Mycobacterial phosphodiesterase Rv0805 is a virulence determinant and its cyclic nucleotide hydrolytic activity is required for propionate detoxification.

Cyclic AMP (cAMP) signaling is essential to Mycobacterium tuberculosis (Mtb) pathogenesis. However, the roles of phosphodiesterases (PDEs) Rv0805, and the recently identified Rv1339, in cAMP homeostasis and Mtb biology are unclear. We found that Rv0805 modulates Mtb growth within mice, macrophages and on host-associated carbon sources. Mycobacterium bovis BCG grown on a combination of propionate and glycerol as carbon sources showed high levels of cAMP and had a strict requirement for Rv0805 cNMP hydrolytic activity. Supplementation with vitamin B12 or spontaneous genetic mutations in the pta-ackA operon restored the growth of BCGΔRv0805 and eliminated propionate-associated cAMP increases. Surprisingly, reduction of total cAMP levels by ectopic expression of Rv1339 restored only 20% of growth, while Rv0805 complementation fully restored growth despite a smaller effect on total cAMP levels. Deletion of an Rv0805 localization domain also reduced BCG growth in the presence of propionate and glycerol. We propose that localized Rv0805 cAMP hydrolysis modulates activity of a specialized pathway associated with propionate metabolism, while Rv1339 has a broader role in cAMP homeostasis. Future studies will address the biological roles of Rv0805 and Rv1339, including their impacts on metabolism, cAMP signaling and Mtb pathogenesis.

Safety and pharmacokinetics of single and multiple intravenous bolus doses of diclofenac sodium compared with oral diclofenac potassium 50 mg: A randomized, parallel-group, single-center study in healthy subjects.

In a randomized, parallel-group, single-center study in 42 healthy adults, the safety and pharmacokinetic parameters of an intravenous formulation of 18.75 and 37.5 mg diclofenac sodium (DFP-08) following single- and multiple-dose bolus administration were compared with diclofenac potassium 50 mg oral tablets. Mean AUC0-inf values for a 50-mg oral tablet and an 18.75-mg intravenous formulation were similar (1308.9 [393.0]) vs 1232.4 [147.6]). As measured by the AUC, DFP-08 18.75 mg and 37.5 mg demonstrated dose proportionality for extent of exposure. One subject in each of the placebo and DFP-08 18.75-mg groups and 2 subjects in the DFP-08 37.5-mg group reported adverse events that were considered by the investigator to be related to the study drug. All were mild in intensity and did not require treatment. Two subjects in the placebo group and 1 subject in the DFP-08 18.75-mg group reported grade 1 thrombophlebitis; no subjects reported higher than grade 1 thrombophlebitis after receiving a single intravenous dose. The 18.75- and 37.5-mg doses of intravenous diclofenac (single and multiple) were well tolerated for 7 days. Additional efficacy and safety studies are required to fully characterize the product.

Biomagnetic detection of injury currents in rabbit ischemic intestine.

The presence of direct current (DC) injury currents in ischemic tissue is an important diagnostic indicator of pathophysiology in cortical spreading depression and particularly in myocardial infarction. To date, no measurements of DC injury currents in the alimentary tract have been reported. We used a SQUID magnetometer to measure changes in the baseline of the magnetic field of intestinal electrical activity during induced segmental ischemia. We computed the magnetic field DC baseline by subtracting sequential recordings made while the bowel segment was first directly beneath the SQUID and then pulled away. We observed a significant baseline decrease of 38% +/- 4% in experimental animals, while the control group decreased by only 1% +/- 6%. This magnetic field baseline decrease is consistent with the flow of injury currents between normally perfused and hypoxic tissue regions. This study is the first report of DC injury currents in ischemic smooth muscle of the alimentary tract.

A simulated-use evaluation of a strategy for preventing biofilm formation in dental unit waterlines.

BACKGROUND: Prevention of biofilm formation is important in the maintenance of dental unit waterline systems. Without effective control measures, the waterlines will become contaminated with routine use. METHODS: The authors used a simulated-use dental unit waterline system to evaluate the ability of a test product, A-dec ICX (A-dec, Newburg, Ore.), to prevent biofilm formation. They evaluated buffered distilled water and hard water models versus mixed-challenge suspensions of Staphylococcus aureus, Klebsiella pneumoniae and Pseudomonas aeruginosa. RESULTS: The authors documented development of significant biofilm in untreated test units, while treated test units showed no indication of biofilm formation throughout the 16-week study. Student t tests and 95 percent confidence intervals performed on the plate count data confirmed that untreated test units had significantly greater bacterial populations than did treated test units (P < .05). Qualitative images by scanning electron microscopy verified these findings. CONCLUSION: In this simulated clinical-use study, the test product effectively reduced bacterial counts in incoming water and produced water quality exceeding stated recommendations of the American Dental Association. CLINICAL IMPLICATIONS: The test product provides an approach to dental unit waterline maintenance that is simple to use and that, by continuously preventing biofilm formation, reduces concerns about bacterial contamination in dental unit water.

Gastrointestinal symptoms are more intense in morbidly obese patients and are improved with laparoscopic Roux-en-Y gastric bypass.

BACKGROUND: Currently there are few reports comparing gastrointestinal (GI) symptoms in the morbidly obese versus control subjects or the effect of laparoscopic Roux-en-Y gastric bypass (LRYGBP) on such symptoms. METHODS: A previously validated, 19-point GI symptom questionnaire was administered prospectively to each patient undergoing LRYGBP, and the questionnaire was re-administered 6 months postoperatively. Six symptom clusters (abdominal pain, irritable bowel [IBS], reflux, gastroesophageal reflux disease [GERD], sleep disturbances, and dysphagia) were compared in the following manner using Students t-test: 1) Control vs. Preop, 2) Control vs Postop, and 3) Preop vs Postop. Results are expressed as mean +/- standard deviation, significance P=0.05. RESULTS: 43 patients (40 female and 3 male, age 37.3 +/- 8.6, BMI 47.8 +/- 4.9) completed the questionnaire preoperatively, and 36 patients (34 female, 2 male, BMI 31.6 +/- 5.3) completed the questionnaire 6 months postoperatively, for a response-rate of 84%. Abdominal pain, IBS, reflux, GERD and sleep disturbance symptoms were significantly worse in preop versus controls. Dysphagia was not different. Postop vs preop scores revealed abdominal pain, IBS, GERD, reflux, and sleep disturbance symptoms to be improved significantly. Dysphagia was not significantly different. Only dysphagia was worse when comparing postoperative to controls. No other symptom cluster was significantly different in controls vs postoperative. CONCLUSIONS: Morbidly obese patients experience more intense GI symptoms than control subjects, and many of these symptoms return to control levels 6 months after LRYGBP. Dysphagia is equivalent to control subjects preoperatively but increases significantly after LRYGBP. This data suggests another quality-of-life improvement (relief of GI symptoms) for morbidly obese patients. Further follow-up is needed to document the long-term reduction of GI symptoms.