Environmental heme-based sensor proteins: implications for understanding bacterial pathogenesis

Abstract Significance: Heme is an important prosthetic group required in a wide array of functions, including respiration, photosynthesis, metabolism, O(2) transport, xenobiotic detoxification, and peroxide production and destruction, and is an essential cofactor in proteins such as catalases, peroxidases, and members of the cytochrome P450 superfamily. Importantly, bacterial heme-based sensor proteins exploit the redox chemistry of heme to sense environmental gases and the intracellular redox state of the cell. Recent Advances: The bacterial proteins FixL (Rhizobium ssp.), CooA (Rhodospirillum rubrum), EcDos (Escherichia. coli), RcoM (Burkholderia xenovorans), and particularly Mycobacterium tuberculosis (Mtb) DosS and DosT have emerged as model paradigms of environmental heme-based sensors capable of detecting multiple gases including NO, CO, and O(2). Critical Issues: How the diatomic gases NO, CO, or O(2) bind to heme iron to generate Fe-NO, Fe-CO, and Fe-O(2) bonds, respectively, and how the oxidation of heme iron by O(2) serves as a sensing mechanism that controls the activity of key proteins is complex and largely unclear. This is particularly important as many bacterial pathogens, including Mtb, encounters three overlapping host gases (NO, CO, and O(2)) during human infection. Future Directions: Heme is an important prosthetic group that monitors the microbe's internal and external surroundings to alter signal transduction or enzymatic activation. Modern expression, metabolomic and biochemical technologies combined with in vivo pathogenesis studies should provide fresh insights into the mechanism of action of heme-based redox sensors. Antioxid. Redox Signal. 17, 1232-1245.     

Nuclear medicine in myeloma: the state of the science and emerging trends

We present the different imaging modalities in relation to myeloma, ranging from the time tested X-ray radiography to the newer promising methods of fluorine-18 fluorodesoxyglucose-positron emission tomography ((18)F-FDG-PET) and technetium-99m methoxy isobutyl isonitrite ((99m)Tc-MIBI) scintigraphy. A small discussion regarding newer methods such as fluoride-18 positron emission tomography ((18)F-PET), fluorine-18-fluoro-deoxy-L-thymidine positron emission tomography ((18)F-FLT PET), carbon-11 methionine positron emission tomography ((11)C-methionine PET) and the tritiated thymidine labeling index is also included. They have different mechanisms of tracer uptake enabling the visualization of the spectrum of the disease manifestations ranging from osteoblastic to osteolytic lesions, and also the study of the metabolic status, proliferative and protein activity, in skeletal and in extra-skeletal sites.     

Photoregulation of drug release in azo-dextran nanogels

A simple photoresponsive azo-dextran polymer has been investigated for its ability to act as a nanogel drug carrier. Self aggregation of the azo-dextran polymer leads to the formation of nanogels, AD (5 and 10) in aqueous media, which were characterized by TEM and DLS. When examined under UV light (365 nm), the unloaded nanogels, which were observed to be in the range of 120-290 nm, show dependence on the degree of crosslinking, pH and ionic concentration of the dispersed media. Nanogels, AD (5 and 10), have been loaded with a model fluorophore, rhodamine B and a drug, aspirin, by freeze drying an aqueous dispersion of the nanogels in the presence of the substrate dissolved in water or PBS buffer. The release pattern of the encapsulated bio-active molecules from these nanogels was regulated by (trans-cis) photoisomerization of the azobenzene moiety present in the crosslinker. A comparison of the release behavior of the loaded (rhodamine, aspirin) AD (5 and 10) nanogels reveal that the rate of release of the encapsulated active molecules from the nanogels was slower when the azo moiety was in E-configuration as compared to that the azo in the Z-configuration. The in vitro release behavior of drug from these polymeric micellar systems is revelative of the potential of the nanogels for targeted drug delivery in nanomedicine.     

Effect of α-Tocopherol on the Cardiac Antioxidant Defense System and Atherogenic Lipids in Cigarette Smoke-Inhaling Mice

The present study was designed to evaluate the role ofα -tocopherol (AT) on the cardiac antioxidant defense system and atherogenic lipid profile in cigarette smoke (CS)-inhaling mice. CS exposure for 10 wk resulted in an increase in the levels of lipid peroxidation (LPO) and reduction in reduced glutathione (GSH) levels in heart. Supplementation with AT reduced LPO and restored GSH levels to almost those of normals. The activities of the antioxidant enzymes catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GR) increased after CS inhalation. However, supplementation with AT resulted in reversing the increase in GSH-Px and GR. The activity of superoxide dismutase (SOD) remained unaltered in all the groups studied. Levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) increased, whereas high-density lipoprotein cholesterol (HDL-C) levels decreased in serum following CS inhalation. Supplementation with AT reduced the levels of LDL-C and TG. On the other hand, AT-fed animals showed an increase in HDL-C levels on CS exposure. Based on the results it appears that AT protects the heart from CS-induced peroxidative damage and has antiatherogenic properties.     

Mesenteric Venous Thrombosis

The prevalence of mesenteric venous thrombosis has increased over the past 2 decades with the routine use of contrast-enhanced computed tomography (CT) in patients presenting with abdominal pain and those with portal hypertension. Concurrent with increasing recognition, routine and frequent use of anticoagulation has reduced the need for surgical intervention and improved outcome in these patients. Acute thrombosis often presents with abdominal pain, whereas chronic disease manifests either as an incidental finding on CT or with features of portal hypertension. Contrast-enhanced CT diagnoses about 90% of cases. The presence of collateral circulation and cavernoma around a chronically thrombosed vein differentiates chronic from acute disease. The superior mesenteric vein is often involved, whereas involvement of the inferior mesenteric vein is rare. Associated portal venous thrombosis can be seen if the disease originates in the major veins instead of the small vena rectae. Thrombophilia and local abdominal inflammatory conditions are common causes. Management is aimed at preventing bowel infarction and recurrent thrombosis. Anticoagulation, the mainstay of management, has also been safely used in patients with cirrhosis and portal hypertension. This review discusses the pathogenesis of thrombosis of mesenteric veins, the diagnosis and differentiation from arterial ischemia, the emergence of the JAK2 (Janus kinase 2) sequence variation as a marker of thrombophilia and myelodysplastic neoplasms, and new anticoagulants. Algorithms for the management of acute and chronic mesenteric venous thrombosis are provided to help readers understand and remember the approach to the management of acute and chronic mesenteric venous thrombosis.     

Self-Expanding Metal Stents for Biliary Drainage in Patients with Resectable Pancreatic Cancer: Single-Center Experience with 79 Cases

Background and Aims

To study pre-operative and peri-operative course and outcome on follow up after pancreaticoduodenenctomy (PD) for resectable pancreatic cancer amongst patients receiving self-expanding metal stents (SEMS).

Methods

Medical charts of consecutively reviewed patients (2005?C2009) with resectable pancreatic cancer and SEMS placement before PD at the MD Anderson Cancer Center (MDACC) were studied.

Results

Seventy-nine patients (mean age, 68 ± 9 years; 54% males) undergoing PD after SEMS placement were analyzed. Of these, 70% (55/79) had come with previous plastic stents placed within a median of 29 (5?C216) days because of presentation and most (95%) underwent neoadjuvant chemoradiation after SEMS placement. The median interval between SEMS placement and PD was 120 (range 28?C306) days. There were no technical difficulties during PD. The resected tumor was stage T3 in 72 patients, positive node in 44, lymphovascular invasion in 47, and perineural invasion in 62. Within 30 days after surgery, 26 (33%) patients developed complications requiring intervention, but none died. During a median follow-up of 349 (14?C1,508) days after surgery, 32 (41%) patients developed metastatic disease, and 20 (25%) died; median survival was approximately 3 years. Development of metastatic disease during follow-up independently predicted survival with hazard ratio of 16 (95% CI: 4?C68; P = 0.0001).

Conclusions

Contrary to the tendency of avoiding the use of metal stents for biliary decompression amongst patients with resectable pancreatic cancer, our study demonstrated that SEMS did not adversely affect surgical technique, postoperative course, or long-term outcome. Therefore, metal stents should be considered for patients with resectable pancreatic cancer who will undergo preoperative chemoradiation.