctors is considered. In the absence of national and international recommendations, the information given here should help doctors to optimise patient outcomes.     

Mortality incidence of patients with non-obstructive coronary artery disease diagnosed by computed tomography angiography

It was previously reported that event-free survival rates of symptomatic patients with coronary artery disease (CAD) diagnosed by computed tomographic angiography decreased incrementally from normal coronary arteries to obstructive CAD. The aim of this study was to investigate the clinical outcomes of symptomatic patients with nonobstructive CAD with luminal stenoses of 1% to 49% on the basis of coronary plaque morphology in an outpatient setting. Among 3,499 consecutive symptomatic subjects who underwent computed tomographic angiography, 1,102 subjects with nonobstructive CAD (mean age 59 ± 14 years, 69.9% men) were prospectively followed for a mean of 78 ± 12 months. Coronary plaques were defined as noncalcified, mixed, and calcified per patient. Multivariate Cox proportional-hazards models were developed to predict all-cause mortality. The death rate of patients with nonobstructive CAD was 3.1% (34 deaths). The death rate increased incrementally from calcified plaque (1.4%) to mixed plaque (3.3%) to noncalcified plaque (9.6%), as well as from single- to triple-vessel disease (p <0.001). In subjects with mixed or calcified plaques, the death rate increased with the severity of coronary artery calcium from 1 to 9 to ≥ 400. The risk-adjusted hazard ratios of all-cause mortality in patients with nonobstructive CAD were 3.2 (95% confidence interval 1.3 to 8.0, p = 0.001) for mixed plaques and 7.4 (95% confidence interval 2.7 to 20.1, p = 0.0001) for noncalcified plaques compared with calcified plaques. The areas under the receiver-operating characteristic curve to predict all-cause mortality were 0.75 for mixed and 0.86 for noncalcified coronary lesions. In conclusion, this study demonstrates that the presence of noncalcified and mixed coronary plaques provided incremental value in predicting all-cause mortality in symptomatic subjects with nonobstructive CAD independent of age, gender, and conventional risk factors.     

Expected response to protease inhibitors of HIV-1 non-B subtype viruses according to resistance algorithms

The expected effectiveness of protease inhibitors was assessed according to the Agence Nationale de Recherches sur le SIDA (ANRS), Rega and Stanford 2007 resistance algorithms in 93 and 87 antiretroviral therapy-naive patients, respectively, infected with B and non-B subtype viruses. Either B or non-B subtypes were considered fully susceptible to protease inhibitors, except to tipranavir/ritonavir, for which the 2007 ANRS algorithm scored non-B subtypes as naturally resistant when this algorithm was extended to these subtypes.     

Evaluation of CD11b expression on peripheral blood neutrophils for early detection of neonatal sepsis

Neonatal sepsis is a disease of infants who are less than 1 month of age. These infants are clinically ill, and their blood culture are positive for bacteria. The reported incidence of neonatal sepsis for all infants is 1 to 10 per 1000 live births. The mortality rate is 4.2-26%. The clinical signs are not specific and diagnosis of neonatal sepsis is one of the most difficult tasks in clinical medicine. The aim of this work was determination of CD11b sensitivity and specificity for early detection of neonatal sepsis. We studied 65 neonates with gestational age of 27 to 38 weeks who were suspected for sepsis within the 28 days of life. Whole blood was obtained from neonates to determine CD11b expression on peripheral blood neutrophils by flow cytometry. C-Reactive protein (CRP) was measured qualitatively. Neonates were divided into two groups. Classification was based on the result of the blood culture. In the sepsis group all of the neonates (n=8) showed positive blood culture and clinical symptoms. In the suspected group (n=57) the neonates showed clinical signs but blood cultures were negative. Sensitivity and specificity of CD11b were 75%, 100% respectively. Also positive and negative predictive values of CD11b were 100% and 86% respectively. Results of present study and previous studies showed that measurement of neutrophil surface markers can be useful for diagnosis of infection in the early phases. Also, the quantitative measurement of CRP in addition to CD11b further enhances the ability to diagnose infections and improves sensitivity and negative predictive value by 100%.     

Risk factors associated with diabetic foot ulcer-free survival in patients with diabetes

Aims

This study was done to assess the risk factors associated with diabetic foot ulcer-free survival in patients with diabetes.

Alteration of cyclic nucleotides levels and oxidative stress in saliva of human subjects with periodontitis

Experimental findings suggest a protective role for cyclic nucleotides against induction of oxidative stress in saliva. Oxidative stress is a major contributor to the pathogenesis of inflammatory diseases. This study was conducted to evaluate salivary oxidative stress along with cGMP and cAMP levels in periodontitis subjects. cAMP and cGMP are second messengers that have important roles in salivary gland functions. Unstimulated whole saliva samples were obtained from periodontitis patients and age- and sex-matched healthy individuals. Saliva samples were analyzed for thiobarbituric reactive substances (TBARS) as a marker of lipid peroxidation, ferric reducing ability (total antioxidant power, TAP), and levels of cAMP and cGMP. Concentrations of cAMP and cGMP were reduced in the saliva of patients with moderate and severe periodontitis. Saliva of patients with severe periodontitis had higher TBARS and lower TAP than control subjects. The presence of oxidative stress and lower levels of salivary cGMP and cAMP in periodontitis are in association with disease severity.     

Cellular and molecular interactions between MC3T3-E1 pre-osteoblasts and nanostructured titanium produced by high-pressure torsion

Ultra-fine surface features are commonly used to modulate cellular activity on a variety of materials. The continuing challenge for materials in contact with bone is the development of a material with both favorable surface and bulk properties to modulate not only the cell-substrate interactions, but also to ensure the long-term stability of the implant. In a combined approach involving material sciences and cell and molecular biology, the nature and mechanism of cell-substrate interaction, in particular, the molecular machinery controlling cell response to the surface of the nanostructured titanium based material produced by the high pressure torsion (HPT) process is assessed. The degree of pre-osteoblast attachment and rate of growth, which are regulated through the activity and interaction of proteins present in the extracellular matrix and associated with cytoskeleton and focal adhesion, are notably increased on the HPT-processed titanium substrates. The improved cell activity is attributed to the nanostructured feature of these substrates consisting of ultra-fine crystals (<50 nm) and a distinct surface oxide layer which provide higher degree of surface wettability. These findings demonstrate the advantages of HPT-processed titanium over the conventional and coated titanium implants, as both mechanical properties and cellular response are improved.